DE10332232A1 - Heteroaryloxy substituted phenylaminopyrimidines - Google Patents

Abstract

The invention relates to heteroaryloxy-substituted phenylaminopyrimidines and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases.

Description

The invention relates to heteroaryloxy-substituted Phenylaminopyrimidines, a process for their manufacture as well their use in the manufacture of medicinal products for treatment and / or prophylaxis of diseases in humans and animals, in particular of cardiovascular Diseases.

An increase in the intracellular calcium concentration is a major trigger for the Contraction of the vascular muscles (Somlyo, A.P. and Himpens, B. FASEB J. 1989, 3, 2266-2276). This happens primarily through agonists such as phenylephrine or Thromboxan A2 after stimulation of the phosphatidylinositol cascade the release of calcium from the sarcoplasmic reticulum cause. The increase of the intracellular Calcium activates the MLC kinase (myosin light chain kinase) phosphorylated the MLC subunits of the myosin molecule (Kamm, K.H. and Stull, J.T., Annu. Rev. Pharmacol.Toxicol. 1985, 25, 593-603). MLC phosphorylation induces smooth muscle contraction, MLC dephosphorylation after a reduction in the intracellular calcium concentration results in the relaxation of the vessel.

In addition to calcium-dependent MLC phosphorylation there is another central but calcium-independent regulatory mechanism of the vascular tone. This is the Rho / Rho kinase signaling pathway (Koda, M. et al., FEBS Lett. 1995, 367, 246-250; Uehata, M. et al., Nature 1997, 389, 990-994; Fukata, Y. et al., Trends in Pharmacological Sciences 2001, 22, 32-39). Bind agonists such as phenylephrine or thromboxane A2 to their receptors, this leads to the activation of the small G proteins Rho, which then interact with the Rho kinase and activate it. The activated Rho kinase inhibits the myosin phosphatase, after phosphorylating a subunit of the enzyme. simultaneously phosphorylated Rho-Kinase MLC at the site, which is also from the MLC-Kinase is phosphorylated. An inhibition of myosin phosphatase and the Phosphorylation of MLC induces contraction of the vascular muscles. In contrast, leads inhibition of Rho kinase to vascular relaxation. Inhibitors of Rho kinase effect hence a decrease in blood pressure and an increase in coronary artery Blood flow.

In addition, inhibitors lead the Rho-Kinase to inhibit the growth of tumor cells and Metastases (Itoh et al. Nat. Med. 1999, 5, 221; Somlyo et al. Biochem. Biophys. Res. Commun. 2000, 269, 652) and inhibit angiogenesis (Uchida et al. Biochem. Biophys. Res. Commun. 2000, 269, 633; Gingras et al. Biochem. J. 2000, 348 Vol. 2, 273).

Structurally similar compounds are known in other indications and for other mechanisms of action. For example, describe US 3,478,030 and US 3,432,493 substituted aminopyrimidines, which can increase the coronary blood flow, but act as carbonic anhydrase inhibitors (J. Chem. Inf. Comp. Sciences 2002, 42, 94-102). Other pyrimidine derivatives are anti-cancer and anti-HIV agents (Debi, M .; Indian J. Exp. Biol. 1997, 35, 1208-1213) or as cdk2 inhibitors (WO-A 01/64654) described.

Object of the present invention is the provision of medicines for the treatment of diseases, especially cardiovascular Diseases.

worin
A einen Rest

bedeutet, worin
X für N oder C-H steht,
Y für N-R⁷, O oder S steht,
worin
R⁷ für Wasserstoff, Benzyl, Phenyl, (C₁-C₆)-Alkyl oder (C₃-C₈)-Cycloalkyl steht,
wobei Alkyl und Cycloalkyl ihrerseits durch Fluor, Hydroxy, Amino, Carboxyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino oder Morpholinyl substituiert sein können,
Z für N oder C-H steht,
R⁶ für Wasserstoff, Halogen, Trifluormethyl, (C₁-C₆)-Alkylamino oder W-R⁷ steht,
worin W für NH, O oder eine Bindung steht, R⁷ die oben angegebene Bedeutung hat und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Halogen oder Cyano bedeuten,
R³ und R⁴ unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von:
Wasserstoff, Hydroxy, Halogen, Trifluormethyl, (C₃-C₈)-Cycloalkyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy,
wobei Cycloalkyl, Alkyl und Alkoxy ihrerseits durch Hydroxy, Carboxyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkoxycarbonyl, (C₆-C₁₀)-Aryl, NR⁸R⁹ oder C(=O)NR⁸R⁹ substituiert sein können, worin
R⁸ und R⁹ unabhängig voneinander für Wasserstoff, (C₁-C₈)-Alkyl, gegebenenfalls durch (C₁-C₆)-Alkyl substituiertes (C₃-C₆)-Cycloalkyl, gegebenenfalls durch Halogen substituiertes (C₆-C₁₀)-Aryl oder 5- bis 10-gliedriges Heteroaryl stehen oder
R⁸ und R⁹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
(C₆-C₁₀)-Aryl, (C₆-C₁₀)-Aryloxy, 5- bis 10-gliedriges Heteroaryl, 5- bis 10-gliedriges Heteroaryloxy, über ein Kohlenstoffatom gebundenes 5- bis 10-gliedriges Heterocyclyl,
wobei Aryl, Aryloxy, Heteroaryl, Heteroaryloxy und Heterocyclyl ihrerseits durch Halogen, Cyano, Nitro, Carboxyl, Amino, Trifluormethyl, gegebenenfalls durch Hydroxy substituiertes (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkanoylamino, (C₁-C₆)-Alkoxycarbonylamino oder 5- oder 6-gliedriges Heterocyclyl substituiert sein können,
NR¹⁰R¹¹,
worin
R¹⁰ und R¹¹ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₆-C₁₀)-Aryl oder 5- bis 10-gliedriges Heteroaryl stehen,
wobei Alkyl und Cycloalkyl ihrerseits durch Hydroxy, (C₁-C₆)-Alkoxy, (C₆-C₁₀)-Aryl, 5- bis 10-gliedriges Heteroaryl oder NR¹⁵R¹⁶ substituiert sein können, worin
R¹⁵ und R¹⁶ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₆)-Cycloalkyl, (C₆-C₁₀)-Aryl oder 5- oder 6-gliedriges Heteroaryl stehen
oder
R¹⁵ und R¹⁶ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
und
Aryl und Heteroaryl ihrerseits durch Halogen, Hydroxy, Amino, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino oder (C₁-C₆)-Alkanoylamino substituiert sein können,
oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch Fluor, Hydroxy, Carboxyl, 5- bis 7-gliedriges Heterocyclyl, das ein oder zwei weitere Heteroatome N und/oder O im Ring enthalten kann und das seinerseits durch (C₁-C₄)- Alkyl oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, (C₁-C₄)-Alkoxy, gegebenenfalls durch Hydroxy, (C₁-C₄)-Alkoxy oder NR¹⁷R¹⁸ substituiertes (C₁-C₄)-Alkyl, (C₁-C₄)-Alkanoyl, (C₁-C₄)-Alkoxycarbonyl oder NR¹²R¹³ substituiert sein kann,
wobei
R¹² und R¹³ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₈)-Cycloalkyl oder (C₁-C₄)-Alkanoyl stehen oder
R¹² und R¹³ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
und R¹⁷ und R¹⁸ unabhängig voneinander für Wasserstoff, gegebenenfalls durch Hydroxy substituiertes (C₁-C₆)-Alkyl, (C₃-C₆)-Cycloalkyl, (C₆-C₁₀)-Aryl oder 5- oder 6-gliedriges Heteroaryl stehen
oder
R¹⁷ und R¹⁸ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
oder R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 7- bis 12-gliedrigen bicyclischen oder ticyclischen Heterocyclus bilden, der anelliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder 0 im Ring aufweisen kann und der durch Fluor, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoyl oder Benzyl substituiert sein kann,
und C(=O)R¹⁴,
worin
R¹⁴ für (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino oder einen über ein Stickstoffatom gebundenen 5- bis 10-gliedrigen mono- oder bicyclischen Heterocyclus, der anelliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder O im Ring aufweisen kann, steht, wobei Alkylamino seinerseits durch einen 5- oder 6-gliedrigen Heterocyclyl substituiert sein kann, und ihre Salze, Hydrate, Hydrate der Salze und Solvate.The present invention relates to compounds of the formula (I)

wherein
A a rest

means what
X represents N or CH,
Y represents NR ⁷ , O or S,
wherein
R ^{7 represents} hydrogen, benzyl, phenyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl,
where alkyl and cycloalkyl in turn can be substituted by fluorine, hydroxy, amino, carboxyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or morpholinyl,
Z represents N or CH,
R ^{6 represents} hydrogen, halogen, trifluoromethyl, (C ₁ -C ₆ ) alkylamino or WR ⁷ ,
wherein W is NH, O or a bond, R ^{7 has} the meaning given above and
* represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, halogen or cyano,
R ³ and R ^{4 are} independently hydrogen, fluorine or chlorine,
R ^{5 represents} a radical which is selected from the group of:
Hydrogen, hydroxy, halogen, trifluoromethyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,
where cycloalkyl, alkyl and alkoxy in turn by hydroxy, carboxyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) aryl, NR ⁸ R ⁹ or C (= O) NR ⁸ R ⁹ can be substituted, wherein
R ⁸ and R ⁹ independently of one another are hydrogen, (C ₁ -C ₈ ) -alkyl, optionally substituted by (C ₁ -C ₆ ) -alkyl (C ₃ -C ₆ ) -cycloalkyl, optionally substituted by halogen (C ₆ - C ₁₀ ) aryl or 5- to 10-membered heteroaryl or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
(C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heterocyclyl bonded via a carbon atom,
where aryl, aryloxy, heteroaryl, heteroaryloxy and heterocyclyl in turn are substituted by halogen, cyano, nitro, carboxyl, amino, trifluoromethyl, optionally substituted by hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino or 5- or 6-membered heterocyclyl can be substituted,
NR ¹⁰ R ¹¹ ,
wherein
R ¹⁰ and R ¹¹ independently of one another represent hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl,
where alkyl and cycloalkyl in turn can be substituted by hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl or NR ¹⁵ R ¹⁶ , in which
R ¹⁵ and R ¹⁶ independently of one another represent hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- or 6-membered heteroaryl
or
R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
and
Aryl and heteroaryl in turn by halogen, hydroxy, amino, cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or (C ₁ -C ₆ ) -alkanoylamino can be substituted,
or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle, which may contain a further hetero atom O or N in the ring and which is fluorine, hydroxyl, carboxyl, 5- to 7 -linked heterocyclyl which can contain one or two further heteroatoms N and / or O in the ring and which in turn can be substituted by (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ - C ₄ ) alkoxy, optionally substituted by hydroxy, (C ₁ -C ₄ ) alkoxy or NR ¹⁷ R ¹⁸ substituted (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl, (C ₁ -C ₄ ) -alkoxycarbonyl or NR ¹² R ¹³ can be substituted,
in which
R ¹² and R ^{13 are} independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₄ ) alkanoyl or
R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
and R ¹⁷ and R ¹⁸ independently of one another for hydrogen, optionally substituted by hydroxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- or 6- membered heteroaryl
or
R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic or ticyclic heterocycle which is fused or spirocyclic and one or two further heteroatoms from the series N and / or 0 im Can have ring and which can be substituted by fluorine, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoyl or benzyl,
and C (= O) R ¹⁴ ,
wherein
R ¹⁴ for (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or a 5- to 10-membered mono- or bicyclic heterocycle bonded via a nitrogen atom, which is fused or spirocyclic and one or two more May have heteroatoms from the series N and / or O in the ring, wherein alkylamino in turn can be substituted by a 5- or 6-membered heterocyclyl, and their salts, hydrates, hydrates of the salts and solvates.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the Compounds of formula (I) of the following mentioned Formulas and their salts, solvates and solvates of the salts as well as the of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds included in formula (I) below are not already salts, solvates and solvates of the salts.

The compounds of the invention can in dependence their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomers isolate uniform components in a known manner.

The invention relates in dependence on the structure of the compounds also tautomers of the compounds.

Salts are within the scope of the invention physiologically acceptable salts of the compounds according to the invention prefers.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ehanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, trifluoroacetic acid and Benzoic acid.

Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, for example and preferably alkali metal salts (e.g. sodium and potassium salts), Alkaline earth salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclo-hexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine.

As solvates within the scope of Invention refers to such forms of connections, which in solid or liquid Condition through coordination with solvent molecules Form complex. Hydrates are a special form of solvate, at which are coordinated with water.

Within the scope of the present invention unless otherwise specified, the substituents have the following Meaning: alkyl per se and "alk" and "alkyl" in alkoxy alkanoakylamino, Alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino stand for one linear or branched alkyl radical with usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably for Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is exemplary and preferred for methoxy, Ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkanoyl is exemplary and preferred for acetyl and propanoyl.

Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylamino, tert.-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N , N-diethylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino. C ₁ -C ₄ alkylamino is, for example, a monoalkylamino radical having 1 to 4 carbon atoms or a dialkylamino radical each having 1 to 4 carbon atoms per alkyl substituent.

Alkoxycarbonyl is an example and preferably for Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkoxycarbonylamino is exemplary and preferably for Methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, Isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.

Alkanoylamino is exemplary and preferably for Acetylamino and ethylcarbonylamino.

Cycloalkyl 1 represents a cycloalkyl group with as a rule 3 to 8, preferably 5 to 7 carbon atoms, for example and preferably for Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl per se and in aryloxy for one mono- to tricyclic aromatic, carbocyclic radical with in usually 6 to 14 carbon atoms; exemplary and preferred for phenyl, Naphthyl and phenanthrenyl.

Aloxy is exemplary and preferred for phenyloxy and naphthyloxy.

Heteroaryl per se and in heteroaryloxy stands for usually have an aromatic, mono- or bicyclic radical 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, exemplary and preferably for Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, Pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, Quinolinyl, isoquinolinyl.

Heteroaryloxy is exemplary and preferably for Pyridyloxy, pyrimidyloxy, indolyloxy, indazolyloxy.

Heterocyclyl and heterocycle stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical with 4 to 10, usually 5 to 8, preferably 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO ₂ . The heterocyclyl residues can be saturated or partially unsaturated. 5- or 6-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series are preferred, such as, for example and preferably, tetrahydrofuran-2-yl, tetrahydrothienyl, pyrrolidin-2-yl, pyrrolidin-3-yl, Pyrrolinyl, pyranyl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-l-yl, morpholin-2-yl, morpholin-3-yl, perhydroazepinyl, Piperazin-l-yl, piperazin-2-yl.

Halogen stands for fluorine, chlorine, bromine and iodine.

If residues in the compounds of the invention can be substituted the residues, unless otherwise specified, one or more times be substituted the same or different. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

worin R⁶ für Wasserstoff, (C₁-C₄)-Alkyl oder NH-R⁷ steht,
R⁷ für Wasserstoff oder (C₁-C₄)-Alkyl steht und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R³ und R⁴ unabhängig voneinander Wasserstoff oder Fluor bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von: Wasserstoff, Chlor, (C₃-C₈)-Cycloalkyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy,
wobei Alkyl und Alkoxy ihrerseits durch Hydroxy, Carboxyl, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkoxycarbonyl, NR⁸R⁹ oder C(=O)NR⁸R⁹ substituiert sein können,
worin R⁸ und R⁹ unabhängig voneinander für Wasserstoff, (C₁-C₈)-Alkyl, gegebenenfalls durch (C₁-C₄)-Alkyl substituiertes (C₃-C₆)-Cycloalkyl, gegebenenfalls durch Halogen substituiertes Phenyl oder 5- oder 6-gliedriges Heteroaryl stehen
oder
R⁸ und R⁹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Morpholin-, Piperazin-, Piperidinoder Pyrrolidinring bilden, wobei die Ringe ihrerseits durch (C₁-C₄)-Alkyl substituiert sein können, (C₆-C₁₀)-Aryl, 5- oder 6-gliedriges Heteroaryl, über ein Kohlenstoffatom gebundenes 5- oder 6-gliedriges Heterocyclyl,
wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits durch Halogen, Cyano, Nitro, Carboxyl, Amino, Trifluormethyl, gegebenenfalls durch Hydroxy substituiertes (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkylamino, (C₁-C₄)-Alkanoyl, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoylamino, (C₁-C₄)-Alkoxycarbonylamino oder 6-gliedriges Heterocyclyl substituiert sein können,
NR¹⁰R¹¹
worin
R¹⁰ und R¹¹ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₈)-Cycloalkyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl stehen,
wobei Alkyl und Cycloalkyl ihrerseits durch Hydroxy, (C₁-C₄)-Alkoxy, Phenyl, 5- oder 6-gliedriges Heteroaryl oder NR¹⁵R¹⁶ substituiert sein können, worin
R¹⁵ und R¹⁶ unabhängig voneinander für Wasserstoff, (C₁-C₄)-Alkyl, (C₃-C₆)-Cycloalkyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl stehen oder
R¹⁵ und R¹⁶ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Morpholin-, Piperazin-, Piperidin- oder Pyrrolidinring bilden, wobei die Ringe ihrerseits durch (C₁-C₄)-Alkyl substituiert sein können,
und Phenyl und Heteroaryl ihrerseits durch Fluor, Chlor, Hydroxy, Amino, Cyano, Trifluormethyl, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkylamino oder (C₁-C₄)-Alkanoylamino substituiert sein können,
oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch Fluor, Hydroxy, Carboxyl, 5- bis 7-gliedriges Heterocyclyl, das ein oder zwei weitere Heteroatome N und/oder 0 im Ring enthalten kann, das seinerseits durch (C₁-C₄)-Alkyl oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, (C₁-C₄)-Alkoxy, gegebenenfalls durch Hydroxy, (C₁-C₄)-Alkoxy oder NR¹⁷R¹⁸ substituiertes (C₁-C₄)-Alkyl, (C₁-C₄)-Alkanoyl, (C₁-C₄)-Alkoxycarbonyl oder NR¹²R¹³ substituiert sein kann,
wobei
R¹² und R¹³ unabhängig voneinander für Wasserstoff oder (C₁-C₄)-Alkyl stehen
oder
R¹² und R¹³ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C1-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
und
R¹⁷ und R¹⁸ unabhängig voneinander für Wasserstoff, gegebenenfalls durch Hydroxy substituiertes (C₁-C₄)-Alkyl oder Phenyl stehen
oder
R¹⁷ und R¹⁸ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidinring bilden, oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 7- bis 12-gliedrigen bicyclischen oder tricyclischen Heterocyclus bilden, der anelliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder O im Ring aufweisen kann und der durch (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoyl oder Benzyl substituiert sein kann,
und C(=O)R¹⁴,
worin
R¹⁴ für (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino oder einen über ein Stickstoffatom gebundenen 5- bis 10-gliedrigen mono- oder bicyclischen Heterocyclus, der anelliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder O im Ring aufweisen kann, steht, wobei Alkylamino seinerseits durch einem 5- oder 6-gliedrigen Heterocyclyl substituiert sein kann, und ihre Salze, Hydrate, Hydrate der Salze und Solvate. Besonders bevorzugt sind Verbindungen der Formel (I), worin
A einen Rest

bedeutet, worin R⁶ für Wasserstoff oder Methyl steht
und * für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R³ und R⁴ Wasserstoff bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von: Wasserstoff, Chlor, Cyclohexyl, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy,
wobei Alkyl und Alkoxy ihrerseits durch Hydroxy, Carboxyl, (C₁-C₄)-Alkoxy, Methyloxycarbonyl, Ethyloxycarbonyl, NR⁸R⁹, oder C(=O)NR⁸R⁹ substituiert sein können,
worin R⁸ und R⁹ unabhängig voneinander für Wasserstoff, (C₁-C₈)-Alkyl, Cyclopropyl, gegebenenfalls durch Methyl substituiertes Cyclopentyl oder gegebenenfalls durch Fluor substituiertes Phenyl stehen oder
R⁸ und R⁹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Piperidin-, 2-Methylpiperidinoder 2,6-Dimethylpiperidinring bilden, Phenyl, Pyridyl, Pynolyl, Piperidin-3-yl, Piperidin-4-yl, Pynolidin-2-yl,
wobei Phenyl, Pyridyl und Pyrrolyl ihrerseits durch Fluor, Chlor, Brom, Cyano, Nitro, Trifluormethyl, Methyl, Hydroxymethyl, Methoxy, Dimethylamino oder Morpholinyl substituiert sein können, und Piperidin-3-yl, Piperidin-4-yl und Pyrrolidin-2-yl ihrerseits durch Methyl, Ethyl, n-Propyl, iso-Propyl, Methylcarbonyl oder Ethylcarbonyl substituiert sein können,
NR¹⁰R¹¹
worin
R¹⁰ und R¹¹ unabhängig voneinander für Wasserstoff, (C₁-C₄)-Alkyl, 3-Hydroxypropyl, 2-Hydroxycyclohexyl, 2-Aminocyclohexyl, Phenyl, Pyridyl oder Pyrazolyl stehen,
wobei Phenyl und Pyridyl ihrerseits durch Chlor, Hydroxy, Amino, Cyano, Methyl oder Methoxy substituiert sein können, oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Piperazin-, 3-Methylpiperazin-, 3,5-Dimethylpiperazin-, 4-Isobutylpiperazin-, Morpholin-, Pyrrolidin-, 3-Aminopyrrolidin-, 3-Methylaminopyrrolidin-, 3-(NN-Dimethylamino)-pyrrolidin-, 2-Aminomethylpyrrolidin-, 3-Hydroxypyrrolidin-, 2-Hydroxymethylpynolidin- oder 2-Methoxymethylpyrrolidinring oder einen Rest

bilden, worin
* für die Anknüpfstelle an den Pyrimidinring steht,
und C(=O)R¹⁴, worin
R¹⁴ für Methoxy, Piperidinyl-N-ethylamino, Piperidinyl oder Piperazinyl steht,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.Compounds of the formula (I) are preferred
wherein
A a rest

where R ^{6 is} hydrogen, (C ₁ -C ₄ ) -alkyl or NH-R ⁷ ,
R ^{7 represents} hydrogen or (C ₁ -C ₄ ) alkyl and
* represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, fluorine or chlorine,
R ³ and R ^{4 are} independently hydrogen or fluorine,
R ⁵ denotes a radical which is selected from the group of: hydrogen, chlorine, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,
where alkyl and alkoxy in turn can be substituted by hydroxy, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, NR ⁸ R ⁹ or C (= O) NR ⁸ R ⁹ ,
wherein R ⁸ and R ⁹ independently of one another are hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl optionally substituted by (C ₁ -C ₄ ) -alkyl, phenyl optionally substituted by halogen or 5 - or 6-membered heteroaryl
or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, the rings themselves being able to be substituted by (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl bonded via a carbon atom,
where aryl, heteroaryl and heterocyclyl in turn are substituted by halogen, cyano, nitro, carboxyl, amino, trifluoromethyl, optionally substituted by hydroxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkylamino, (C ₁ -C ₄ ) Al kanoyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoylamino, (C ₁ -C ₄ ) alkoxycarbonylamino or 6-membered heterocyclyl may be substituted,
NR ¹⁰ R ¹¹
wherein
R ¹⁰ and R ¹¹ independently of one another represent hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
where alkyl and cycloalkyl in turn can be substituted by hydroxy, (C ₁ -C ₄ ) alkoxy, phenyl, 5- or 6-membered heteroaryl or NR ¹⁵ R ¹⁶ , in which
R ¹⁵ and R ^{16 are} independently hydrogen, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, phenyl or 5- or 6-membered heteroaryl or
R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, where the rings in turn can be substituted by (C ₁ -C ₄ ) alkyl,
and phenyl and heteroaryl in turn by fluorine, chlorine, hydroxy, amino, cyano, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylamino or (C ₁ -C ₄ ) -alkanoylamino can be substituted,
or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle, which may contain a further hetero atom O or N in the ring and which is fluorine, hydroxyl, carboxyl, 5- to 7 -linked heterocyclyl, which can contain one or two further heteroatoms N and / or 0 in the ring, which in turn can be substituted by (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ - C ₄ ) alkoxy, optionally substituted by hydroxy, (C ₁ -C ₄ ) alkoxy or NR ¹⁷ R ¹⁸ substituted (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl, (C ₁ -C ₄ ) -alkoxycarbonyl or NR ¹² R ¹³ can be substituted,
in which
R ¹² and R ^{13 are} independently hydrogen or (C ₁ -C ₄ ) alkyl
or
R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C1-C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
and
R ¹⁷ and R ^{18 are} independently hydrogen, optionally substituted by hydroxy (C ₁ -C ₄ ) alkyl or phenyl
or
R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a pyrrolidine ring, or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic or tricyclic heterocycle which is fused or spirocyclic and one or two further heteroatoms from the series N and / or O in the ring and which can be substituted by (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoyl or benzyl,
and C (= O) R ¹⁴ ,
wherein
R ¹⁴ for (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or a 5- to 10-membered mono- or bicyclic heterocycle bonded via a nitrogen atom, which is fused or spirocyclic and one or two more May have heteroatoms from the series N and / or O in the ring, wherein alkylamino in turn can be substituted by a 5- or 6-membered heterocyclyl, and their salts, hydrates, hydrates of the salts and solvates. Compounds of the formula (I) in which
A a rest

means in which R ^{6 represents} hydrogen or methyl
and * represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, fluorine or chlorine,
R ³ and R ^{4 are} hydrogen,
R ⁵ denotes a radical which is selected from the group of: hydrogen, chlorine, cyclohexyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy,
where alkyl and alkoxy in turn can be substituted by hydroxy, carboxyl, (C ₁ -C ₄ ) alkoxy, methyloxycarbonyl, ethyloxycarbonyl, NR ⁸ R ⁹ , or C (= O) NR ⁸ R ⁹ ,
wherein R ⁸ and R ^{9 are} independently hydrogen, (C ₁ -C ₈ ) alkyl, cyclopropyl, cyclopentyl optionally substituted by methyl or phenyl optionally substituted by fluorine or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a piperidine, 2-methylpiperidine or 2,6-dimethylpiperidine ring, phenyl, pyridyl, pynolyl, piperidin-3-yl, piperidin-4-yl, pynolidin- 2-yl,
where phenyl, pyridyl and pyrrolyl in turn can be substituted by fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, methyl, hydroxymethyl, methoxy, dimethylamino or morpholinyl, and piperidin-3-yl, piperidin-4-yl and pyrrolidin-2- yl may in turn be substituted by methyl, ethyl, n-propyl, isopropyl, methylcarbonyl or ethylcarbonyl,
NR ¹⁰ R ¹¹
wherein
R ¹⁰ and R ¹¹ independently of one another represent hydrogen, (C ₁ -C ₄ ) -alkyl, 3-hydroxypropyl, 2-hydroxycyclohexyl, 2-aminocyclohexyl, phenyl, pyridyl or pyrazolyl,
where phenyl and pyridyl in turn can be substituted by chlorine, hydroxy, amino, cyano, methyl or methoxy, or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached are a piperazine, 3-methylpiperazine, 3,5-dimethylpiperazine, 4-isobutylpiperazine, morpholine, pyrrolidine, 3-aminopyrrolidine, 3- Methylaminopyrrolidine, 3- (NN-dimethylamino) pyrrolidine, 2-aminomethylpyrrolidine, 3-hydroxypyrrolidine, 2-hydroxymethylpynolidine or 2-methoxymethylpyrrolidine ring or a radical

form what
* represents the point of attachment to the pyrimidine ring,
and C (= O) R ¹⁴ , wherein
R ^{14 represents} methoxy, piperidinyl-N-ethylamino, piperidinyl or piperazinyl,
and their salts, hydrates, hydrates of the salts and solvates.

bedeutet, worin
R⁶ für Wasserstoff oder Methyl steht und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht.Compounds of the formula (I) in which A is a radical are also particularly preferred

means what
R ^{6 represents} hydrogen or methyl and
* stands for the point of attachment to the phenolic oxygen.

Compounds of the formula (I) in which R ^{1 is} fluorine are also particularly preferred.

Compounds of the formula (I) in which R ^{2 is} fluorine or hydrogen are also particularly preferred.

Compounds of the formula (I) in which R ³ and R ^{4 are} hydrogen are also particularly preferred.

Combinations are very particularly preferred of two or more of the preferred areas mentioned above.

worin
X für N oder C-H steht,
Y für N-R⁷, O oder S steht, worin
R⁷ für Wasserstoff, Benzyl, Phenyl, (C₁-C₆)-Alkyl oder (C₃-C₈)-Cycloalkyl steht,
wobei Alkyl und Cycloalkyl ihrerseits durch Fluor, Hydroxy, Amino, Carboxyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino oder Morpholinyl substituiert sein können,
Z für N oder C-H steht,
R⁶ für Wasserstoff, Halogen, Trifluormethyl, (C₁-C₆)-Alkylamino oder W-R⁷ steht,
worin
W für NH, O oder eine Bindung steht,
R⁷ die oben angegebene Bedeutung hat
und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Halogen oder Cyano bedeuten,
R³ und R⁴ unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von:
Hydroxy, Halogen, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₃-C₈)-Cycloalkyl, wobei Alkyl, Alkoxy und Cycloalkyl ihrerseits durch Hydroxy, (C₁-C₆)-Alkoxy, (C₆-C₁₀)-Aryl oder NR⁸R⁹ substituiert sein können,
worin
R⁸ und R⁹ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl oder 5- bis 10-gliedriges Heteroaryl stehen oder
R⁸ und R⁹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
(C₆-C₁₀)-Aryl, (C₆-C₁₀)-Aryloxy, 5- bis 10-gliedriges Heteroaryl, 5- bis 10-gliedriges Heteroaryloxy,
wobei Aryl, Aryloxy, Heteroaryl und Heteroaryloxy ihrerseits durch Halogen, Nitro, Carboxyl, Amino, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkanoylamino oder (C₁-C₆)-Alkoxycarbonylamino substituiert sein können,
und NR¹⁰R¹¹, worin
R¹⁰ und R¹¹ unabhängig voneinander für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₆-C₁₀)-Aryl oder 5- bis 10-gliedriges Heteroaryl stehen,
wobei Alkyl und Cycloalkyl ihrerseits durch Hydroxy, (C₁-C₆)-Alkoxy, (C₆-C₁₀)-Aryl, 5- bis 10-gliedriges Heteroaryl oder NR⁸R⁹ substituiert sein können
worin R⁸ und R⁹ die oben angegebene Bedeutung haben und Aryl und Heteroaryl ihrerseits durch Fluor, Chlor, Amino, Trifluormethyl, (C₁-C₆)-Alkyl (C₁-C₆)-Alkylamino oder (C₁-C₆)-Alkanoylamino substituiert sein können,
oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der durch Fluor, Carboxyl, 1,1-Dioxyethylen, 5- oder 6-gliedriges Heterocyclyl mit einem oder zwei Heteroatomen N und/oder O, das seinerseits durch (C₁-C₄)-Alkyl substituiert sein kann, (C₁-C₄)-Alkoxy, durch Hydroxy oder (C₁-C₄)-Alkoxy substituiertes (C₁-C₄)-Alkyl, (C₁-C₄)-Alkanoyl oder NR¹²R¹³ substituiert ist,
worin
R¹² und R¹³ unabhängig voneinander Wasserstoff, (C₁-C₆)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₈)-Cycloalkyl oder (C₁-C₄)-Alkanoyl bedeuten
oder
R¹² und R¹³ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)- Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann, oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 7- bis 12-gliedrigen bicyclischen Heterocyclus bilden, der anneliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder O im Ring aufweisen kann und der durch Fluor, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoyl oder Benzyl substituiert sein kann,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.
Bevorzugt sind Verbindungen der Formel (I),
worin
A einen Rest

worin
R⁶ für Wasserstoff, (C₁-C₄)-Alkyl, Hydroxy, Fluor, Chlor oder NH-R⁷ steht,
R⁷ für Wasserstoff oder (C₁-C₄)-Alkyl, das durch Fluor, Hydroxy, Methoxy, (C₁-C₄)-Alkylamino oder Morpholinyl substituiert sein kann, steht
und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R³ und R⁴ Wasserstoff bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von: Hydroxy, Chlor, Trifluormethyl,
(C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₃-C₈)-Cycloalkyl, wobei Alkyl, Alkoxy und Cycloalkyl ihrerseits durch NR⁸R⁹ substituiert sein können,
worin R⁸ und R⁹ unabhängig voneinander für Wasserstoff, (C₁-C₄)-Alkyl oder 5- oder 6-gliedriges Heteroaryl stehen oder
R⁸ und R⁹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Morpholin-, Piperazin- oder N-Methylpiperazinring bilden,
(C₆-C₁₀)-Ary1, (C₆-C₁₀)-Aryloxy, 5- bis 10-gliedriges Heteroaryl, 5- bis 10-gliedriges Heteroaryloxy,
wobei Aryl, Aryloxy, Heteroaryl und Heteroaryloxy ihrerseits durch Fluor, Chlor, Nitro, Carboxyl, Amino, Trifluormethyl, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkylamino, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoylamino oder (C₁-C₄)-Alkoxycarbonylamino substituiert sein können,
und NR¹⁰R¹¹,
worin R¹⁰ und R¹¹ unabhängig von einander für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₆-C₁₀)-Aryl oder 5- bis 10-gliedriges Heteroaryl stehen, wobei Alkyl und Cycloalkyl ihrerseits durch Hydroxy, (C₁-C₆)-Alkoxy, (C₆-C₁₀)-Aryl, 5- bis 10-gliedriges Heteroaryl oder NR⁸R⁹ substituiert sein können
worin R⁸ und R⁹ die oben angegebene Bedeutung haben
und
Aryl und Heteroaryl ihrerseits durch Fluor, Chlor, Amino, Trifluormethyl, (C₁-C₆)-Alkyl (C₁-C₆)-Alkylamino oder (C₁-C₆)-Alkanoylamino substituiert sein können,
oder R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der durch Fluor, Carboxyl, 1,1-Dioxyethylen, 5- oder 6-gliedriges Heterocyclyl mit einem oder zwei Heteroatomen N und/oder O, das seinerseits durch (C₁-C₄)-Alkyl substituiert sein kann, (C₁-C₄)-Alkoxy, durch Hydroxy oder (C₁-C₄)-Alkoxy substituiertes (C₁-C₄)-Alkyl, (C₁-C₄)-Alkanoyl oder NR¹²R¹³ substituiert ist,
worin
R¹² und R¹³ unabhängig voneinander Wasserstoff, (C₁-C₆)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₈)-Cycloalkyl oder (C₁-C₄)-Alkanoyl bedeuten
oder
R¹² und R¹³ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden, der ein weiteres Heteroatom O oder N im Ring enthalten kann und der durch (C₁-C₆)-Alkyl, (C₁-C₆)-Alkanoyl oder (C₁-C₆)-Alkoxycarbonyl substituiert sein kann,
oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 7- bis 12-gliedrigen bicyclischen Heterocyclus bilden, der anneliert oder spirocyclisch ist und ein oder zwei weitere Heteroatome aus der Reihe N und/oder O im Ring aufweisen kann und der durch Fluor, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxycarbonyl, (C₁-C₄)-Alkanoyl oder Benzyl substituiert sein kann,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.The present invention relates to compounds of the formula (I) in which
A a rest

wherein
X represents N or CH,
Y represents NR ⁷ , O or S, wherein
R ^{7 represents} hydrogen, benzyl, phenyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl,
where alkyl and cycloalkyl in turn can be substituted by fluorine, hydroxy, amino, carboxyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or morpholinyl,
Z represents N or CH,
R ^{6 represents} hydrogen, halogen, trifluoromethyl, (C ₁ -C ₆ ) alkylamino or WR ⁷ ,
wherein
W represents NH, O or a bond,
R ^{7 has} the meaning given above
and
* represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, halogen or cyano,
R ³ and R ^{4 are} independently hydrogen, fluorine or chlorine,
R ^{5 represents} a radical which is selected from the group of:
Hydroxy, halogen, trifluoromethyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, alkyl, alkoxy and cycloalkyl being in turn substituted by hydroxy, (C ₁ - C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl or NR ⁸ R ⁹ can be substituted,
wherein
R ⁸ and R ⁹ independently of one another represent hydrogen, (C ₁ -C ₆ ) -alkyl or 5- to 10-membered heteroaryl or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
(C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy,
where aryl, aryloxy, heteroaryl and heteroaryloxy are themselves halogen, nitro, carboxyl, amino, trifluoromethyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkanoylamino or (C ₁ -C ₆ ) alkoxycarbonylamino may be substituted,
and NR ¹⁰ R ¹¹ , wherein
R ¹⁰ and R ¹¹ independently of one another represent hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl,
where alkyl and cycloalkyl in turn can be substituted by hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl or NR ⁸ R ⁹
wherein R ⁸ and R ^{9 have} the meaning given above and aryl and heteroaryl in turn by fluorine, chlorine, amino, trifluoromethyl, (C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkylamino or (C ₁ -C ₆ ) -Alkanoylamino can be substituted,
or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, which is characterized by fluorine, carboxyl, 1,1-dioxyethylene, 5- or 6-membered heterocyclyl having one or two heteroatoms N and / or O, is substituted by hydroxy, or may in turn be substituted by (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkoxy, (C ₁ -C ₄₎ alkoxy substituted (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl or NR ¹² R ^{13 is} substituted,
wherein
R ¹² and R ¹³ independently of one another are hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₄ ) alkanoyl
or
R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted, or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic heterocycle which is fused or spirocyclic and can have one or two further heteroatoms from the series N and / or O in the ring and which may be substituted by fluorine, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoyl or benzyl,
and their salts, hydrates, hydrates of the salts and solvates.
Compounds of the formula (I) are preferred
wherein
A a rest

wherein
R ^{6 represents} hydrogen, (C ₁ -C ₄ ) alkyl, hydroxy, fluorine, chlorine or NH-R ⁷ ,
R ^{7 represents} hydrogen or (C ₁ -C ₄ ) alkyl, which can be substituted by fluorine, hydroxy, methoxy, (C ₁ -C ₄ ) alkylamino or morpholinyl
and
* represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, fluorine or chlorine,
R ³ and R ^{4 are} hydrogen,
R ⁵ denotes a radical which is selected from the group of: hydroxy, chlorine, trifluoromethyl,
(C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, where alkyl, alkoxy and cycloalkyl can in turn be substituted by NR ⁸ R ⁹ ,
wherein R ⁸ and R ^{9 are} independently hydrogen, (C ₁ -C ₄ ) alkyl or 5- or 6-membered heteroaryl or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a morpholine, piperazine or N-methylpiperazine ring,
(C ₆ -C ₁₀ ) Ar1, (C ₆ -C ₁₀ ) aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy,
where aryl, aryloxy, heteroaryl and heteroaryloxy are themselves fluorine, chlorine, nitro, carboxyl, amino, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) - Alkylamino, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkanoylamino or (C ₁ -C ₄ ) -alkoxycarbonylamino may be substituted,
and NR ¹⁰ R ¹¹ ,
wherein R ¹⁰ and R ^{11 are} independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl , where alkyl and cycloalkyl in turn can be substituted by hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl or NR ⁸ R ⁹
wherein R ⁸ and R ^{9 have} the meaning given above
and
Aryl and heteroaryl can in turn be substituted by fluorine, chlorine, amino, trifluoromethyl, (C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkylamino or (C ₁ -C ₆ ) alkanoylamino,
or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which is substituted by fluorine, carboxyl, 1,1-dioxyethylene, 5- or 6-membered heterocyclyl with one or two Heteroatoms N and / or O, which in turn can be substituted by (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, by (C ₁ -C ₄ ) alkoxy substituted by (C ₁ - C ₄ ) alkoxy C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl or NR ¹² R ^{13 is} substituted,
wherein
R ¹² and R ¹³ independently of one another are hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₄ ) alkanoyl
or
R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is represented by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted,
or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic heterocycle which is fused or spirocyclic and can have one or two further heteroatoms from the series N and / or O in the ring and which may be substituted by fluorine, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoyl or benzyl,
and their salts, hydrates, hydrates of the salts and solvates.

bedeutet,
worin
R⁶ für Wasserstoff oder Amino steht
und
* für die Anknüpfstelle an den phenolischen Sauerstoff steht,
R¹ und R² unabhängig voneinander Wasserstoff, Fluor oder Chlor bedeuten,
R³ und R⁴ Wasserstoff bedeuten,
R⁵ einen Rest bedeutet, der ausgewählt ist aus der Gruppe von: (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy,
wobei Alkyl und Alkoxy ihrerseits durch Amino oder Morpholinyl substituiert sein können,
Phenyl, Phenoxy, Pyridyl, Pyridyloxy, wobei Phenyl, Phenoxy, Pyridyl und Pyridyloxy ihrerseits durch Fluor, Chlor, Amino, Methyl oder NH-CO-CH₃ substituiert sein können,
und NR¹⁰R¹¹ worin
R¹⁰ und R¹¹ unabhängig voneinander für Wasserstoff, 2-Hydroxyethyl, 3-Hydroxypropyl, 2-Aminoethyl, 3-Aminopropyl, 2-Morpholinoethyl, 3-Morpholinopropyl, 2-Aminocyclohexyl, Pyridyl oder Aminopyridyl stehen oder
R¹⁰ und R¹¹ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Piperazin-, N-Methylpiperazin- oder N-Isopropylpiperazinring oder einen Rest

worin
* für die Anknüpfstelle an den Pyrimidinring steht, und ihre Salze, Hydrate, Hydrate der Salze und Solvate.Compounds of the formula (I) are particularly preferred
wherein
A a rest

means
wherein
R ^{6 represents} hydrogen or amino
and
* represents the point of attachment to the phenolic oxygen,
R ¹ and R ² independently of one another denote hydrogen, fluorine or chlorine,
R ³ and R ^{4 are} hydrogen,
R ^{5 represents} a radical which is selected from the group of: (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy,
where alkyl and alkoxy in turn can be substituted by amino or morpholinyl,
Phenyl, phenoxy, pyridyl, pyridyloxy, where phenyl, phenoxy, pyridyl and pyridyloxy can in turn be substituted by fluorine, chlorine, amino, methyl or NH-CO-CH ₃ ,
and NR ¹⁰ R ¹¹ wherein
R ¹⁰ and R ¹¹ independently of one another represent hydrogen, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-aminocyclohexyl, pyridyl or aminopyridyl or
R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, a piperazine, N-methylpiperazine or N-isopropylpiperazine ring or a radical

wherein
* represents the point of attachment to the pyrimidine ring, and its salts, hydrates, hydrates of the salts and solvates.

worin
A, R¹, R², R³ und R⁴ die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel {III)

worin
R⁵ die oben angegebene Bedeutung aufweist und
X¹ für Wasserstoff, B(OH)₂ oder einen Boronsäureester wie

oder [B] Verbindungen der Formel (IV)

worin
R⁵ die oben angegebene Bedeutung aufweist, mit Verbindungen der Formel (V)

worin
A, R¹, R², R³ und R⁴ die oben angegebene Bedeutung aufweisen, zu Verbindungen der Formel (I) umsetzt.The present invention further provides a process for the preparation of the compounds of the formula (I), which is characterized in that either [A] compounds of the formula (II)

wherein
A, R ¹ , R ² , R ³ and R ^{4 have} the meaning given above, with compounds of the formula {III)

wherein
R ^{5 has} the meaning given above and
X ¹ for hydrogen, B (OH) ₂ or a boronic ester such as

or [B] compounds of the formula (IV)

wherein
R ^{5 has} the meaning given above, with compounds of the formula (V)

wherein
A, R ¹ , R ² , R ³ and R ^{4 have} the meaning given above, to give compounds of the formula (I).

In process step [A] if X ^{1 is} hydrogen, the reaction takes place, optionally in the presence of a base, either in inert solvents at atmospheric pressure in a temperature range from 20 ° C. to the reflux of the solvents or at elevated pressure in the autoclave at temperatures above the boiling point of the solvent up to 250 ° C or alternatively in bulk in the melt.

Inert solvents are, for example Alcohols such as methanol, ethanol, propanol, isopropanol, or butanol 2-ethylhexanol, N-alkylated carboxamides such as dimethylformamide, Dimethylacetamide or N-methylpyrrolidone, alkyl sulfoxides such as dimethyl sulfoxide, or other solvents such as acetonitrile or pyridine. Preferred are ethanol, butanol, 2-ethylhexanol, N-methylpyrrolidone or dimethylformamide.

Bases are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, or alkali alcoholates such as sodium or potassium tert-butoxide, or alkali carbonates such as cesium carbonate, Sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine are preferred Diisopropylethylamine or triethylamine.

In process step [A] if X ^{1 is} B (OH) ₂ or an equivalent group such as a boronic acid ester, the reaction to give compounds of the formula (I) is generally carried out in inert solvents in the presence of a transition metal catalyst in the presence a base preferably in a temperature range from 70 ° C to 150 ° C at normal pressure.

Inert solvents are, for example Ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, nitroaromatics such as nitrobenzene, if appropriate N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide or cyclic lactams such as N-methylpyrrolidone. The solvents may be used with the addition of ethanol or water. Preferred solvents are dimethylformamide, 1,2-dimethoxyethane and toluene / ethanol.

As transition metal catalysts are preferred palladium (0) - or palladium (II) compounds, in particular Bis (diphenylphosphanferrocenyl) palladium (II) chloride, dichlorobis (triphenylphosphine) palladium or Tetrakis (triphenylphosphine) palladium (0) used.

Sodium or potassium tert-butoxide, or alkali metal hydroxides or salts such as potassium acetate, sodium hydroxide, Sodium bicarbonate, sodium carbonate or potassium carbonate, if appropriate in the form of their watery Solutions, prefers.

In process step [B] the conversion to compounds of formula (I) in aqueous hydrochloric acid solution, preferably in a temperature range from 70 ° C to 110 ° C at normal pressure.

unter Reaktionsbedingungen, wie für den Verfahrensschritt [B] beschrieben, um.To prepare the compounds of the formula (II) from process step [A], compounds of the formula (V) are used with the compound of the formula (VI)

under reaction conditions as described for process step [B] to.

worin
R⁵ die oben angegebene Bedeutung aufweist, in Phosphorylchlorid unter Zugabe von 0,01 bis einem Äquivalent Dimethylformamid oder N,N-Dimethylanilin oder N,N-Diethylanilin, bevorzugt in einem Temperaturbereich von 50°C bis zur Rückflusstemperatur des Lösungsmittels bei Normaldruck um.To prepare the compounds of the formula (N) from process step [B], compounds of the formula (VII)

wherein
R ^{5 has} the meaning given above, in phosphoryl chloride with addition of 0.01 to one equivalent of dimethylformamide or N, N-dimethylaniline or N, N-diethylaniline, preferably in a temperature range from 50 ° C. to the reflux temperature of the solvent at atmospheric pressure.

In another process variant compounds are used to prepare the compounds of the formula (IV) of the formula (VI) with compounds of the formula (III) under reaction conditions, as for described the process step [A] in order.

worin
R⁵ die oben angegebene Bedeutung aufweist und
X2 für Alkyl, bevorzugt für Methyl oder Ethyl, steht, mit der Verbindung der Formel (IX)

oder deren Salzen, vorzugsweise deren Caxbonat, um.To prepare the compounds of the formula (VII), compounds of the formula (VIII)

wherein
R ^{5 has} the meaning given above and
X2 represents alkyl, preferably methyl or ethyl, with the compound of the formula (IX)

or their salts, preferably their caxbonate, um.

Implementation of the connections of the For example, formulas (VIII) and (IX) are initially carried out in two stages concentrated hydrochloric acid in ethanol, preferably in a temperature range from 50 ° C to Reflux the solvent at normal pressure, and then with watery Sodium hydroxide solution, preferably in a temperature range from 50 ° C to backflow the solvent at normal pressure.

worin R¹, R², R³ und R⁴ die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel (XI)

worin
A die oben angegebene Bedeutung aufweist und
X³ für Halogen, bevorzugt Fluor oder Chlor steht, um.To prepare the compounds of the formula (V) from process step [B], either compounds of the formula (X)

wherein R ¹ , R ² , R ³ and R ^{4 have} the meaning given above, with compounds of the formula (XI)

wherein
A has the meaning given above and
X ^{3 represents} halogen, preferably fluorine or chlorine.

In the event that X ³ is bound to a pyridine ring, X ³ can represent a nitro group.

The implementation is preferably carried out in bulk in the presence of potassium hydroxide as a base in the melt at a temperature of 200 ° C up to 280 ° C or in an inert solvent such as N, N-dimethylformamide, N-methylpyrrolidone or Nitrobenzene in the presence of a base such as potassium hydroxide, Potassium tert-butoxide or sodium hydride at a temperature of 120 ° C to 280 ° C.

worin
A, R¹, R², R³ und R⁴ die oben angegebene Bedeutung aufweisen,
mit Reduktionsmitteln umgesetzt werden.Alternatively, compounds of the formula (V) can be prepared by compounds of the formula (XII)

wherein
A, R ¹ , R ² , R ³ and R ^{4 have} the meaning given above,
be implemented with reducing agents.

The implementation is generally done in inert solvents, preferably in a temperature range from room temperature to backflow the solvent at normal pressure up to 3 bar.

Reducing agents are, for example Palladium on activated carbon and hydrogen, platinum oxide on activated carbon and hydrogen, tin dichloride or titanium trichloride is preferred Palladium on activated carbon and hydrogen in the presence of hydrazine hydrate or platinum oxide on activated carbon and hydrogen.

Inert solvents are, for example Ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, Dioxane, tetrahydrofuran, glycol dimethyl ether or di ethylene glycol dimethyl ether, Alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, tert-butanol or 2-ethylhexanol, hydrocarbons such as benzene, xylene, toluene, hexane, Cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, as a solvent are preferably ethanol, n-butanol or 2-ethylhexanol.

worin
R¹, R², R³ und R⁴ die oben angegebene Bedeutung aufweisen und
X⁴ für Halogen, bevorzugt Fluor oder Chlor, steht,
mit Verbindungen der Formel (XIV)

worin
A die oben angegebene Bedeutung aufweist,
um.To prepare the compounds of the formula (XII), compounds of the formula (XIII) are used

wherein
R ¹ , R ² , R ³ and R ^{4 have} the meaning given above and
X ^{4 represents} halogen, preferably fluorine or chlorine,
with compounds of the formula (XIV)

wherein
A has the meaning given above,
around.

The implementation is generally done in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to reflux the solvent at normal pressure.

Inert solvents are, for example Halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably acetonitrile, dimethylformamide or 1,2-dimethoxyethane.

Bases are, for example, alkali carbonates like cesium carbonate, Sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or Amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, preferably potassium tert-butoxide, cesium carbonate, Potassium carbonate or sodium carbonate.

The compounds of formula (III) (VI), (VIII), (IX), (X), (XI), (XIII) and (XIV) are known to the person skilled in the art known per se or can be according to the usual literature Establish process.

Leave the compounds of formula (I) continue, for example, by reaction with oxidizing agents derivatized.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes.

The compounds of the invention show a unpredictable, valuable pharmacological and pharmacokinetic Spectrum.

They are therefore suitable for use as a medicine for the treatment and / or prophylaxis of diseases in humans and animals.

The pharmaceutical effectiveness of compounds of the invention can be explained by their action as Rho kinase inhibitors.

Another subject of the present The invention is the use of the compounds according to the invention for treatment and / or prophylaxis of diseases, preferably cardiovascular diseases.

The compounds according to the invention are suitable for the Prophylaxis and / or treatment of cardiovascular diseases such as High blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic disorders and ischemia such as myocardial infarction, stroke, transitory and ischemic Attacks, peripheral circulatory disorders, subarachnoid hemorrhage, Prevention of restenosis such as after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal Coronary angioplasty (PTCA), bypass and for prophylaxis and / or Treatment of arteriosclerosis, asthmatic diseases, COPD and diseases of the genitourinary system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, Gastroparesis and incontinence.

Furthermore, the compounds of the invention for the prophylaxis and / or treatment of cancer, in particular of tumors.

In the context of the present invention, the definition of tumors includes both benign and malignant tumors and thus, for example, also benign neoplasias, dysplasias, hyperplasias, and also neoplasias with metastasis formation. Further examples of tumors are carcinomas, sarcomas, carcinosarcomas, tumors of the hematopoietic organs, tumors of the nerve tissue, for example of the brain, or tumors of skin cells. Tumor formation leads to uncontrolled or insufficiently controlled cell division. The Tu mor may be localized, but it may also infiltrate the surrounding tissue and then settle to a new location through the lymphatic system or through the bloodstream. Thus there are primary and secondary tumors. Primary tumors originated in the organ in which they are found. Secondary tumors have established themselves in another organ through metastasis and then spread to their new location.

Another subject of the present The invention is the use of the compounds according to the invention for prophylaxis and / or treatment of diseases, in particular the aforementioned Diseases.

Another subject of the present The invention is the use of the compounds according to the invention for the preparation a drug for the prophylaxis and / or treatment of diseases, especially the previously mentioned clinical pictures.

Another subject of the present Invention is a method for the prophylaxis and / or treatment of Diseases, especially the aforementioned diseases, under Using a cardiovascular effective amount of the compound of the invention.

Another subject of the present Invention are medicaments containing a compound according to the invention and one or more other active ingredients, in particular for prophylaxis and / or treatment of the aforementioned diseases.

The compound of the invention can be systemic and / or act locally. To this end, it can do so in an appropriate manner can be applied, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic, as Stents or as an implant.

For the compound according to the invention can use these application routes in a suitable manner Application forms are administered.

For The oral application is suitable according to the state of the art rapidly and / or modifying the compounds according to the invention Application forms that the compounds of the invention in crystalline and / or contain amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example with gastric juice-resistant or delayed dissolving insoluble coatings that control the release of the compounds according to the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, capsules, coated tablets, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

Parenteral administration can bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with activation absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral application are suitable as application forms Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes are e.g. Inhalation dosage forms (e.g. powder inhalers, nebulizers), nasal drops 1 solutions, sprays; Tablets to be applied lingually, sublingually or buccally or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The compounds of the invention can in in a manner known per se can be converted into the application forms mentioned. This is done using inert non-toxic, pharmaceutical suitable auxiliaries. Which includes et al excipients (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), Emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. Polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), Stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste and / or Odors.

Another subject of the present Invention are medicaments which contain at least one compound according to the invention, preferably together with one or more inert non-toxic, Contain pharmaceutically suitable excipient, and their use for the aforementioned purposes.

In general, it has both proven beneficial in both human and veterinary medicine, the compound of the invention in total amounts from about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight 24 hours each, possibly in the form of several individual doses, for Achieving the desired Deliver results. The compound according to the invention contains a single dose preferably in amounts from about 0.1 to about 80, in particular 0.1 up to 30 mg / kg body weight.

Nevertheless, it may be necessary be different from the amounts mentioned, depending on of body weight, Application route, individual behavior towards the active ingredient, type of Preparation and time or interval at which the application he follows. In some cases it can be sufficient with less than the aforementioned minimum amount get along while in other cases the specified upper limit was exceeded must become. In the case of application of larger quantities, it can be recommended be spread over the day in several separate doses.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration Information on liquid / liquid solutions relates to volume.

A. Examples

Abbreviations:

DC

TLC

DCI

direct chemical ionization (for MS)

DCM

dichloromethane

DIEA

N, N-diisopropylethylamine

DMA

dimethylacetamide

DMF

N, N-dimethylformamide

DMSO

dimethyl sulfoxide

d. Th.

the theory

EE

ethyl acetate (Ethyl acetate)

EGG

Electron impact ionization (for MS)

IT I

Electrospray ionization (for MS)

Mp.

melting point

ges.

saturated

H

hour

HATU

O- (7-azabenzotriazol-l-yl) -N, N, N; N'-tetramethyluronium-

hexafluorophosphate

HOAT

3H- [1,2,3] triazole [4,5-b] pyridine-3-ol

HOBt

1-hydroxy-1H-benzotriazole × H ₂ O

HPLC

High pressure, high performance liquid chromatography

conc.

concentrated

LC-MS

Liquid chromatography-coupled mass spectroscopy

LDA

Lithium DÜsopropylamid

minute

minutes

MPLC

medium pressure, Mittelleistungsflüssigchromatographie

MS

mass spectroscopy

NMR

Nuclear Magnetic Resonance Spectroscopy

org.

organic

proc.

percent

RF

backflow

R _f

retention factor (at DC)

RP-HPLC

Reverse HPLC phase

RT

room temperature

R _t

retention time (with HPLC)

TFA

trifluoroacetic

THF

tetrahydrofuran

HPLC, LCMS and GCMS methods:

Method 1 (LC / MS)

Instrument: Micromass Platform LCZ, HP1100; Pillar: Symmetry C18, 50 mm × 2.1 mm, 3.5 µm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.

Method 2 (LC / MS)

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Pillar: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C, Flow: 0.8 ml / min, UV detection: 208-400 nm.

Method 3 (LC / MS)

Instrument: Finnigan MAT 9005, TSP: P4000, AS3000, UV3000HR; Pillar: Symmetry C 18, 150 mm × 2.1 mm, 5.0 µm; Eluent C: water, eluent B: water + 0.3 g 35% hydrochloric acid, eluent A: acetonitrile; Gradient: 0.0 min 2% A → 2.5 min 95% A → 5 min 95 % A; Oven: 70 ° C; Flow: 1.2 ml / min; UV detection: 210 nm.

Method 4 (LC / MS)

Instrument: Micromass Quattro LCZ, HP 1100; Pillar: Symmetry C 18, 50 mm × 2.1 mm, 3.5 µm; Eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1 % Formic acid; Gradient: 0.0 min 10% A → 4.0 min 90% A → 6.0 min 90% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.

Method 5 (LC / MS)

Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; Pillar: UPTISPHERE HDO, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 l water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C, Flow: 0.8 ml / min, UV detection: 208-400 nm.

Method 6 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Uptisphere C 18, 50 mm × 2.0 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min → 4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min; UV detection: 210 nm.

Method 7 (HPLC)

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 µm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C; UV detection: 210 nm.

Method 8 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min → 4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min; UV detection: 210 nm.

Method 9 (LC / MS)

Instrument: Micromass Quattro LCZ, with HPLC Agilent series 1100; Pillar: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 l water + 1 ml 50% formic acid, eluent B: 1 l acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C, Flow: 0.8 ml / min, UV detection: 208-400 nm.

Method 10 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 µm; Eluent A: water + 500 μl 50% formic acid / l, Eluent B: acetonitrile + 500 μl 50% formic acid / l; Gradient: 0.0 min 0% B → 2.9 min 70% B → 3.1 min 90% B → 4.5 min 90% B; Oven: 50 ° C, Flow: 0.8 ml / min, UV detection: 210 nm.

Method 11 (HPLC)

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min, temp .: 30 ° C, UV detection: 210 nm.

Method 12 (LC / MS)

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Pillar: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 l water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C, Flow: 0.8 ml / min, UV detection: 210 nm.

Method 13 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Pillar: Phenomenex Synergi 2μ hydro RP Mercury 20mm × 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A flow 1 ml / min → 2.5 min 30% A flow 2 ml / min → 3.0 min 5% A flow 2 ml / min → 4.Smin 5% A flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 14 (LC / MS)

Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; Pillar: Phenomenex Synergi 2μ hydro RP Mercury 20mm × 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A flow 1 ml / min → 2.5 min 30% A flow 2 ml / min → 3.0 min 5% A flow 2 ml / min → 4.5 min 5% A flow 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.

Method 15 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Pillar: Phenomenex Synergi 2μ hydro RP Mercury 20mm × 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A flow 1 ml / min → 2.5 min 30% A flow 2 ml / min → 3.0 min 5% A flow 2 ml / min → 4.5 min 5% A flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 16 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Pillar: Merck Chromolith SpeedROD RP-18e 50 mm × 4.6 mm; Eluent A: water + 500 μl 50% formic acid / l; Eluent B: acetonitrile + 500 μl 50% formic acid / l; Gradient: 0.0 min 10% B → 3.0 min 95% B → 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min, 3.0 min 3.0 ml / min, 4.0 min 3.0 ml / min; UV detection: 210 nm.

Method 17 (LC / MS)

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Pillar: Phenomenex Synergi 2μ hydro RP Mercury 20mm × 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A flow 1 ml / min → 2.5 min 30% A flow 2 ml / min → 3.0 min 5% A flow 2 ml / min → 4.5min 5% A flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 18 (LC / MS)

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 µm; Eluent A: water + 500 μl 50% formic acid / l, Eluent B: acetonitrile + 500 μl 50% formic acid / l; Gradient: 0.0 min 70% B → 4.5 min 90% B; Oven: 50 ° C, Flow: 0.8 ml / min, W detection: 210 nm.

Preparative HPLC

Pillar: YMC Gel ODS-AQ S-5/15 μM, 250 mm × 30 mm, eluent A: water, eluent B: acetonitrile; Gradient: 0.00 min 30% B → 3.00 min 30% B → 34.0 min 95% B → 38.0 min 30% B; Temp .: room temperature; Flow: 50 ml / min; UV detection.

starting compounds

Example I 3-methyl-1H-indazol-4-ol

800 mg (5.26 mmol) of 2,6-dihydroxyacetophenone are mixed with 526 mg (10.5 mmol) of hydrazine hydrate and 1 ml of glacial acetic acid. After stirring at 110 ° C. for 15 minutes, the reaction mixture is cooled to room temperature. After adding 6 ml of polyphosphoric acid, the mixture is heated to 120 ° C. for 20 minutes. After cooling to room temperature, 0.8 g (7.89 mmol) of acetic anhydride are added dropwise. The mixture is heated again to 120 ° C. for 20 min. The reaction mixture, cooled to room temperature, is then poured onto ice. It is neutralized with 1N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are washed twice with water. After drying over sodium sulfate, the solvent is removed in vacuo. The product is purified using column chromatography. A mixture of cyclohexane and ethyl acetate (1: 1) is used for elution.
Yield: 429 mg (55%)
LC-MS (method 1): R _t = 1.8 min.
MS (ESI pos.): M / z = 149 (M + H) ^+
1 H-DMSO-d ₆ , 300 MHz): δ = 2.54 (s, 3H), 6.31 (d, 1H), 6.79 (d, 1H), 7.02 (t, 1 H), 9.84 (s, 1 H) , 12.3 (s, 1H).

Example II 4- (2-Fluoro-4-nitrophenoxy) 3 methyl-1H-indazole

100 mg (0.63 mmol) 3,4-difluoronitrobenzene with 93.1 mg (0.63 mmol) of 3-methyl-1H-indazol-4-ol (from Example I) and 95.6 mg (0.69 mmol) of potassium carbonate in 5 ml of anhydrous Dimethylformamide suspended and stirred at 50 ° C for five hours. Then will the reaction solution diluted with water and extracted twice with ethyl acetate. The united organic Phases are over Dried sodium sulfate. The solvent is removed in vacuo and the residue by means of column chromatography cleaned. A mixture of cyclohexane and ethyl acetate is used for elution (1: 1) used.

Yield: 93 mg (51.5%)
LC-MS (Method 2): R _t = 3.7 min.
MS (ESI pos.): M / z = 288 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 2.36 (s, 3H), 6.73 (dd, 1H), 7.07 (t, 1H), 7.37 (m, 2H), 8.06 (m, 1 H) , 8.3 7 (dd, 1 H), 13.06 (s, 1 H).

75 mg (0.26 mmol) 4-(2-Fluor-4-nitrophenoxy)-3-methyl-1H-indazol (aus Beispiel II) werden in 3 ml Ethanol gelöst und mit 261 mg (5.22 mmol) Hydrazinhydrat sowie mit 10 mg 10 %igem Palladium auf Aktivkohle versetzt. Man erhitzt zwei Stunden auf 80°C. Anschließend wird über Kieselgur filtriert. Das Filtrat wird im Vakuum eingeengt. Example III 3-Fluoro-4 - [(3-methyl-1H-indazol-4-yl) oxy] phenylamine

75 mg (0.26 mmol) 4- (2-fluoro-4-nitrophenoxy) -3-methyl-1H-indazole (from Example II) are dissolved in 3 ml ethanol and with 261 mg (5.22 mmol) hydrazine hydrate and with 10 mg 10 % palladium added to activated carbon. The mixture is heated to 80 ° C. for two hours. It is then filtered through diatomaceous earth. The filtrate is concentrated in vacuo.

Yield: 65 mg (96.8%)
LC-MS (Method 5): R _t = 3.23 min.
MS (ESI pos.): M / z = 258 (M + H) ^+
1 H NMR DMSO-d6, 300 MHz): δ = 2.61 (s, 3H), 5.32 (s, 2H), 6.06 (d, 1H), 6.41 (dd, 1 H), 6.52 (dd, 1 H) , 6.96 (t, 1H), 7.08 (m, 2H), 12.63 (s, 1H).

Example IV 4-methoxy-1,2-benzisoxazol-3-amine

709.5 mg (9.45 mmol) of acetohydroxamic acid submitted in 8 ml of anhydrous dimethylformamide and at room temperature 1.06 g (9.45 mmol) of potassium tert-butoxide were added. After stirring for 40 minutes, 1 g (6.62 mmol) of 2-fluoro-6-methoxybenzonitrile added. One warms up 16 hours at 60 ° C. Then will 20 ml of saturated sodium chloride solution are added to the reaction mixture. The crystals that precipitate are suctioned off and washed with water washed.

Yield: 358 mg (23%)
LC-MS (Method 6): R _t = 2.59 min.
MS (ESI pos.): M / z = 165 (M + H) ⁺ 1H-NMR DMSO-d6, 300 MHz): δ = 3.91 (s, 3H), 5.91 (s, 2H), 6.71 (d, 1H ), 6.98 (d, 1H), 7.43 (t, 1H).

250 mg (1.52 mmol) 4-Methoxy-l,2-benzisoxazol-3-amin (aus Beispiel IV) werden in 5 ml absolutem Methylenchlorid gelöst und unter Argon mit 7.6 ml (7.6 mmol) 1M-Bortribromid-Lösung in Methylenchlorid versetzt. Man rührt über Nacht bei Raumtemperatur und hydrolysiert dann vorsichtig mit Wasser. Der ausgefallene Niederschlag wird abfiltriert, mit Wasser gewaschen und im Hochvakuum getrocknet.Example V 3-amino-1,2-benzisoxazol-4-ol

250 mg (1.52 mmol) of 4-methoxy-1,2-benzisoxazol-3-amine (from Example IV) are dissolved in 5 ml of absolute methylene chloride and 7.6 ml (7.6 mmol) of 1M boron tribromide solution in methylene chloride are added under argon. The mixture is stirred overnight at room temperature and then carefully hydrolyzed with water. The precipitate is filtered off, washed with water and dried under high vacuum.

Yield: 195 mg (85.3%)
LC-MS (Method 6): R _t = 1.78 min.
MS (ESI pos.): M / z = 151 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 5.90 (s, 2H), 6.70 (d, 1H), 6.97 (d, 1H), 7.42 (t, 1 H).

94.37 mg (0.63 mmol) 3-Amino-l,2-benzisoxazol-4-ol (aus Beispiel V) werden mit 100 mg (0.63 mmol) 3,4-Difluornitrobenzol und 95.56 mg (0.69 mmol) Kaliumcarbonat in 3 ml wasserfreiem Dimethylformamid suspendiert und 16 Stunden bei Raumtemperatur gerührt. Anschließend wird die Reaktionslösung mit Wasser verdünnt und der ausgefallene Niederschlag abfiltriert. Das Produkt wird im Hochvakuum getrocknet.Example VI 4- (2-Fluoro-4-nitrophenoxy) -1,2-benzisoxazol-3-amine

94.37 mg (0.63 mmol) of 3-amino-1,2-benzisoxazol-4-ol (from Example V) are mixed with 100 mg (0.63 mmol) of 3,4-difluoronitrobenzene and 95.56 mg (0.69 mmol) of potassium carbonate in 3 ml of anhydrous dimethylformamide suspended and stirred for 16 hours at room temperature. The reaction solution is then diluted with water and the precipitate which has separated out is filtered off. The product is dried in a high vacuum.

Yield: 151 mg (83.1%)
LC-MS (Method 2): R _t = 3.5 min.
MS (ESI pos.): M / z = 290 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 6.15 (s, 2H), 6.64 (d, 1H), 7.28 (d, 1H), 7.49 (m, 2H), 8.14 (m, 1 H) , 8.39 (dd, 1H).

Example VII 4- (4-Amino-2-fluorophenoxy) -1,2-benzisoxazol-3-amine

s120 mg (0.41 mmol) 4- (2-fluoro-4-nitrophenoxy) -1,2-benzisoxazol-3-amine (from Example VI) with 468 mg (2.07 mmol) of tin (II) chloride dihydrate dissolved in 8 ml of ethyl acetate and 4 hours at 70 ° C heated. After cooling to room temperature, the reaction solution is saturated Sodium bicarbonate solution adjusted to pH 9, a colorless precipitate being formed. The suspension is mixed with 5 g of diatomaceous earth and filtered. The The filtrate is extracted several times with ethyl acetate. The United organic phases are washed with water and over sodium sulfate dried. After removing the solvent the product is obtained in vacuo.

Yield: 102 mg (94.8%)
LC-MS (Method 2): R _t = 2.95 min.
MS (ESI pos.): M / z = 260 (M + H) ^{+ 1} H-NMR (DMSO-d ₆ , 300 MHz): δ = 5.40 (s, 2H), 6.03 (s, 2H), 6.24 ( d, 1H), 6.43 (m, 1H), 6.46 (dd, 1H), 7.04 (m, 2H), 7.34 (t, 1H).

Example VIII 1H-Indazol-6-ol

8.00 g (60.1 mmol) 6-aminoindazole are mixed with dilute sulfuric acid (8 ml concentrated sulfuric acid in 52.8 ml H ₂ O) and cooled to 0 ° C. An aqueous sodium nitrite solution (4.48 g sodium nitrite in 12.8 ml water) is slowly added dropwise. The mixture is stirred at 0 ° C for 1 hour. After adding 5.60 g (90.6 mmol) of boric acid and a further 8 ml of dilute sulfuric acid, the mixture is heated under reflux for 15 minutes. The reaction solution is cooled and neutralized with 25% ammonia solution. The solid that has precipitated is filtered off and boiled in water. It is filtered hot. The filtrate is extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated.

Yield: 5.15 g (58%)
LC-MS (method 2): R _t = 2.25 min.
MS (ESI pos.): M / z = 134 (M + H) ^+
1 H NMR DMSO-db, 200 MHz): δ = 6.62 (dd, 1H), 6.77 (d, 1H), 7.51 (d, 1H), 7.88 (s, 1 H), 9.63 (s, 1 H) , 12.5 8 (s, 1H).

Example IX 5- (2-Fluoro-4-nitrophenoxy) -1 H-indazole

s5.00 g (37.3 mmol) 5-hydroxyindazole are dissolved in 40 ml of anhydrous DMF. Add 5.93 g (37.3 mmol) 3,4-difluoronitrobenzene and 5.15 g (37.3 mmol) potassium carbonate and leaves overnight Stir at 40 ° C. to Processing is sucked over Diatomaceous earth, diluted with water and extracted three times with ethyl acetate. The United organic phases are washed 1x with saturated aqueous sodium chloride solution, over sodium sulfate dried and concentrated on a rotary evaporator. The residue is over twice Chromatograph silica gel with cyclohexane / ethyl acetate 3: 1 → 1: 1 → 1: 2 and subsequently by means of preparative HPLC cleaned.

Yield: 4.02 g (39%)
MS (ESI pos.): M / z = 274 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 6.98 (t, 1H), 7.22 (dd, 1H), 7.58 - 7.69 (m, 2H), 7.95 - 8.12 (m, 2H), 8.33 ( dd, 1H), 13.20 - 13.36, br. s, 1H).

Beispiel XII 5-(4-Amino-2-fluorphenoxy)-1H-indazol

The following are produced in an analogous manner:

Example XII 5- (4-Amino-2-fluorophenoxy) -1H-indazole

1.96 g (7.17 mmol) of 5- (2-fluoro-4-nitrophenoxy) -1H-indazole (from Example IX) are dissolved in 50 ml of ethanol. 0.16 g (0.71 mmol) of platinum (N) oxide is added and the mixture is hydrogenated at room temperature for 2 hours under atmospheric pressure. For working up, it is suctioned off through kieselguhr, washed with ethanol and the filtrate is concentrated.
Yield: 1.66 g (95%)
MS (ESI pos.): M / z = 244 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 5.26 (s, 2H), 6.39 (dd, 1H), 6.49 (dd, 1H), 6.88 (t, 1 H), 7.00 (d, 1 H) ), 7.08 (dd, 1 H), 7.48 (d, 1 H), 7.90 (s, 1 H), 12.83 - 13.04, br. s, 1 H).

Beispiel XV 1H-Pyrro1o [2,3-b]pyridin-7-oxid

The following are produced in an analogous manner:

Example XV 1H-Pyrro1o [2,3-b] pyridine-7-oxide

539.7 g (2.35 mol) of 3-chloroperbenzoic acid dissolved in 6.11 1 dichloromethane and separated water is separated. The organic phase is about Dried sodium sulfate and cooled to 0 ° C. Then you issue a solution 163 g (1.38 mo1) 1H-pyrrolo [2,3-b] pyridine in 1.00 1 dichloromethane to and allows the Temperature rise to room temperature. After 2 hours you give so much methanol that the precipitate formed again dissolves. The mixture is over Filtered silica gel (eluent: dichloromethane / methanol 95: 5) and the Product fractions dried after concentration in a high vacuum.

Yield: 145 g (75%)
HPLC (method 7): R _t = 2.02 min.
MS (ESI pos.): M / z = 135 (M + H) ⁺ , 152 (M + NH4) ⁺ , 269 (2M + H) ^+
1 H NMR DMSO-d ₆ , 200 MHz): δ = 6.58 (d, 1H), 7.07 (dd, 1H), 7.48 (d, 1H), 7.65 (d, 1 H), 8.17 (d, 1 H ), 12.42 - 12.64 (br. S, 1 H).

Eine Durchführung größerer Ansätze als der im folgenden beschriebene ist aufgrund der Ergebnisse der Differentialthermoanalyse nicht empfehlenswert.Example XVI 4-Nitro-1 H-pynolo [2,3-b] pyridine-7-oxide

Based on the results of the differential thermal analysis, it is not advisable to carry out approaches larger than those described below.

A solution of 20.0 g (149 mmol) 1H-Pynolo [2,3-b] pyridine-7-oxide (from Example XV) in 160 ml of trifluoroacetic acid cooled to room temperature. Subsequently 69.3 ml of 65% nitric acid are slowly added dropwise and the mixture is left overnight stir at room temperature. You pour on ice and make with 45% sodium hydroxide solution a pH of 8-9. The precipitate is filtered off and with Washed water. The raw products from 4 approaches of described size and one carried out analogously 13 g batch combined and cleaned together. The raw products are slurried in water and with 2N sodium hydroxide solution adjusted to pH 8-9. After 10 min stirring the precipitate suctioned off and dried in a high vacuum.

Yield: 29.7 g (24%)
HPLC (method 7): R _t = 3.02 min.
MS (ESI pos.): M / z = 180 (M + H) ⁺ , 197 (M + NH4) ⁺ , 359 (2M + H) ⁺
1H-NMR (DMSO-d ₆ , 200 MHz): δ = 7.03 (d, 1H), 7.80 (d, 1H), 8.03 (d, 1H), 8.31 (d, 1 H), 13.22 - 13 .41 ( br. s, 1 H).

Example XVII 4-Amino-1 H-pyrrolo [2,3-b] pyridine

To a solution of 3.00 g (16.8 mmol) of 4-nitro-lH-pyrrolo [2,3-b] pyridine-7-oxide (from Example XVI) in 225 ml of acetic acid, 9.35 g (167 mmol) of iron powder is added and 2 hours heated under reflux. The Raw mixtures of two such approaches are combined and further processed together. The solid is separated off and washed with 50 ml of acetic acid and 100 ml of tetrahydrofuran. The filtrate is evaporated to dryness on a rotary evaporator. The residue is diluted with 50 ml of water and the solution made alkaline with 45% sodium hydroxide solution. Then dichloromethane is added and the mixture is suctioned off through diatomaceous earth. The filtrate is extracted six times with 100 ml dichloromethane each time, the organic phase is dried over sodium sulfate and evaporated to dryness on a rotary evaporator. The residue is dried in a high vacuum. For further purification, it is triturated with tetrahydrofuran and the solid is filtered off with suction. The filtrate is concentrated, the residue is taken up in dichloromethane, dried and concentrated.

Yield: 3.5 g (78%)
MS (ESI pos.): M / z = 134 (M + H) ⁺ , 267 (2M + H) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 6.05 (s, 2H), 6.09 (d, 1H), 6.47 (d, 1H), 7.02 (d, 1 H), 7.70 (d, 1 H), 10.90 -11.28 (br. S, 1 H).

750 mg (5.63 mmol) 4-Amino-1H-pyrrolo[2,3-b]pyridin (aus Beispiel XVII) werden in einer Mischung aus 67.5 ml Eisessig und 0.67 ml konzentrierter Schwefelsäure gelöst. Die Mischung wird auf 12°C gekühlt. Dazu tropft man langsam 3.67 ml (3.20 g, 117 mmol) Isopentylnitrit und lässt 3 Stunden bei 12°C rühren. Nun gibt man diese Lösung zu einer 50°C warmen Suspension aus 6.07 g (61.4 mmol) Kupfer(I)chlorid in 34 ml konzentrierter Salzsäure und erhitzt anschließend 30 min auf 80-90°C. Man lässt auf RT abkühlen und über Nacht rühren. Zur Aufarbeitung engt man die Reaktionslösung ein, stellt mit 1N wässriger Natriumhydroxid-Lösung alkalisch, saugt über Kieselgur die ausgefallenen Kupfersalze ab und extrahiert 3x mit Ethylacetat. Die organische Phase wird über Magnesiumsulfat getrocknet und am Rotationsverdampfer eingeengt.Example XVIII 4-Chloro-1 H-pyrrolo [2,3-b] pyridine

750 mg (5.63 mmol) of 4-amino-1H-pyrrolo [2,3-b] pyridine (from Example XVII) are dissolved in a mixture of 67.5 ml of glacial acetic acid and 0.67 ml of concentrated sulfuric acid. The mixture is cooled to 12 ° C. 3.67 ml (3.20 g, 117 mmol) of isopentyl nitrite are slowly added dropwise and the mixture is stirred at 12 ° C. for 3 hours. Now this solution is added to a 50 ° C warm suspension of 6.07 g (61.4 mmol) copper (I) chloride in 34 ml concentrated hydrochloric acid and then heated to 80-90 ° C for 30 min. Allow to cool to RT and stir overnight. For working up, the reaction solution is concentrated, made alkaline with 1N aqueous sodium hydroxide solution, the precipitated copper salts are filtered off with kieselguhr and extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator.

Yield: 548 mg (64%)
LC-MS (Method 5): R _t = 3.21 min.
MS (ESI pos.): M / z = 153 (M + H) ^+
1 H-NMR DMSO-d ₆ , 200 MHz): δ = 6.44 - 6.55 (m, 1H), 7.20 (d, 1H), 7.60 (t, 1H), 8.10 - 8.27 (m, 1H), 12.05 ( br. s, 1 H).

The connection described above (Example XVIII) can alternatively also be produced by the following method become:

100 mg (0.76 mmol) 1H-Pyrrolo[2,3-b]pyridin-7-oxid (aus Beispiel XV) werden in 3 ml Phosphoroxychlorid so lange zum Rückfluss erhitzt, bis sich eine klare Lösung bildet. Nach Abkühlen auf Raumtemperatur wird die Reaktionsmischung vorsichtig mit Eis hydrolysiert. Man macht mit Ammoniak alkalisch und extrahiert mehrfach mit Ethylacetat. Die organische Phase wird mit Wasser und gesättigter Natriumchlorid-Lösung gewaschen. Nach Trocknen über Magnesiumsulfat wird das Lösungsmittel im Vakuum entfernt. Man erhält ein gelbes Ö1, welches mittels präparativer HPLC gereinigt wird.Example XVIII (Alternative Manufacturing Method) 4-Chloro-1 H-pyrrolo [2,3-b] pyridine

100 mg (0.76 mmol) of 1H-pyrrolo [2,3-b] pyridine-7-oxide (from Example XV) are refluxed in 3 ml of phosphorus oxychloride until a clear solution forms. After cooling to room temperature, the reaction mixture is carefully hydrolyzed with ice. It is made alkaline with ammonia and extracted several times with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed in vacuo. A yellow oil is obtained, which is purified by means of preparative HPLC.

Yield: 210 mg (73%)
LC-MS (Method 8): R _t = 2.9 min.
MS (ESI pos.): M / z = 153 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 6.51 (dd, 1H), 7.20 (d, 1H), 7.60 (t, 1H), 8.17 (d, 1 H), 12.05 (s, 1 H).

Example XIX 3-fluoro-4- (1 H-pyrrolo [2, 3-b] pyridin-4-yloxy) aniline

543 mg (3.56 mmol) of 4-chloro-1H-pyrrolo [2,3-b] pyridine (from Example XVIII, 905 mg (7.12 mmol) 3-fluoro-4-hydroxyaniline and 399 mg (7.12 mmol) of powdered potassium hydroxide are 8 hours to 260 ° C heated. Another 905 mg (7.12 mmol) of 3-fluoro-4-hydroxyaniline are added and 200 mg (3.56 mmol) of powdered potassium hydroxide and leave more 8 h at 260 ° C react. Cools for workup one dilutes to room temperature with water and extracted three times with ethyl acetate. The organic Phase is about Dried magnesium sulfate and concentrated on a rotary evaporator. The residue is about preparative HPLC cleaned. The fractions containing 39% product according to LC-MS are used in the next reaction without further purification.

The connection described above (Example XIX) can alternatively also be produced using the following method become:

3.2 g (11.5 mmol) {4-[(6-Chlor-lH-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluor-phenyl}-amin (aus Beispiel XXXI) werden in Ethanol bei 50°C gelöst. Dann läßt man die Lösung auf RT abkühlen und gibt 2.45 g (2.30 mmol) 10% Palladium auf Aktivkohle hinzu. Das Gemisch wird über Nacht unter 2 bar Wasserstoff Druck hydriert. Das Palladium wird anschließend über Kieselgur abgesaugt, mit Ethanol nachgewaschen und das Filtrat eingeengt.Example XIX (Alternative Manufacturing Method) 3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline

3.2 g (11.5 mmol) {4 - [(6-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] -3-fluorophenyl} amine (from Example XXXI) are in ethanol dissolved at 50 ° C. The solution is then allowed to cool to RT and 2.45 g (2.30 mmol) of 10% palladium on activated carbon are added. The mixture is hydrogenated overnight under 2 bar hydrogen pressure. The palladium is then suction filtered through diatomaceous earth, washed with ethanol and the filtrate is concentrated.

Yield: 2.5 g (89%)
LC-MS (Method 8): R _t = 2.43 min.
MS (ESI pos.): M / z = 244 (M + H) ^{+ 1} H-NMR (DMSO-d ₆ , 200 MHz): δ = 5.45 (mc, 2H), 6.25 (mc, 2H), 6.40- 6.55 (br. 2H), 7.05 (t, 1 H), 7.33 (mc, 1 H), 8.25 (d, 1 H), 11.69 (s, 1 H).

100 mg (660 μmol) 4-Chlor-lH-pyrrolo[2,3-b]pyridin (aus Beispiel XVIII), 166 mg (1.31 mmol) 2-Fluor-4-hydroxyanilin und 73.5 mg (1.31 mmol) gepulvertes Kaliumhydroxid werden 8 Stunden auf 260°C erhitzt. Zur Aufarbeitung kühlt man auf Raumtemperatur ab, verdünnt mit Wasser und extrahiert dreimal mit Ethylacetat. Die organische Phase wird über Magnesiumsulfat getrocknet und am Rotationsverdampfer eingeengt. Der Rückstand wird durch präparative HPLC gereinigt.Example XX 2-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline

100 mg (660 μmol) of 4-chloro-1H-pyrrolo [2,3-b] pyridine (from Example XVIII), 166 mg (1.31 mmol) of 2-fluoro-4-hydroxyaniline and 73.5 mg (1.31 mmol) of powdered potassium hydroxide Heated to 260 ° C for 8 hours. For working up, the mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is purified by preparative HPLC.

Yield: 11 mg (6.7%)
LC-MS (Method 6): R _t = 2.37 min.

Example XXI 1-Benzofuran-4-ol

3.76 g (27.6 mmol) 6,7-dihydro-l-benzofuran-4 (5H) -one (manufactured according to Tetrahedron Lett. 1994, 35, 6231) with 10% Palladium on activated carbon in 34 ml decalin and 6 ml dodecene overnight to 200 ° C heated in a metal bath. It is cooled to 80 ° C., mixed with ethanol and over Celite filtered off. The Celite is washed twice with ethanol and that Concentrated filtrate. The residue that still contains decalin and dodecene is mixed with petroleum ether and cooled in an ice bath. An oily precipitate settles out from. The solvent is decanted and the oil over a preparative HPLC cleaned.

Yield: 180 mg (5%) LC-MS (method 5): R _t = 3.1 min.

Example XXII 4- (2-Fluoro-4-nitrophenoxy) -1-benzofuran

2.40 g (5.37 mmol) 1-benzofuran-4-ol (from Example XXI), with 0.90 g (5.64 mmol) of 3,4-difluoronitrobenzene and 1.48 g (10.7 mmol) of potassium carbonate in 20 ml of anhydrous dimethylformamide suspended and five Hours at 50 ° C touched. Subsequently becomes the reaction solution diluted with water and extracted twice with ethyl acetate. The united organic Phases are over Dried sodium sulfate. The solvent is removed in vacuo. The crude product is purified on a silica gel column (Eluent: Cyclohexane: ethyl acetate (10: 1)).

Yield: 254 mg (38%)
LC-MS (Method 6): R _t = 4.14 min.
MS (ESI pos.): M / z = 291 (M + NH ₄ ) ⁺ Example XXIII 4- (1-Benzofuran-4-yloxy) -3-fluorophenylamine

150 mg (0.55 mmol) 4- (2-fluoro-4-nitrophenoxy) -1-benzofuran (from Example XXII) in 5 ml of ethanol / tetrahydrofuran (1: 1) submitted under argon, platinum (IV) oxide is added and 2 hours hydrogenated at normal pressure. The suspension is filtered through Celite, with Washed ethanol and evaporated.

Yield: 33 mg (25%)
LC-MS (Method 2): R _t = 3.7 min.
MS (ESI pos.): M / z = 261 (M + NH ₄ ) ^+
1 H-NMR DMSO-d ₆ , 200 MHz): δ = 6.49 (m, 2H), 6.60 (d, 1H), 6.84 (dd, 1H), 7.00 (t, 1 H), 7.24 (m, 2H) , 7.95 (d, 1H).

Example XXIV 1H-Indazo1-4-ol

s500 mg (375 mmol) 1H-indazol-4-ylamine (manufactured according to J. Chem. Soc. 1955, 2412, 2419) are added in 10% sulfuric acid 180 ° C in Autoclaves at autogenous pressure Stirred at night. The reaction solution is cooled to room temperature with 1N sodium hydroxide solution neutralized and filtered off from the salts. The filtrate becomes Dry evaporated.

Yield: 480 mg (95%)
LC-MS (Method 6): R _t = 1.22 min.
MS (ESI pos.): M / z = 135 (M + H) ^+
1 H NMR (DMSO-d ₆ , 300 MHz): δ = 6.38 (d, 1H), 6.92 (d, 1H), 7.11 (t, 1H), 8.0 (s, 1 H), 9. 8 (s , 1 H), 12.8 (s, 1 H).

Example XXV 4- (2-fluoro-4-nitrophenoxy) -1H-indazole

100 mg (0.75 mmol) 1H-indazo1-4-o1 (from Example XXIV), with 94 mg (0.64 mmol) of 3,4-difluoronitrobenzene and 103 mg (0.75 mmol) of potassium carbonate in 2 ml of anhydrous dimethylformamide suspended and 5 hours at 50 ° C touched. Subsequently becomes the reaction solution diluted with water and extracted 2x with ethyl acetate. The combined organic phases are about Dried sodium sulfate. The solvent will removed in vacuum. The raw product is prepared by means of HPLC cleaned.

Yield: 78 mg (38%)
LC-MS (Method 6): R _t = 3.5 min.
MS (ESI pos.): M / z = 274 (M + H) ^+
1 H NMR (DMSO-d ₆ , 300 MHz): δ = 6.79 (d, 1H), 7.20 (t, 1H), 7.41 (m, 2H), 7.94 (s, 1H), 8.07 (m, 1H ), 8.3 6 (dd, 1 H), 13.39 (s, 1 H).

Example XXVI 3-fluoro-4- (1H-indazol-4-yloxy) aniline

60 mg (0.22 mmol) 4- (2-fluoro-4-nitrophenoxy) -1H-indazole (from Example XXV) in 5 ml of ethanol / tetrahydrofuran (1: 1) submitted under argon, 9.97 mg (0.04 mmol) platinum (IV) oxide are added and hydrogenated at normal pressure for 2 hours. The suspension is over Celite filtered off, washed with ethanol and concentrated in vacuo.

Yield: 50 mg (94%)
LC-MS (Method 6): R _t = 2.9 min.
MS (ESI pos.): M / z = 244 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 5.36 (s, 2H), 6.24 (d, 1H), 6.42 (dd, 1H), 6.51 (dd, 1 H), 7.0 (t, 1 H) ), 7.17 (m, 2H), 7. 8 8 (s, 1 H), 13 .13 (s, 1 H).

Example XXVII 3-Oxo-3- (4-pyridinyl) propanoic acid ethyl ester

25 g (203 mmol) isonicotinic acid, 35.12 g (243.7 mmol) of 2,2-dimethyl-1,3-dioxolane-4,6-dione and 49.6 g (406 mmol) of 4-dimethylaminopyridine are placed in 300 ml dichloromethane and cooled to 0 ° C. It becomes a 1N solution of 46.1 g (223.4 mmol) 1,3-dicyclohexylcarbodiimide in dichloromethane dropwise. The mixture is stirred at room temperature for 2 hours. The precipitate formed is filtered off and with dichloromethane rewashed. The filtrate is concentrated in vacuo. The residue is dissolved in 1200 ml of ethanol and with a solution from 96.6 g (507.7 mmol) of p-toluenesulfonic acid monohydrate in 300 ml of ethanol spiked and refluxed for an hour touched. After cooling the ethanol is removed in vacuo. The residue is dissolved in 1000 ml of ethyl acetate and 900 ml of water and dissolved in the heat. The organic phase is separated off with 600 ml of saturated sodium bicarbonate solution and saturated Sodium chloride solution washed and over Dried sodium sulfate. It is concentrated in vacuo. The raw product is about filter a silica gel frit with dichloromethane-methanol 10: 1. Because the watery Phase still contains product it is extracted with dichloromethane and dried over sodium sulfate and concentrated in vacuo. The crude product is carried over a silica gel frit Filtered dichloromethane-methanol 10: 1. In total you get 25.9 g (42% of theory) of product.

LC-MS (Method 3): R _t = 2.40 min. MS (ESIpos): m / z = 194 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.17 (t, 3H), 4.12 (q, 2H), 4.25 (s, 2H), 7.82 (dd, 2H), 8.83 (dd, 2H) ,

Example XXVIII 2-Amino-6- (4-pyridinyl) -4-pyrimidinol

25 g (81.52 mmol) of the compound (from Example XXVII) and 13.22 g (73.37 mmol) guanidinium carbonate are dissolved in 250 ml of ethanol, mixed with 2.5 ml (29.76 mmol) of concentrated hydrochloric acid and overnight backflow touched. After cooling the precipitate is filtered off, washed with ethanol and in High vacuum dried. 250 ml of 1N sodium hydroxide solution are added to the solid and 2 hours under reflux touched. After cooling with concentrated acetic acid acidified, the precipitated product is suctioned off and with diethyl ether rewashed. After drying in a high vacuum, 12.52 is obtained g (82% of theory) of product.

LC-MS (Method 4): R _t = 0.30 min.
MS (ESIpos): m / z = 189 (M + H) ^+
1 H NMR 300 MHz, DMSO-d ₆ ): δ = 6.23 (s, 1H), 6.89 (br.s, 2H), 7.86 (dd, 2H), 8.64 (dd, 2H).

Example XXIX 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine

32 g (170.04 mmol) of the compound (from Example XXVIII) in 87.1 ml (0.93 mmol) of phosphoryl chloride solved. 2.80 ml (22.11 mmol) of N, N-dimethylaniline are slowly added dropwise and one hour at 100 ° C touched. Subsequently becomes the reaction solution stirred for 2 hours at room temperature. The phosphoryl chloride is spun off in vacuo. The residue is mixed with water dichloromethane 9: 1 and boiled for 5 minutes. Then becomes saturated sodium bicarbonate neutralized, the product suctioned off and dried in a high vacuum.

Yield: 18.8 g (48%)
LC-MS (Method 4): R _t = 1.08 min.
MS (ESIpos): m / z = 207 (M + H) ^+
1 H NMR 300 MHz, DMSO-d ₆ ): δ = 7.31 (br.s, 2H), 7.38 (s, 1H), 8.00 (dd, 2H), 8.74 (dd, 2H).

Example XXX 6-chloro-4-nitro-1H-pyrrolo [2,3-b] pyridine

s5.00 g (27.9 mmol) of 4-nitro-1H-pyrrolo [2,3-b] pyridine-7-oxide (from Example XVI) and 11.8 ml (55.8 mmol) of hexamethyldisilazane presented in 290 ml of THF under an argon atmosphere. 10.8 ml (139.6 mmol) of methyl chloroformate are at RT added. The solution is about Stirred overnight at RT. The reaction solution is about a silica gel cartridge is filtered and washed with DCM / methanol 10: 1.

Yield: 2.8 g (70%)
LC-MS (Method 8): R _t = 2.74 min.
MS (ESI pos.): M / z = 198 (M + H) ^+
1 H NMR (DMSO-d ₆ , 200 MHz): δ = 7.00 (mc, 1H), 7.97 (s, 1H), 8.00 (t, 1H), 12.79 (s, 1 H).

Example XXXI {4 - [(6-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] -3-fluorophenyl} amine

4-Amino-2-fluorophenol (0.77 g, 6.07 mmol) is dissolved in DMF. Potassium tert-butoxide (0.68 g, 6.07 mmol) is added and the mixture is stirred for 30 minutes at room temperature. Potassium carbonate (0.35 g, 2.53 mmol) and 1 g (5.06 mmol) of 6-chloro-4-nitro-lH-pyrrolo [2,3-b] pyridine (from Example XXX), which are powdered in succession, are then added. The mixture is stirred at 120 ° C for 12 hours. After cooling down diluted it with ethyl acetate (200 ml). The suspension is filtered off with Celite ^® and washed with ethyl acetate. The solution is shaken out successively with aqueous sodium hydrogen carbonate solution and sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, eluent: DCM: acetone = 5: 1). 0.95 g (67% of theory) of product are obtained.

LC-MS (method 16): R _t = 1.99 min. MS (ESIpos): m / z = 278 (M + H) + s

Example XXXII 4-amino-2,6-difluorophenol

1.00 g (5.71 mmol) of 2,6-difluoro-4-nitrophenol (prepared by nitrating 2,6-difluorophenol according to Kirk, K.L .; J. Heterocycl. Chem. 1976, 13, 1253-1256) are placed in 35 ml of ethanol. you adds 80 mg palladium on carbon (10%) and hydrogenates for 1.5 hours under normal pressure. 2 ml of conc. Dropped in hydrochloric acid. The catalyst is filtered off and the solvent is removed in a vacuum. The residue is suspended with diethyl ether and a little methanol. You suck and washes with and diethyl ether the title compound (Qiu, Jian; Stevenson, Scott H .; O'Beirne, Michael J .; Silverman, Richard B .; J. Med. Chem. 1999, 42 (2), 329-332) as Hydrochloride.

Yield: 939 mg (91%)
LC-MS (method 9): R _t = 0.29 min.
MS (ESI pos.): M / z = 146 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 6.89 (mc, 2H), 4.5-9.0 (br. S, 3H), 10.1 (br. S, 1 H).

Example XXXII {4 - [(6-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] -3,5-difluorophenyl} amine.

664 mg (3.36 mmol) 6-chloro-4-nitro-1H-pyrrolo [2,3-b] pyridine (from Example XXX), 1.39 g (10.1 mmol) of powdered potassium carbonate and 877 mg (5.04 mmol) sodium dithionite are suspended in 10 ml DMSO. The The mixture is degassed and 915 mg (5.04 mmol) of 4-amino-2,6-difluorophenol hydrochloride (from Example XXXII) are added. The mixture is heated for 4 hours 120 ° C. To Add ethyl acetate is about Aspirated Celite and with ethyl acetate rewashed. The filtrate is washed three times with sat. Sodium bicarbonate solution and with sat. Sodium chloride solution shaken. You dry over Sodium sulfate and removes the solvent in a vacuum. The residue is by column chromatography purified (silica gel 60, eluent: DCM: methanol = 50: 1).

Yield: 356 mg (36%)
HPLC (method 7): R _t = 4.12 min.
MS (ESI pos.): M / z = 296 (M + H) ⁺
1H-NMR (DMSO-d ₆ , 400 MHz): δ = 5.84 (s, 2H), 6.28 (mc, 1H), 6.38 - 6.41 (m, 3 H), 7.42 (mc, 1 H), 12.02 (s , 1 H).

Analog Beispiel XIX (Alternativmethode) wird die Titelverbindung durch katalytische Hydrierung von 408 mg (1.38 mmol) {4-[(6-Chlor-1H-pynolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorphenyl}amin (aus Beispiel XXXIII) gewonnen. Example XXXIV [3,5-difluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine

Analogously to Example XIX (alternative method), the title compound is catalytically hydrogenated to 408 mg (1.38 mmol) {4 - [(6-chloro-1H-pynolo [2,3-b] pyridin-4-yl) oxy] -3.5 -difluorophenyl} amine (from Example XXXIII).

Yield: 360 mg (100%)
LC-MS (method 10): R _t = 2.19 min.
MS (ESI pos.): M / z = 262 (M + H) ⁺

Example XXXV 2- (4-Amino-2-chlorophenoxy) -6-fluorobenzonitrile

1.00 g (7.19 mmol) 2,6-difluorobenzonitrile are placed in 10 ml of acetonitrile. 1.99 g (14.4 mmol) are used Potassium carbonate and 1.03 g (7.19 mmol) 3-chloro-4-hydroxyaniline added and heated for 45 min. on reflux. It is filtered and washed with ethyl acetate and DCM after. The solvent is removed in vacuo and the residue by column chromatography (Silica gel 60, gradient column: Eluens: DCM: petroleum ether = 2: 1, then DCM).

Yield: 1.13 g (60%)
HPLC (method 7): R _t = 4.04 min.
MS (DCI): m / z = 280 (M + NH ₄ ) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 5.53 (br. S, 2H), 6.51 (d, 1H), 6.59 '(dd, 1H), 6.76 (d, 1 H), 7.10 ( d, 1H), 7.17 (t, 1H), 7.65 (dt, 1H).

Example XXXVI 4- (4-Amino-2-chlorophenoxy) -1 H -indazol-3-amine

s60 mg (0.23 mmol) 2- (4-amino-2-chlorophenoxy) -6-fluorobenzonitrile (from Example XXXV) with 17 mg (0.34 mmol) hydrazine hydrate in 0.2 ml 1-butanol in a pressure vessel overnight to 120 ° C heated. Then the solvent removed in vacuo, suspended with DCM and suction filtered.

Yield: 47 mg (73%)
HPLC (method 7): R _t = 3.05 min.
MS (ESI pos.): M / z = 275 (M + H) ^+
1 H NMR DMSO-d ₆ , 200 MHz): δ = 5.03 (br. S, 2H), 5.37 (br. S, 2H), 5.78 (d, 1H), 6.5 8 (dd, 1H), 6.74 (d, 1 H), 6. 82 (d, 1 H), 6.96 - 7.05 (m, 2H), 11.52 (br. s, 1 H).

Example XXXVII 3-methyl-1 H-pyrrolo [2,3-b) pyridine-7-oxide

The title compound is analogous to Example XV by oxidation of 11 g (54.1 mmol) of 3-methyl-1H-pyrrolo [2,3-b] pyridine (Hands, D .; Bishop, B .; Cameron, M .; Edwards, T.S .; Cottrell, LF .; Wright, S.H.B .; Synthesis 1996 (7), 877-882) with 24.2 g (108.2 mmol) 3-chloroperbenzoic won.

Yield: 5.4 g (67%)
LC-MS (method 13): R _t = 1.19 min.
MS (ESI pos.): M / z = 149 (M + H) ⁺ DMSO-d ₆ , 300 MHz): δ = 2.25 (m, 3H), 7.05 (m, 1H), 7.21 (s, 1H), 7.59 (m, 1 H), 8.10 (s, 1 H), 12.06 (s, 1 H).

Example VIII 4-Chloro-3-methyl-1 H-pyrrolo [2,3-b] pyridine

1.00 g (6.75 mmol) 3-methyl-1H-pyrrolo [2,3-b] pyridine-7-oxide (from Example XXXVII) are suspended in 5 ml of phosphoryl chloride. Then 2 ml of chloroform are added and the mixture is added overnight backflow heated. You leave cool to RT and pours on ethyl acetate / ice water. Subsequently add solid sodium carbonate. The phases are separated and the watery Phase with ethyl acetate washed. The organic phases are dried over sodium sulfate and constricted. The residue is by column chromatography purified (silica gel 60, eluent: cyclohexane: methanol = 4: 1).

Yield: 200 mg (18%)
LC-MS (method 13): R _t = 2.05 min.
1H-NMR (DMSO-d ₆ , 200 MHz): δ = 2.41 (m, 3H), 7.10 (d, 1H), 7.31 (s, 1H), 8.07 (d, 1 H), 12.44 (s, 1 H) ).

Example XXXIX 4-chloro-3-methyl-1 H-pyrrolo [2,3-b] pyridine-7-oxide

The title compound is analogous to Example XV by oxidation of 898 mg (5.39 mmol) 4-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridine (from Example XXXXVIII) with 2.42 g (10.78 mmol) of 3-chloroperbenzoic acid.

Yield: 688 mg (70%)
LC-MS (method 13): R _t = 1.75 min.
MS (ESI pos.): M / z = 183 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 2.41 (m, 3H), 7.10 (d, 1H), 7.30 (s, 1H), 8.07 (d, 1 H), 12.44 (s, 1 H).

Example XL 1-acetyl-4,6-dichloro-3-methyl-1 H-pyrrolo [2,3-b] pyridine

The title compound is analogous to example XXX from 688 mg (3.77 mmol) of 4-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridine-7-oxide (from Example XXXIX) and 1.78 g (18.84 mmol) methyl chloroformate and 0.61 g (3.77 mmol) of hexamethyldisilazane.

Yield: 420 mg (22%)
LC-MS (method 13): R _t = 2.44 min.
MS (ESI pos.): M / z = 259 (M + H) ^+
1 H NMR DMSO-d ₆ , 200 MHz): δ = 3.99 (s, 3H), 2.40 (m, 3H), 7.61 (s, 1H), 7.77 (d, 1 H).

Example XLI {4 - [(6-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] -3-fluorophenyl} amine

300 mg (1.16 mmol) of 1-acetyl-4,6-dichloro-3-methyl-1H-pyrrolo [2,3-b] pyridine (from Example XL) and 320 mg (2.32 mmol) of powdered potassium carbonate are dissolved in 9 ml of DMSO suspended. The mixture is degassed and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120 ° C. for 4 hours. After the addition of ethyl acetate, the product is filtered off with suction through Celite and washed with ethyl acetate. The filtrate is washed three times with sat. Sodium bicarbonate solution and with sat. Shaken sodium chloride solution. It is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by column chromatography (Kiese1gel 60, eluent: DCM: methanol = 50: 1).
Yield: 142 mg (42%)
LC-MS (method 13): R _t = 2.32 min.
MS (ESI pos.): M / z = 292 (M + H) ⁺ example XLII {3-fluoro-4 - [(3-methyl-1 H-pyrrolo [2,3-b] pyridin-4-yl) oxy] phenyl} amine

Analogous to example XIX (alternative method) the title compound by catalytic hydrogenation of 142 mg (0.49 mmol) {4 - [(6-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] -3-fluorophenyl} amine (from example XLI) won.

Yield: 125 mg (100%)
LC-MS (method 13): R _t = 1.58 min.
The following is produced analogously to example XLVII:

Example XLIV N- [3-fluoro-4 - ({1 - [(4-methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl} oxy) phenyl] -4-methylphenylsulfonamide

147 mg (0.60 mmol) of the compound from Example XIX are dissolved in 10 ml of THF, with 48 mg (1.21 mmol) of sodium hydride (in THF) and then stirred at RT for one hour. Then 242 mg (1.27 mmol) of p-toluenesulfonic acid chloride are added and the reaction solution for one Hour at 60 ° C further stirred. The suspension is over Celite filtered and washed with THF and a little DCM / methanol 10: 1 and rotated in. The piston residue is taken up in DMSO and by means of RP-HPLC chromatography (Gradient: acetonitrile / water).

Yield: 94 mg (28%)
LC-MS (method 15): R _t = 2.72 min.
¹ H-NMR DMSO-d ₆ , 300 MHz): δ = 2.35 (s, 3H), 2.37 (s, 3H), 6.49-6.52 (m, 2H), 6.95 (m, 1H), 7.10 (m, 1 H), 7.31 (t, 1 H), 7.41 (m, 4H), 7.69 (m, 2H), 7.79 (d, 1 H), 7.98 (d, 2H), 8.19 (d, 1H), 10.55 ( s, 1H).

Example XLV N- [3-fluoro-4 - ({1 - [(4-methylphenyl) sulfonyl] -2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl} oxy) phenyl] -4-methylphenylsulfonamide

50 mg (0.09 mmol) N- [3-fluoro-4 - ({1 - [(4-methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl} oxy) phenyl] -4 -methylphenylsulfonamid (from example XLIV) are dissolved in 30 ml of methanol and 48.2 mg (0.05 mmol) of 10% Palladium on activated carbon added. The mixture is left overnight Hydrogenated under 3.5 bar hydrogen pressure. The palladium is then over diatomaceous earth suction filtered, washed with ethanol and the filtrate concentrated.

Yield: 48 mg (95%)
LC-MS (method 9): R _t = 3.35 min.

Example XLVI [4- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yloxy) -3-fluorophenyl] amine

50 mg (0.09 mmol) N- [3-fluoro-4 - ({1 - [(4-methylphenyl) sulfonyl] -2,3-dihydro-1Hpyrrolo [2,3-b] pyridin-4-yl} oxy) phenyl] -4-methylphenylsulfonamide (from example XLV) are in 1.00 ml of sulfuric acid (95%) solved and over Stirred at RT overnight. The reaction solution is under ice cooling neutralized with 20% sodium hydroxide solution and three times with ethyl acetate extracted. The organic phase is over anhydrous magnesium sulfate dried and concentrated.

Yield: 20 mg (91%)
LC-MS (Method 8): R _t = 2.22 min.

Example XLVII 4 - [(2-amino-6-chloropyrimidin-4-yl) amino] benzonitrile

300 mg (1.83 mmol) of 2-amino-4,6-dichloropyrimidine and 216 mg (1.83 mmol) 4-aminobenzonitrile are suspended in 6 ml of water. Add 180 μl concentrated hydrochloric acid and leave over Night at 100 ° C stir. The precipitate is suctioned off.

Yield: 450 mg (96%)
LC-MS (method 9): R _t = 2.39 min.
MS (ESI pos.): M / z = 246 (M + H) ⁺
1H-NMR (DMSO-d ₆ , 200 MHz): δ = 4.98 (m, 2H), 6.14 (s, 1H), 7.69 - 7.99 (m, 4H), 9.99 (s, 1H).

Analog to example XLVII, the following are produced:

Example LII 4- (4-Amino-2-chlorophenoxy) -2-fluorobenzonitrile

2.00 g (14.4 mmol) of 2,4-difluorobenzonitrile, 2.06 g (14.4 mmol) of 3-chloro-4-hydroxyaniline and 3.97 g (28.8 mmol) of potassium carbonate are heated to RF in 20 ml of acetonitrile for one hour. Ethyl acetate is added; filtered and the solvent removed in vacuo. The mixture is purified by column chromatography (silica gel 60) and the product obtained, which is a regioisomer mixture in a ratio of 62:38.
Yield: 2.55 g (68%)
HPLC (method 7): R _t = 3.90 min (main isomer), 4.01 min (minor isomer).
MS (ESI pos.): M / z = 263 (M + H) ⁺

Example LIII 6- (4-Amino-2-chlorophenoxy) -1-methyl-1H-indazol-3-amine

1.00 g (3.81 mmol) of 4- (4-amino-2-chlorophenoxy) -2-fluorobenzonitrile (contaminated with its regioisomer; from Example LII) with 1.05 g (22.8 mmol) of methylhydrazine in 4 ml of 1-butanol for 5 hours RF heated. You remove volatile ones Components in a vacuum and cleans the residue by preparative HPLC.

Yield: 496 mg (45%)
HPLC (method 7): R _t = 3.26 min.
MS (ESI pos.): M / z = 289 (M + H) ^+
1 H NMR DMSO-d ₆ , 200 MHz): δ = 3.57 (s, 3H), 5.33 (s, 2H), 5.37 (s, 2H), 6.47 - 6.59 (m, 3H), 6.72 (d, 1H ), 6.91 (d, 1H), 7.58 (m, 1H).

Example LIV 6- (4-amino-2-chlorophenoxy) -1H-indazol-3-amine

The title link becomes analogous to Example LIII from 2.3 g (8.76 mmol) of 4- (4-amino-2-chlorophenoxy) -2-fluorobenzonitrile (from Example LII) and hydrazine hydrate synthesized.

Yield: 750 mg (31%)
HPLC (method 7): R _t = 3.24 min.
MS (ESI pos.): M / z = 275 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 5.29 (br. S, 2H), 5.35 (br. S, 2H), 6.30 (d, 1H), 6.53 - 6.62 (m, 2H), 6.73 (d, 1H), 6.94 (d, 1H), 7.59 (d, 1H), 11.06 (s, 1H).

Example LV 3- (2-amino-6-oxo-i, 6-dihydropyrimidin-4-yl) benzonitrile

12.0 g (49.8 mmol) of 3- (3-cyanophenyl) -3-oxopropanoic acid, ethyl ester (Fevig, John M. et al .; Bioorg.Med.Chem.Lett. 2001, 11 (5), 641-646) dissolved in 110 ml of ethanol. You add 5.39 g (29.9 mmol) guanidinium carbonate and 0.95 ml conc. Hydrochloric acid and over heated Night on RF. Allow to cool, suck the precipitated crystals and wash off with ethanol. you receives the title link.

Yield: 8.02 g (76%)
HPLC (method 7): R _t = 2.99 min.
MS (ESI pos.): M / z = 213 (M + H) ⁺
1H NMR DMSO-d ₆ , 200 MHz): δ = 6.27 (s, 1H), 6.71 (br. S, 2H), 7.65 (t, 1H), 7.91 (d, 1H), 8.28 (d, 1 H), 8.39 (s, 1H), 10.96 (s, 1H).

Example LVI 3- (2-amino-6-chloropyrimidin-4-yl) benzonitrile

2.00 g (9.42 mmol) 3- (2-amino-6-oxo-l, 6-dihydropyrimidin-4-yl) benzonitrile (from Example LV) are suspended in 10 ml of phosphoryl chloride. 180 mg (1.23 mmol) of N, N-diethylaniline are added dropwise within one Hour and heats to 115 ° C within a further hour. Then it will be for one Heated to RF for one hour. You let go Cool RT and pours on ice water. It is extracted twice with ethyl acetate and removed the solvent in a vacuum. The residue is suspended in water. The solution is neutralized under ice cooling by adding conc. Sodium hydroxide solution. Saturated sodium carbonate solution is added and stir overnight at RT. The precipitate is filtered off and washed with water. The title compound is obtained.

Yield: 1.58 g (73%)
LC-MS (method 9): R _t = 2.54 min.
MS (ESI pos.): M / z = 231 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 7.27 (br. S, 2H), 7.41 (s, 1H), 7.73 (t, 1H), 8.00 (dt, 1 H), 8.42 (dt, 1 H), 8.5 3 (t, 1 H).

Beispiel LXIX Ethyl-(2-amino-6-chlorpyrimidin-4-yl)acetat

Analogously to example LVI, the following are produced:

Example LXIX ethyl (2-amino-6-chloropyrimidin-4-yl) acetate

The title link becomes analogous to Example LVI synthesized in two stages from 3-diethyl-3-oxopentanedioate.

Yield: 394 mg (32%)
LC-MS (method 10): R _t = 2.62 min.
MS (ESI: pos.): M / z = 216 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.18 (t, 3H), 3.60 (s, 2H), 4.09 (q, 2H), 6.65 (s, 1H), 7.11 (s, 2H) ,

Example LXX 4- (2-amino-6-chloropyrimidin-4-yl) butyric acid

The title link becomes analogous to Example LVI synthesized in two stages from 3-oxoheptanedioate. Doing so during the second reaction stage of the esters hydrolyzed to carboxylic acid.

Yield: 394 mg (32%)
LC-MS (method 12): R _t = 2.46 min.
MS (ESI pos.): M / z = 216 (M + H) ^+
1 H-NMR DMSO-d ₆ , 400 MHz): δ = 1.83 (tt, 2H), 2.23 (t, 2H), 2.50 (t, 2H), 6.65 (s, 1 H), 7.02 (s, 2H) , August 12 (br. S, 1 H).

Example LXXI Benzyl-3- (2-amino-6-hydroxypyrimidin-4-yl) piperidine-1-carboxylate

2 g (7.59 mmol) piperidine-l, 3-dicarboxylic acid l-benzyl ester, 1.31 g (9.11 mmol) of 2,2-dimethyl-1,3-dioxolane-4,6-dione and 1.85 g (15.19 mmol) of 4-dimethylaminopyridine are dissolved in 12 ml of dichloromethane submitted and at 0 ° C cooled. 1.60 g (8.35 mmol) of (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride are added. It is 1 hour at 0 ° C and then stirred for 18 hours at room temperature. The reaction mixture is diluted with dichloromethane (50 ml), successively with water (20 ml), 1N hydrochloric acid (30 ml), saturated aqueous sodium bicarbonate (30 ml) and more saturated aqueous Sodium chloride solution washed. The organic phase is over anhydrous magnesium sulfate dried. The solution will be concentrated in vacuo. The residue (1.2 g) is dissolved in 30 ml of ethanol and with 0.13 ml (0.61 mmol) of 37% hydrochloric acid spiked and refluxed for an hour touched. After cooling 0.59 g (3.18 mmol) guanidinium carbonate are added, and that The reaction mixture is stirred at reflux (oil bath temperature 93 ° C.) for 18 hours. The solution is restricted. The crude product is over a silica gel column with dichloromethane-methanol 20: 1 cleaned. You get 0.68 g (27% of theory) of product.

HPLC (method 7): R _t = 3.77 min.
MS (ESIpos): m / z = 329 (M + H) ^+
1 H-NMR 200 MHz, DMSO-d ₆ ): δ = 1.29 (m, 2H), 1.76 (dd, 2H), 2.29 (m, 1H), 2.79 (m, 2H), 4.03 (m, 2H), 5.07 (s, 2H), 5.42 (s, 1H), 6.49 (s, 2H), 7.35 (m, 5H), 10.65 (s, 1H).

Example LXXII Benzyl-3- (2-amino-6-chloropyrimidin-4-yl) piperidine-1-carboxylate

4.14 g (12.60 mmol) benzyl-3 = (2-amino-6-hydroxypyrimidin-4-yl) piperidine carboxylate (from Example LXXI) are suspended in 150 ml of acetonitrile. To 3.29 ml (18.91 mmol) of N, N-diisopropylethylamine are successively and 0.57 g (2.52 mmol) of benzyltriethylammonium chloride. The The mixture is cooled to 0 ° C. 4.7 ml (50.43 mmol) of phosphoryl chloride are then slow at 0 ° C dropwise. The mixture is stirred at room temperature for 18 hours. to The reaction solution is worked up to 0 ° C chilled and carefully dropped onto ice water (150 ml). The aqueous suspension is neutralized with a 45% sodium hydroxide solution and three times extracted with ethyl acetate (70 ml each). The organic phase is about dried anhydrous magnesium sulfate and concentrated. The residue is about a column of silica cleaned with dichloromethane-methanol 30: 1. You get 2.80 g (64% of theory) of product.

HPLC (method 7): R _t = 4.30 min. MS (ESIpos): m / z = 347 (M + H) ^{+ 1} H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.44 (m, 1H), 1.67 (m, 2H), 1.92 (m, 1H), 2.57 (m, 1H), 2.91 (m, 2H), 4.04 (dd, 2H), 5.09 (m, 2H), 6.61 (s, 1H), 7.02 (s, 2H), 7.35 (m , 5H).

Example LXXIII ethyl (2-amino-6-chloropyrimidin-4-yl) acetate

The title link becomes analogous to Example LXXI synthesized in two stages from cyclohexane carboxylic acid.

Yield: 100 mg (44%)
LC-MS (method 16): R _t = 2.27 min.
MS (ESI pos.): M / z = 212 (M + H) ^+
1 H-NMR DMSO-d ₆ , 200 MHz): δ = 1.35 (m, 5H), 1.75 (m, 5H), 2.40 (m, 1H), 6.54 (s, 1 H), 6.97 (s, 2H) ,

Example LXXIV Benzyl-3- (2-amino-6- {[3-fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) piperidine-l-carboxylate

1.05 g (2.89 mmol) benzyl-3- (2-amino-6-chloropyrimidin-4-yl) piperidine-l-carboxylate (from example LXXII) and 0.75 g (2.89 mmol) [3-fluoro-4- (1H- pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XIX) are suspended in 35 ml of water and 4 ml of ethanol. 0.29 ml (3.47 mmol) of 37% hydrochloric acid are added. The mixture is stirred at 100 ° C for 18 hours. After cooling, it is neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate (30 ml each). The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified over a silica gel column with dichloromethane = methanol 20: 1. 1.38 g (86% of theory) of product are obtained.
HPLC (method 7): R _t = 4.23 min. MS (ESIpos): m / z = 554 (M + H) ^+
1 H-NMR 200 MHz, DMSO-d ₆ ): δ = 1.55 (m, 2H), 1.67 (m, 2H), 1.84 (m, 2H), 2.54 (m, 1 H), 2.85 (m, 2H) , 4.10 (dd, 2H), 5.09 (s, 2H), 5.92 (s, 1 H), 6.25 (dd, 1 H), 6.3 5 (m, 3H), 7.27 (t, 1H), 7.36 (m, 7H), 8.06 (d, 1H), 8.21 (dd, 1H), 9.42 (s, 1H), 11.08 (s, 1H).

Beispiel LXXVIII (2-Amino-6-chlorpyrimidin-4-yl)methanol

The following are produced analogously to example LXXIV:

Example LXXVIII (2-amino-6-chloropyrimidin-4-yl) methanol

10.5 g (55.97 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (manufactured according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and CC Cheng, J. Org. Chem., 26 (1961), 2755-2763) are placed in 450 ml of ethanol. 21.17 g (559.74 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 2 hours. 500 ml of ethyl acetate and 500 ml of water are added and the solution is stirred for 30 minutes. The phases are separated and the aqueous phase is extracted three times with ethyl acetate (100 ml each). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated. 7.21 g (85% of theory) of product are obtained.

LC-MS (method 13): R _t = 0.58 min. MS (ESIpos): m / z = 160 (M + H) ^+
1 H-NMR 200 MHz, DMSO-d ₆ ): δ = 4.31 (d, 2H), 5.49 (t, 1H), 6.66 (s, 1H), 7.05 (s, 2H).

Example LXXIX 4- (bromomethyl) -6-chloropyrimidin-2-amine and 4- (bromomethyl) -6-bromopyrimidin-2-amine

0.55 g (3.49 mmol) (2-amino-6-chloropyrimidin-4-yl) methanol (from example LXXVIII) are placed in 11 ml of THF. To do this 0.73 ml (7.67 mmol) of phosphorus tribromide are added and the mixture is Stirred for 3 hours at room temperature. 20 ml of ethyl acetate and 20 ml of ice water are added and the solution Stirred for 30 minutes. The phases are separated and the aqueous phase - is three times extracted with ethyl acetate (10 ml each). The united organic Phases become more saturated aqueous Sodium bicarbonate and sodium chloride solution washed with anhydrous Magnesium sulfate dried and concentrated. You get 0.55 g (62% of theory) of a mixture of A and B (8: 1).

LC-MS (method 14): R _t = 1.74 min and 1.83 min.
MS (ESIpos): m / z = 224 and 268 (M + H) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 4.34 (d, 0.7 H), 4.37 (d, 1.3 H), 6.81 (s, 0.7 H), 6.94 (s, 0.3 H), 7.28 ( s, 2H).

Example LXXX 4 - [(tert-Butylamino) methyl] -6-chloropyrimidin-2-amine and 4 - [(tert-butylamino) methyl] -6-bromopyrimidin-2-amine

0.1 g (0.45 mmol) of the mixture 4- (bromomethyl) -6-chloropyrimidin-2-amine and 4- (bromomethyl) -6-bromopyrimidin-2-amine (from example LXXIX) are placed in 1 ml of dimethylformamide. 0.07 ml (0.67 mmol) of tert-butylamine are added and the mixture is stirred for 2 hours at room temperature. The solution is analyzed using RP-HPLC chromatography (Gradient: acetonitrile / water). You get 0.063 g (65%) product.

LC-MS (method 14): R _t = 0.46 min.

Analog zu Beispiel LXXIV wird hergestellt:

Herstellungsbeispiele: Beispiel 1 N-[2-Amino-6-(4-pyridinyl)-4-pyrimidinyl]-N- { 3-fluor-4-[(3-methyl-1H-indazol-4-yl)oxy]phenyl } amin

MS (ESIpos): m / z = 215 and 259 (M + H) ⁺ Analog to example LXXX are produced:

The following is produced analogously to example LXXIV:

Preparation examples: Example 1 N- [2-amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- {3-fluoro-4 - [(3-methyl-1H-indazol-4-yl) oxy] phenyl } amine

60 mg (0.23 mmol) 3-fluoro-4 - [(3-methyl-1H-indazol-4-yl) oxy] phenylamine (from Example III) are mixed with 48 mg (0.23 mmol) 4-chloro-6- (4th -pyridinyl) -2-pyrimidinamine (from Example XXIX) suspended in 4 ml of water and mixed with 0.02 ml of concentrated hydrochloric acid. The reaction mixture is heated to reflux overnight, whereupon a brown precipitate forms. This is filtered off, washed several times with water and dried in a high vacuum. 65 mg (65% of theory) of the product are obtained as a brown solid.
LC-MS (Method 2): R _t = 2.9 min.
MS (ESI pos.): M / z = 428 (M + H) ⁺
+ H NMR DMSO-d ₆ , 300 MHz): δ = 2.56 (s, 3H), 6.27 (d, 1H), 6.79 (s, 1H), 7.18 (m, 3H), 7.47 (d, 1H), 7.89 (d, 2H), 8.22 (d, 1H), 8.86 (d, 2H), 10.88 (s, 1H), 12.75 (s, 1H).

Example 2 N- {4 - [(3-amino-1,2-benzisoxazol-4-yl) oxy] -3-fluorophenyl} -N- [2-amino-6- (4-pyridinyl) -4-pyrimidinyl] amine

70 mg (0.27 mmol) 4- (4-amino-2-fluorophenoxy) -1,2-benzisoxazol-3-amine (from Example VII) with 55.8 mg (0.27 mmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) suspended in 4 ml of water and concentrated with 0.02 ml hydrochloric acid added. The reaction mixture becomes reflux overnight heated, forming a light precipitate. This will filtered off, washed several times with water and dried under high vacuum.

Yield: 60 mg (52% of theory)
LC-MS (Method 6): R _t = 2.7 min.
MS (ESI pos.): M / z = 429 (M + H) ^+
1 H NMR DMSO-d ₆ , 300 MHz): δ = 5.28 (m, 4 H), 6.33 (d, 1H), 6.97 (s, 1H), 7.14 (d, 1H), 7.43 (m, 2H) , 7.58 (d, 1H), 8.02 (d, 2H), 8.28 (d, 1H), 8.93 (d, 2H), 11.43 (s, 1H).

Example 3 N- {4 - [(3-amino-1,2-benzisoxazol-4-yl) oxy] -3-fluorophenyl} -N- (2-amino-6-chloro-4-pyrimidinyl) amine

100 mg (0.39 mmol) 4- (4-amino-2-fluorophenoxy) -1,2-benzisoxazol-3-amine (from Example VII) with 63.3 mg (0.39 mmol) of 2-amino-4,6-dichloropyrimidine suspended in 3 ml of water and mixed with 0.04 ml of concentrated hydrochloric acid. The reaction mixture is over Night to reflux heated, forming a colorless precipitate. This will filtered off, washed several times with water and dried under high vacuum.

Yield: 100 mg (67% of 7h.)
LC-MS (Method 8): R _t = 3.38 min.
MS (ESI pos.): M / z = 387 (M + H) ⁺ Example 4 4 - [(4aR, 7aR) -octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -6- ({4 - [(3-amino-l, 2-benzisoxazole-4- yl) oxy] -3-fluorophenyl} amino) -2-pyrimidinylamine

88 mg (0.23 mmol) of N- {4 - [(3-amino-1,2-benzisoxazol-4-yl) oxy] -3-fluorophenyl} -N (2-amino-6-chloro-4-pyrimidinyl) amine (from Example 3) and 114.8 mg (0.91 mmol) of [(4aR, 7aR) -octahydro-6H-pyrrolo [3,4-b] pyridine are dissolved in 4 m12-ethylhexanol with 294.1 mg (2.28 mmol) of diisopropylethylamine and 3 h stirred at 150 ° C. After cooling, the reaction mixture is filtered and water is added. It is extracted several times with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The residue is purified by means of preparative HPLC.
Yield: 15 mg (14% of theory)
LC-MS (Method 8): R _t = 2.2 min.
MS (ESI pos.): M / z = 477 (M + H) ⁺ Example 5 N- [2-amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- [3-fluoro-4- ( 1 H-indazol-5-yloxy) phenyl] amine

600 mg (2.47 mmol) of 5- (4-amino-2-fluorophenoxy) -1H-indazole (from Example XII are suspended in 100 ml of water. 510 mg (2.47 mmol) of 4-chloro-6- (4- pyridinyl) -2-pyrimidinamine (from Example XXIX) and 0.25 ml of concentrated aqueous hydrogen chloride solution and the mixture is stirred overnight at 100 ° C. For working up, the reaction solution was made alkaline with saturated sodium bicarbonate solution and extracted 3 times with ethyl acetate, which contained the resulting precipitate The organic phase is dried with sodium sulfate and concentrated on a rotary evaporator, the residue is combined with the precipitate and purified by means of preparative HPLC.
Yield: 631 mg (62% of theory)
MS (ESI pos.): M / z = 414 (M + H) ^+
1 H NMR DMSO-d ₆ , 200 MHz): δ = 6.56 (s, 1H), 6.63 (s, 2H), 7.06 - 7.19 (m, 3H), 7.33 (d, 1 H), 7.53 (d, 1 H), 7.84 (dd, 2H), 7.97 (s, 1 H), 8.22 (dd, 1 H), 8.72 (dd, 2H), 9.60 (s, 1 H), 13.03 -13.12 (br. S, 1 H).

Beispiel 8 N-[2-Amino-6-chlor-4-pyrimidinyl]-N-[3-fluor-4-(1 H-indazol-5-yloxy)phenyl]amin

The following are prepared analogously to Example 5:

Example 8 N- [2-Amino-6-chloro-4-pyrimidinyl] -N- [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amine

1.65 g (6.78 mmol) 5- (4-amino-2-fluorophenoxy) -1H-indazole (from Example XII) are suspended in 90 ml of water. There are 1.11 g (6.78 mmol) of 4,6-dichloro-2-pyrimidinamine and 0.68 ml were concentrated aqueous hydrogen chloride solution and leaves overnight at 100 ° C stir. For working up, the reaction solution is saturated Sodium bicarbonate solution made alkaline and extracted 3 times with ethyl acetate. The organic Phase is dried with sodium sulfate and on a rotary evaporator concentrated.

Beispiel 11 6-[(4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-N4-[3-fluor-4-(1 H-indazol-5-yloxy)phenyl]-2,4-pyrimidindiamin

Yield: 2.88 g (quantitative)
LC-MS (Method 8): R _t = 3.21 min.
MS (ESI pos.): M / z = 371 (M + H) ⁺ Analogously to Example 8, the following are produced:

Example 11 6 - [(4aR, 7aR) -octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -N4- [3-fluoro-4- (1H-indazol-5-yloxy) phenyl ] -2,4-pyrimidinediamine

127 mg (340 μmol) of N- [2-amino-6-chloro-4-pyrimidinyl] -N- [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amine (from Example 8) are described in 10 ml of 2-ethylhexanol suspended. 173 mg (1.37 mmol) of [(4aR, 7aR) -octahydro-6H-pynolo [3,4-b] pyridine and 0.60 ml (3.43 mmol) of diisopropylethylamine are then added and the mixture is stirred at 150 ° C. overnight. The reaction solution is concentrated by means of MPLC with dichloromethane / methanol aqueous ammonia solution 20: 1: 0 → 10: 1: 0 -i 5: 1: 0 → 3: 1: 0.1 chromatographed.
Yield: 147 mg (93%)
LC-MS (method 5): R _t = 3.12 min.
MS (ESI pos.): M / z = 461 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.17-1.30 (m, 1H), 1.60-1.85 (m, 4H), 2.54-2.70 (m, 1H), 2.80-2.97 (m, 1H ), 3.05-3.63 (several m, partially overlaid with H ₂ O peak, total 4 H), 3.65-3.80 (m, 1H), 5.12 (s, 1H), 5.98 (s, 2H), 6.92-7.26 ( m, 4H), 7.52 (d, 1 H), 7.93 (s, 1 H), 8.11 (dd, 1 H), 8.94 (s, 1 H), 13.05 (s, 1 H).

Beispiel 18 N-(2-Amino-6-phenyl-4-pyrimidinyl)-N-[3-fluor-4-(1 H-indazol-5-yloxy)phenyl]amin

The following are prepared analogously to Example 11:

Example 18 N- (2-Amino-6-phenyl-4-pyrimidinyl) -N- [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amine

50 mg (130 μmol) N- [2-amino-6-chloro-4-pyrimidinyl] -N- [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amine (from Example 8) are suspended in 3 ml of toluene / ethanol (2: 1) and 4.68 mg of tetrakis (triphenylphosphine) palladium (0) were added. To Add 19.7 mg (160 μmol) phenylboronic and 0.50 ml of 2M aqueous sodium carbonate solution is stirred at 100 ° C. overnight. The Mixture is evaporated to dryness on a rotary evaporator and by means of preparative HPLC cleaned.

Yield: 10 mg (17% of theory)
LC-MS (method 9): R _t = 3.55 min.
MS (ESI pos.): M / z = 413 (M + H) ⁺ Example 19 N- [2-amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- [3-fluoro-4- ( 1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine

55.6 mg (230 μmol) 3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline (from Example XIX) are suspended in 5 ml of water. 47.2 mg (230 μmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Bei game XXIX) and 0.01 ml concentrated hydrochloric acid and allowed to stir overnight at 100 ° C. For working up, the reaction solution is made alkaline with saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried over sodium sulfate and concentrated on a rotary evaporator. The residue is purified by preparative HPLC
Yield: 6.5 mg (6.0% of theory)
LC-MS (Method 6): Rf = 2.52 min.
MS (ESI pos.): M / z = 207 (M + H) ²⁺
MS (ESI neg.): M / z = 412 (MH) ^- Example 20 N- [2-amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- [2-fluoro-4- (1 H -pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine

11 mg (50 μmol) of 2-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline (from Example XX) are suspended in 5 ml of water. 9.3 mg (50 μmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) and 0.01 ml of concentrated hydrochloric acid are added and the mixture is stirred at 100 ° C. overnight. For working up, the reaction solution is made alkaline with saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried over sodium sulfate and concentrated on a rotary evaporator.
Yield: 20 mg (98% of theory)
LC-MS (Method 6): R _t = 2.47 min.
MS (ESI pos.): M / z = 414 (M + H) ⁺ , 207 (M + H) ²⁺
MS (ESI neg.): M / z = 412 (MH) -
¹ H NMR DMSO-d ₆ , 400 MHz): δ = 6.25 (d, 1H), 6.45 (s, 1H), 6.52 (d, 1H), 6.76 (s, 2H), 7.00 (d, 1 H) , 7.23 (dd, 1 H), 7.3 8 (s, 1 H), 7.80 - 7.89 (m, 2H), 8.14 (d, 1 H), 8.25 (t, 1H), 8.62 - 8.77 (m, 2H) , 9.06 (s, 1H), 11.88 - 12.08 (br. S, 1H).

Example 21 N- [2-Amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- [4- (1-benzofuran-4-yloxy) -3-fluorophenyl] amine

32 mg (0.13 mmol) of 4- (1-benzofuran-4-yloxy) -3-fluorophenylamine (from Example XXIII) with 28.5 mg (0.14 mmol)) 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) suspended in 1.5 ml of water and concentrated with 19 μl hydrochloric acid added. The reaction mixture becomes reflux overnight heated, forming a brown precipitate. The suspension comes with 1N sodium hydroxide solution adjusted to pH 10. The precipitate is filtered off and the filtrate discarded. The crude product is purified using preparative HPLC.

Yield: 43 mg (79% of theory)
LC-MS (Method 2): R _t = 3.2 min.
MS (ESI pos.): M / z = 414 (M + H) +
¹ H NMR (DMSO-d ₆ , 200 MHz): δ = 6.67 (s, 2H), 6.88 (s, 1H), 7.32 (m, 4H), 7.86 (m, 2H), 8.00 (d, 1H ), 8.28 (dd, 1H), 8.84 (d, 2H), 10.46 (s, 1H).

Example 22 N- [2-Amino-6- (4-pyridinyl) -4-pyrimidinyl] -N- [3-fluoro-4- (1H-indazol-4-yloxy) phenyl] amine

45 mg (0.19 mmol) 3-fluoro-4- (1H-indazol-4-yloxy) aniline (from Example XXVI) with 40.1 mg (0.19 mmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) suspended in 2 ml of water and concentrated with 27 ul hydrochloric acid added. The reaction mixture becomes reflux overnight heated, forming a brown precipitate. The suspension with 1N sodium hydroxide solution pH 10 adjusted. The precipitation is from the aqueous Phase filtered off and the filtrate discarded. The raw product is cleaned by HPLC.

Yield: 20 mg (26% of theory)
LC-MS (Method 2): R _t = 2.9 min.
MS (ESI pos.): M / z = 414 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 6.34 (dd, 1H), 6.64 (s, 2H), 6.60 (s 1H), 7.28 (m, 4H), 7.85 (d, 2H), 7.96 (s, 1H), 8.26 (dd, 1H), 8.70 (d, 2H), 9.67 (s, 1H), 13.2 (s, 1H).

Example 23 N ⁴ - {3-Fluoro-4 - [(3-methyl-1 H-pyrrolo [2,3-b] pyridin-4-yl) oxy] phenyl} -6-pyridin-4-ylpyrimidin-2, 4-diamine

s10 mg (0.04 mmol) {3-fluoro-4 - [(3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] phenyl} amine (from Example XLII) and 8.40 mg (0.04 mmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) are suspended in 1.5 ml of water 5.6μl concentrated hydrochloric acid and leaves overnight at 100 ° C stir. For working up, the reaction solution is saturated sodium made alkaline, extracted three times with ethyl acetate, over sodium sulfate dried and concentrated on a rotary evaporator. The residue is done by means of preparative HPLC cleaned.

Yield: 3.30 mg (20% of theory)
LC-MS (method 9): R _t = 1.97 min.

Example 24 N ⁴ - {3-Fluoro-4 - [(3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] phenyl} -6- (4-fluorophenyl) pyrimidin-2, 4-diamine

180 mg (0.70 mmol) {3-fluoro-4 - [(3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) oxy] phenyl} amine (from Example XLII) and 191 mg (0.73 mmol) 4-chloro-6- (4-fluorophenyl) pyrimidin-2-amine (from Example LIX) are suspended in 10 ml of water. There are one 101 μl concentrated hydrochloric acid and leaves overnight at 100 ° C stir. For working up, the reaction solution is saturated sodium made alkaline, extracted three times with ethyl acetate, over sodium sulfate dried and concentrated on a rotary evaporator. The residue is done by means of preparative HPLC cleaned.

Yield: 70 mg (23% of theory)
LC-MS (method 17): R _t = 1.73 min.
MS (ESI pos.): M / z = 445 (M + H) ⁺

36 mg (0.15 mmol) 3-Fluor-4-(1H-pynolo[2,3-b]pyridin-4-yloxy)anilin (aus Beispiel XIX) und 38.5 mg (0.15 mmol) 4-Chlor-6-(4-fluorphenyl)pyrimidin-2-amin (aus Beispiel LIX) werden in 1.5 ml Wasser suspendiert und mit 0.1 ml 2 molarer Salzsäure versetzt. Man erhitzt über Nacht unter Rückfluss. Dann wird mit Essigsäureethylester und einigen Tropfen Dimethylformamid versetzt. Man stellt mit gesättigter Natriumcarbonatlösung alkalisch, trennt die organische Phase ab und entfernt das Lösungsmittel im Vakuum. Man reinigt mittels präparativer HPLC.
Ausbeute: 28 mg (40% d. Th.)
LC-MS (Methode 10): R_t = 2.22 min. MS (ESI pos.): m/z = 431 (M+H)^+
1H-NMR (DMSO-d₆, 400 MHz): δ = 6.27 (d, 1H), 6.37 (d, 1H), 6.50 (s, 1H), 6.52 (s, 2H), 7.27 – 7.43 (m, 5H), 8.00 (dd, 2H), 8.07 (d, 1H), 8.28 (dd, 1H), 9.58 (s, 1H), 11.75 (s, 1H).Example 25 6- (4-Fluorophenyl) -N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine

36 mg (0.15 mmol) 3-fluoro-4- (1H-pynolo [2,3-b] pyridin-4-yloxy) aniline (from Example XIX) and 38.5 mg (0.15 mmol) 4-chloro-6- (4th -fluorophenyl) pyrimidin-2-amine (from Example LIX) are suspended in 1.5 ml of water and mixed with 0.1 ml of 2 molar hydrochloric acid. The mixture is heated under reflux overnight. Then ethyl acetate and a few drops of dimethylformamide are added. It is made alkaline with saturated sodium carbonate solution, the organic phase is separated off and the solvent is removed in vacuo. It is cleaned by means of preparative HPLC.
Yield: 28 mg (40% of theory)
LC-MS (Method 10): R _t = 2.22 min. MS (ESI pos.): M / z = 431 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 6.27 (d, 1H), 6.37 (d, 1H), 6.50 (s, 1H), 6.52 (s, 2H), 7.27 - 7.43 (m, 5H), 8.00 (dd, 2H), 8.07 (d, 1H), 8.28 (dd, 1H), 9.58 (s, 1H), 11.75 (s, 1H).

Analog zu Beispiel 25 wird die Titelverbindung aus 100 mg (0.36 mmol) [3,5-Difluor-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amin (aus Beispiel HIV) und 110 mg (0.36 mmol) 4-Chlor-6-(4-fluorphenyl)pyrimidin-2-amin (aus Beispiel LIX) synthetisiert. Nach Reinigung mittels präparativer HPLC erhält man das Produkt.
Ausbeute: 17 mg (10% d. Th.)
LC-MS (Methode 10): R_t = 2.32 min.
MS (ESI pos.): m/z = 449 (M+H)^+
1H-NMR (DMSO-d₆, 400 MHz): δ = 6.31 (dd, 1H), 6.43 (d, 1H), 6.48 (s, 1H), 6.63 (br. s, 2H), 7.33 (t, 2H), 7.41 (dd, 1 H), 7.83 (d, 2H), 8.01 (dd, 2H), 8.09 (d, 1 H), 9.72 (s, 1 H), 11.82 (s, 1 H). Example 26 N ⁴ - [3,5-difluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6- (4-fluorophenyl) pyrimidine-2,4-diamine

Analogously to Example 25, the title compound is made from 100 mg (0.36 mmol) of [3,5-difluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example HIV) and 110 mg (0.36 mmol) 4-chloro-6- (4-fluorophenyl) pyrimidin-2-amine (from Example LIX) synthesized. After cleaning by means of preparative HPLC, the product is obtained.
Yield: 17 mg (10% of theory)
LC-MS (method 10): R _t = 2.32 min.
MS (ESI pos.): M / z = 449 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 6.31 (dd, 1H), 6.43 (d, 1H), 6.48 (s, 1H), 6.63 (br. S, 2H), 7.33 (t, 2H), 7.41 (dd, 1 H), 7.83 (d, 2H), 8.01 (dd, 2H), 8.09 (d, 1 H), 9.72 (s, 1 H), 11.82 (s, 1 H).

Example 27 N ⁴ - [3,5-Difluoro-4- (1H-pyno1o [2,3-b] pyridin-4-yloxy) phenyl] -6-pyridin-4-ylpyrimidine-2,4-diamine

Analogously to Example 25, the title compound is obtained from 100 mg (0.36 mmol) of [3,5-difluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XXXIV) and 87 mg (0.36 mmol) 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX) synthesized. After cleaning by means of preparative HPLC, the product is obtained.
Yield: 67 mg (43% of theory)
LC-MS (method 10): R _t = 2.17 min.
MS (ESI pos.): M / z = 432 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 6.32 (dd, 1H), 6.44 (d, 1H), 6.59 (s, 1H), 6.76 (br. S, 2H), 7.41 (dd, 1H), 7.82 - 7.88 (m, 4H), 8.09 (d, 1H), 8.72 (d, 2H), 9.85 (s, 1 H), 11. 83 (s, 1 H).

Example 28 N ⁴ - [4- (2,3-Dihydro-1H-pynolo [2,3-b] pyridin-4-yloxy) -3-fluorophenyl] -6-pyridin-4-ylpyrimidine-2,4- diamine

Analogously to Example 25, the title compound is made from 19.7 mg (0.08 mmol) of [4- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yloxy) -3-fluorophenyl] amine (from Example XLVI ) and 17.4 mg (0.08 mmol) of 4-chloro-6- (4-pyridinyl) -2-pyrimidinamine (from Example XXIX). After cleaning by means of preparative HPLC, the product is obtained.
Yield: 7 mg (21% of theory)
LC-MS (method 12): R _t = 1.74 min.
MS (ESI pos.): M / z = 416 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 2.85 (t, 2H), 3.50 (t, 2H), 5.92 (d, 1H), 6.55 (s, 1 H), 6.60 (s, 2H) , 6.85 (s, 1 H), 7.22 (t 1 H), 7.40 (m, 1 H), 7.62 (d, 1 H), 7.85 (d, 2H), 8.30 (m 1H), 8.70 (d, 2H ), 9.62 (s, 1H).

Example 29 N ⁴ - [4- (2,3-Dihydro-1H-pyrrolo [2,3-b] pyridin-4-yloxy) -3-fluorophenyl] -6- (4-fluorophenyl) pyrimidine-2,4- diamine.

Analogously to Example 25, the title compound is obtained from 35 mg (0.14 mmol) [4- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yloxy) -3-fluorophenyl] amine (from Example XLVI ) and 39 mg (0.15 mmol) of 4-chloro-6- (4-fluorophenyl) pyrimidin-2-amine (from Example LIX). After cleaning by means of preparative HPLC, the product is obtained.
Yield: 20 mg (32% of theory)
LC-MS (method 9): R _t = 2.35 min.
MS (ESI pos.): M / z = 433 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 2.85 (t, 2H), 3.51 (t, 2H), 5.85 (d, 1H), 6.55 - 6.65 (m, 4H), 7.10 - 7.40 (m , 4H), 7.62 (d, 1H), 7.95 (m, 2H), 8.25 (m 1H), 9.52 (s, 1H).

The following are prepared analogously to Example 25:

0.209 g (1.12 mmol) Methyl-2-amino-6-chlorpyrimidin-4-carboxylat (hergestellt nach G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) und 0.4 g (1.12 mmol) [3-Fluor-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amin (Beispiel XIX) werden in 5 ml Wasser und 5 ml Ethanol suspendiert. Dazu werden 0.11 ml (1.34 mmol) 37%ige Salzsäure gegeben. Das Gemisch wird bei 100°C 18 Stunden nachgerührt. Nach dem Abkühlen wird es mit einer wässrigen gesättigten Natriumhydrogencarbonatlösung neutralisiert. Der resultierende Niederschlag wird abgesaugt und getrocknet. Man erhält 0.46 g Produkt (68% d. Th.).
HPLC (Methode 11): R_t = 3.53 min.
MS (ESIpos): m/z = 395 (M+H)^+
1H-NMR 400 MHz, DMSO-d₆): δ = 3.82 (s, 3H), 6.17 (s, 1H), 6.25 (dd, 1H), 6.36 (d, 1H), 6.68 (s, 1H), 6.78 (s, 2H), 7.31 (t, 1H), 7.37 (dd, 2H), 7.39 (dd, 1H), 8.06 (d, 1H), 8.25 (dd, 1H), 9.76 (s, 1H), 11.75 (s, 1H).Example 53 Methyl 2-amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidine-4-carboxylate

0.209 g (1.12 mmol) methyl 2-amino-6-chloropyrimidine-4-carboxylate (manufactured according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and CC Cheng, J. Org. Chem., 26 (1961) , 2755-2763) and 0.4 g (1.12 mmol) [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (Example XIX) are dissolved in 5 ml of water and 5 ml of ethanol suspended. 0.11 ml (1.34 mmol) of 37% hydrochloric acid are added. The mixture is stirred at 100 ° C for 18 hours. After cooling, it is neutralized with an aqueous saturated sodium hydrogen carbonate solution. The resulting precipitate is filtered off and dried. 0.46 g of product (68% of theory) is obtained.
HPLC (method 11): R _t = 3.53 min.
MS (ESIpos): m / z = 395 (M + H) ^+
1 H-NMR 400 MHz, DMSO-d ₆ ): δ = 3.82 (s, 3H), 6.17 (s, 1H), 6.25 (dd, 1H), 6.36 (d, 1H), 6.68 (s, 1H), 6.78 (s, 2H), 7.31 (t, 1H), 7.37 (dd, 2H), 7.39 (dd, 1H), 8.06 (d, 1H), 8.25 (dd, 1H), 9.76 (s, 1H), 11.75 (s, 1H).

Example 54 Methyl 2-amino-6- {[3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amino} pyrimidine-4-carboxylate

Analogously to Example 53, the title compound from 1.01 g (4.05 mmol) of 5- (4-amino-2-fluorophenoxy) -1H-indazole (from example XII) and 0.84 g (4.06 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate synthesized.

Yield: 1.55 g (93% of theory)
LC-MS (method 16): R _t = 1.56 min.
MS (ESI pos.): M / z = 395 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.85 (s, 3H), 6.72 (s, 1H), 7.101 (t, 1H), 7.15 (dd, 1H), 7.20 (d, 1 H), 7.34 (m, 1 H), 7.56 (d, 1 H), 7.98 (s, 1 H), 8.16 (dd, 1 H), 10.04 (s, 1H), 13.06 (s, 1H).

Example 55 N ⁴ - [3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6- (piperazin-l-ylcarbonyl) pyrimidine-2,4-diamine

0.072 g (0.18 mmol) methyl 2-amino-6 - {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidine-4-carboxylate (from Example 53) are suspended in 3 ml of water. 0.9 ml of a 1 molar sodium hydroxide solution are added. The reaction mixture is stirred at 100 ° C for 18 hours. After cooling, the mixture is brought to pH 4.5 with 0.95 ml of a 1N hydrochloric acid solution. The precipitate formed is suction filtered and dried. The solid is suspended in DMF. 0.066 mg (0.175 mmol) HATU, 0.025 g (0.184 mmol) HOAT, 0.064 ml (0.368 mmol) diisopropylethylamine and 0.031 g (0.368 mmol) piperazine are added in succession. The reaction mixture is stirred at 40 ° C for 5 hours. After cooling, the solution is purified using preparative HPLC. 0.012 g (15% of theory) of product is obtained.
LC-MS (method 14): R _t = 1.24 min.
MS (ESIpos): m / z = 449 (M + H) ^+
1 H-NMR 200 MHz, DMSO-d ₆ ): δ = 2.76 (m, 4H), 3.54 (m, 4H), 6.05 (s, 1H), 6.25 (dd, 1H), 6.36 (d, 1H), 6.78 (s, 2H), 7.30 (t, 1H), 7.36 (m, 2H), 8.07 (d, 1H), 8.23 (dd, 1 H), 9.62 (s, 1 H), 11.77 (s, 1 H) ,

Beispiel 60 6-Chlor-N⁴-[3-fluor-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]pyrimidin-2,4-diamin

The following are prepared analogously to Example 55:

Example 60 6-Chloro-N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine

Analogously to Example 8, the title compound is made from 266 mg (1.09 mmol) of 3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline (from Example XIX) and 179 mg (1.09 mmol) Synthesized 4,6-dichloro-2-pyrimidinamine.
Yield: 275 mg (68% of theory)
LC-MS (method 10): R _t = 2.41 min.
MS (ESI pos.): M / z = 371 (M + H) ^+
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 6.04 (s, 1H), 6.25 (dd, 1H), 6.36 (d, 1H), 6.86 (br. S, 2H), 7.25 - 7.37 (m , 3H), 8.07 (d, 1H), 8.17 (dd, 1H), 9.60 (s, 1H), 11.73 (s, 1H).

Analog zu Beispiel 8 wird die Titelverbindung aus 384 mg (1.47 mmol) [3,5-Difluor-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amin (aus Beispiel XXXIV) und 241 mg (1.47 mmol) 4,6-Dichlor-2-pyrimidinamin synthetisiert.
Ausbeute: 550 mg (96% d. Th.)
HPLC (Methode 7): R_t = 2.41 min.
MS (ESI pos.): m/z = 389 (M+H)⁺
1H-NMR (DMSO-d₆, 400 MHz): δ = 6.04 (s, 1H), 6.31 (dd, 1H), 6.42 (d, 1H), 7.00 (br. s, 2H), 7.41 (dd, 1 H), 7.75 (d, 2H), 8.08 (d, 1 H), 9.79 (s, 1 H), 11.83 (s, 1 H).Example 61 6-Chloro-N ⁴ - [3,5-difluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine

Analogously to Example 8, the title compound is made from 384 mg (1.47 mmol) [3,5-difluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XXXIV) and 241 mg (1.47 mmol) of 4,6-dichloro-2-pyrimidinamine.
Yield: 550 mg (96% of theory)
HPLC (method 7): R _t = 2.41 min.
MS (ESI pos.): M / z = 389 (M + H) ⁺
1H-NMR (DMSO-d ₆ , 400 MHz): δ = 6.04 (s, 1H), 6.31 (dd, 1H), 6.42 (d, 1H), 7.00 (br. S, 2H), 7.41 (dd, 1 H), 7.75 (d, 2H), 8.08 (d, 1H), 9.79 (s, 1H), 11.83 (s, 1H).

Example 62 N ⁴ - [3-Fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-piperazin-l-ylpyrimidine -

75 mg (0.20 mmol) 6-chloro-N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine (from Example 60 ) are dissolved in 3 ml of 1-butanol. 0.35 ml of N-ethyldiisopropylamine and 70 mg (0.81 mmol) of piperazine are added and the mixture is heated under reflux for 5 hours. The solvent is then removed in vacuo and the residue is purified by preparative HPLC.

Yield: 37 mg (44% of theory)
LC-MS (method 12): R _t = 1.60 min.
MS (ESI neg.): M / z = 419 (MH) ^-
1H-NMR (DMSO-d ₆ , 400 MHz): δ = 2.75 - 2.82 (m, 4H), 3.24 - 3.26 (m, 2H), 3.41 - 3.44 (m, 2H), 4.18 (mc, 1 H), 5 .41 (s, 1 H), 6.02 (br. S, 2H), 6.34 (mc, 1 H), 6.42 (d, 1 H), 7.3 0 (t, 1 H), 7.3 5 - 7.3 8 ( m, 1 H), 7.44 (mc, 1 H), 8.14 (d, 1 H), 8.25 (dd, 1 H), 9.07 (s, 1 H), 11.81 (s, 1 H).

Example 63 N ⁴ - [3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-morpholin-4-ylpyrimidine-2,4-diamine

52 mg (0.14 mmol) 6-chloro-N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine (from Example 60 ) are dissolved in 2.5 ml of 2-ethylhexanol. 0.24 ml of N-ethyldisopropylamine and 36 mg (0.42 mmol) of morpholine are added and the mixture is heated to a bath temperature of 150 ° C. for 20 hours. After cooling, a little DMF is added and chromatographed on silica gel 60 (gradient column: eluent: DCM: methanol = 50: 1, then 3: 1). An oil is obtained which is purified by means of preparative HPLC.
Yield: 13 mg (22% of theory)
HPLC (method 7): R _t = 3.61 min. MS (ESI pos.): M / z = 422 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 3.39 (mc, 4H), 3.66 (mc, 4H), 5.33 (s, 1H), 6.00 (br. S, 2H), 6.25 (mc, 1H), 6.32 (d, 1H), 7.22 (t, 1H), 7.27 - 7.30 (m 1H), 7.35 (dd, 1 H), 8.05 (d, 1 H), 8.17 (d, 1 H), 9.05 (s, 1H), 11.73 (s, 1H).

The following are prepared analogously to Example 63:

34 mg (0.06 mmol) der Verbindung aus Beispiel 84 werden in 1 ml 4 molarer Chlorwasserstofflösung in Dioxan bei RT gerührt. Dann wird im Vakuum eingeengt und mit Diethylether verrieben. Man dekantiert ab, trocknet den Rückstand im Hochvakuum und erhält das Hydrochlorid der Titelverbindung.Example 100 6- [3- (1,4-Diazepan-l-yl) azetidin-l-yl] -N4- [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy ) phenyl] pyrimidine-2,4-diamine

34 mg (0.06 mmol) of the compound from Example 84 are stirred in 1 ml of a 4 molar hydrogen chloride solution in dioxane at RT. The mixture is then concentrated in vacuo and triturated with diethyl ether. It is decanted off, the residue is dried under high vacuum and the hydrochloride of the title compound is obtained.

Yield: 30 mg (96% of theory)
LC-MS (method 17): R _t = 1.18 min.
MS (ESI pos.): M / z = 490 (M + H) ⁺

Example 101 3 - [(2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) amino] propane -1-ol

78 mg (0.21 mmol) 6-chloro-N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine (from Example 60 ) are heated with 190 mg (0.84 mmol) of 3 - [(2,4-dimethoxybenzyl) amino] propan-1-ol in 1 ml of 1-butanol and 0.37 ml of N-ethyl diisopropylamine in a closed pressure vessel at 130 ° C. overnight. Volatiles are removed in vacuo and the residue is purified by preparative HPLC. The substrate obtained is taken up in 2 ml of DCM and 0.5 ml of TFA is added. The mixture is stirred for 20 min. at RT, then gives up to ethyl acetate and shakes with sat. Sodium carbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by preparative HPLC.
Yield: 10 mg (16% of theory)
LC-MS (method 10): R _t = 1.85 min.
MS (ESI pos.): M / z = 410 (M + H) ⁺

Example 102 N ⁴ - [3-Fluoro-4- (1H-indazol-5-yloxy) phenyl] -6- [4- (trifluoromethyl) phenyl] pyrimidine-2,4-diamine

52.55 mg (0.14 mmol) 6-chloro-N ⁴ - [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] pyrimidine-2,4-diamine (from Example 8) and 35.71 mg (0.42 mmol) Sodium bicarbonate is stirred in 2.4 ml of dimethoxyethane and 0.7 ml of water at 85 ° C for 30 minutes. 5 mg (0.007 mmol) 1; 1'-bis (diphenylphosphino) fenocene palladium (II) chloride are added. The mixture is stirred at 85 ° C for 12 hours. For working up, it is diluted with dimethoxyethane and washed with a saturated sodium chloride solution. The organic phase is dried and concentrated. The residue is purified by means of preparative HPLC. 2.80 g (64% of 7 hours) of product are obtained.
LC-MS (method 16): R _t = 1.84 min.
MS (ESIpos): m / z = 481 (M + H) ^+
1 H-NMR 200 MHz, DMSO-d ₆ ): δ = 6.57 (s, 3H), 7.10 (dd, 1H), 7.16 (m, 2H), 7.34 (dd, 1H), 7.56 (d, 1H), 7.86 (d, 2H), 7.98 (s, 1H), 8.14 (m, 2H), 8.21 (dd, 1H), 9.56 (s, 1 H), 13 .07 (s, 1 H).

Beispiel 109 N⁴-[3-Fluor-4-(1 H-indazol-5-yloxy)phenyl]pyrimidin-2,4,6-triamin

The following are prepared analogously to Example 102:

Example 109 N ⁴ - [3-Fluoro-4- (1 H -indazol-5-yloxy) phenyl] pyrimidine-2,4,6-triamine

Analogously to Example 25, the title compound is made from 150 mg (0.62 mmol) of [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] amine (from Example XII) and 94 mg (0.65 mmol) of 6-chloropyrimidine-2 , 4-diamine synthesized. After cleaning by means of preparative HPLC, the product is obtained.
Yield: 11mg (5% of theory)
LC-MS (Method 8): Rt = 2.10 min.
MS (ESI pos.): M / z = 416 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 5.19 (m, 1H), 5.67 (m, 2H), 5.82 (m, 2H), 7.02 (t, 1H), 7.10 - 7.30 (m, 3H), 7.53 (m, 1H), 7.90 - 8.10 (m, 2H), 8.70 (s, 1H), 13.00 (s, 1H).

Example 110 4 - [(2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) amino] benzonitrile

Analogously to Example 25, the title compound is prepared from 51 mg (0.21 mmol) [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XIX) and 54 mg ( 0.22 mmol) 4 - [(2-amino-6-chloropyrimidin-4-yl) amino] benzonitrile (from Example XLVII). After cleaning by means of preparative HPLC, the product is obtained.
Yield: 8 mg (8% of theory)
LC-MS (Method 8): R _t = 2.30 min.
MS (ESI pos.): M / z = 453 (M + H) ⁺
1H-NMR (DMSO-d ₆ , 300 MHz): δ = 5.62 (s, 1H), 6.25 (m, 1H), 6.30 (s, 2H), 6.35 (d, 1H), 7.25 (m, 1H), 7.30 - 7.40 (m, 2H), 7.65 (d, 2H), 7.90 (d, 2H), 8.00 - 8.19 (m, 2H), 9.15 (s, 1 H), 9.3 5 (s, 1 H), 11.70 (s, 1H).

Beispiel 116 Benzyl-6-[(tert-butylamino)methyl]-N⁴-[3-fluor-4-(1 H-pynolo [2,3-b]pyridin-4-yloxy)phenyl]pyrimidin-2,4-diamin

The following are prepared analogously to Example 110:

Example 116 Benzyl-6 - [(tert-butylamino) methyl] -N ⁴ - [3-fluoro-4- (1 H-pynolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4 diamine

0.060 g (0.28 mmol) of 4 - [(tert-butylamino) methyl] -6-chloropyrimidin-2-amine and 4 - [(tert-butylamino) methyl] -6-bromopyrimidin-2-amine (from Example LXXX) and 0.068 g (0.28 mmol) [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XIX) are suspended in 2 ml of water and 2 ml of ethanol. 0.051 ml (0.61 mmol) of 37% hydrochloric acid are added. The mixture is stirred at 100 ° C for 18 hours. After cooling, it is neutralized with a 12N sodium hydroxide solution. After adding 1 ml of DMSO, the suspension is brought back into solution and purified by means of preparative HPLC. 0.074 g (63% of theory) of product are obtained.
LC-MS (method 15): R _t = 1.12 min.
MS (ESIpos): m / z = 422 (M + H) ^+
1 H NMR 200 MHz, DMSO-d ₆ ): δ = 1.11 (s, 9H), 3.52 (s, 2H), 6.17 (s, 1H); 6.27 (m, 1 H), 6.34 (m, 3 H), 7.27 (t, 1 H), 7.39 (m, 2H), 8.06 (d, 1 H), 8.24 (dd, 1 H), 9.46 (see , 1H), 11.76 (s, 1H).

Example 117 N ⁴ - [3-Fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6- (piperidin-l-ylmethyl) pyrimidine-2,4-diamine

Analogously to Example 116, the title compound is reacted by reacting 33 mg (0.137 mmol) [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XIX) and 31 mg (0.137 mmol) of 4-chloro-6- (piperidin-l-ylmethyl) pyrimidin-2-amine (from Example LXXXI).
Yield: 13 mg (22% of theory)
LC-MS (method 13): R _t = 1.39 min.
MS (ESIpos): m / z = 218 1/2 (M + H) ²⁺
1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.42 (m, 2H), 1.54 (m, 4H), 2.39 (m, 4H), 3.17 (d, 2H), 4.06 (q, 1H), 6.19 (s, 1H), 6.24 (dd, 1H), 6.28 (s, 2H), 6.35 (d, 1H), 7.26 (t, 1 H), 7.37 (m, 2H), 8.06 (d, 1 H) , 8.21 (dd, 1H), 9.37 (s, 1H), 11.71 (s, 1H).

Beispiel 127 (2-Amino-6-{ [3-fluor-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)methanol

The following are prepared analogously to Example 116:

Example 127 (2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) methanol

Analogously to Example 116, the title compound is obtained by reacting 106 mg (0.44 mmol) [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amine (from Example XIX) with 70 mg (0.44 mmol) (2-amino-6-chloropyrimidin-4-yl) methanol (from Example LXXVIII).
Yield: 49 mg (30% of theory)
LC-MS (method 14): R _t = 1.30 min.
MS (ESIpos): m / z = 367 (M + H) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 4.22 (d, 2H), 5.24 (t, 1H), 6.25 (m, 4H), 6.37 (d, 1 H), 7.28 (t, 1 H), 7.39 (m, 2H), 8.05 (d, 1 H), 8.22 (dd, 1 H), 9.42 (s, 1 H), 11.71 (s, 1 H).

Example 128 (2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) ethyl acetate

The title compound is prepared analogously to Example 25 from 220 mg (0.908 mmol) 3-fluoro-4- (1H-pyrro1o [2,3-b] pyridin-4-yloxy) aniline (from Example XIX) and 195 mg (0.908 mmol) Ethyl (2-amino-6-chloropyrimidin-4-yl) acetate (from Example LXIX) synthesized.
Yield: 16 mg (4% of theory)
LC-MS (method 16): R _t = 1.44 min.
MS (ESI pos.): M / z = 423 (M + H) ⁺
1H NMR DMSO-d ₆ , 400 MHz): δ = 1.20 (t, 3H), 3.46 (s, 2H), 4.09 (q, 2H), 6.01 (s, 1H), 6.25 (m, 1H), 6.35 (d, 1H), 6.43 (s, 2H), 7.28 (t, 1H), 7.37 (m, 2H), 8.06 (d, 1 H), 8.21 (dd, 1 H), 9.46 (s, 1 H) , 11.74 (s, 1H).

Example 129 N ⁴ - [3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-methylpyrimidine-2,4-diamine

In example 128, the title compound is formed as a by-product by hydrolysis of the ethyl ester and subsequent decarboxylation.
Yield: 22 mg (7% of theory)
LC-MS (method 16): R _t = 1.35 min.
MS (ESI pos.): M / z = 351 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 2.12 (s, 3H), 5.90 (s, 1H), 6.26 (m, 1H), 6.32 (s, 2H), 6.34 (d, 1H) , 7.27 (t, 1H), 7.36 (m, 2H), 8.06 (d, 1H), 8.21 (dd, 1H), 9.34 (s, 1 H), 11.74 (s, 1 H).

Example 130 4- (2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) butyric acid

The title compound is prepared analogously to Example 25 from 327 mg (1.34 mmol) of 3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) aniline (from Example XIX) and 230 mg (1.34 mmol) 4- (2-Amino-6-chloropyrimidin-4-y1) butyric acid (from Example LXX) synthesized and isolated as the hydrochloride.
Yield: 414 mg (67% of theory)
LC-MS (method 15): R _t = 1.15 min. MS (ESI pos.): M / z = 423 (M + H) ⁺

1H NMR DMSO-d ₆ , 200 MHz): δ = 1.87 (tt, 2H), 2.34 (t, 2H), 2.62 (t, 2H), 4.02 (3H), 6.30 (s, 1H), 6.42 (m , 1H), 6.61 (d, 1H), 7.44 - 7.61 (m, 3H), 8.24 (d, 1H), 8.25 - 8.35 (m, 1 H), 11.13 (s, 1 H), 12.40 (s, 1 H), 12.93 (s, 1H).

Example 131 N ⁴ - [3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6- (4-oxo-4-piperidyl-butyl) pyrimidine-2, 4-diamine

70 mg (0.17 mmol) 4- (2-amino-6 - {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) Butyric acid (from Example 130) are dissolved in 2.0 ml of DMF and mixed with 60 mg (0.16 mmol) of HATU, 23 mg (0.17 mmol) of 1-hydroxy-1-hazobenzotriazole hydrate, 43 mg (0.33 mmol) of diisopropylamine and 28 mg (0.33 mmol) of piperidine and stirred for 20 hours at RT. Volatiles are removed in vacuo and purified by preparative HPLC. The product obtained is further purified by means of thick layer chromatography (1 mm silica gel coating, eluent: DCM methanol = 9: 1).
Yield: 25 mg (31% of theory)
LC-MS (method 13): R _t = 1.69 min. MS (ESI pos.): M / z = 490 (M + H) ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 1.40 - 1.47 (mc, 4H), 1.56 (mc, 2H), 1.82 (tt, 2H), 2.32 (t, 2H), 2.40 (t, 2H), 3.42 (m, 4H), 5.90 (s, 1H), 6.25 - 6.29 (m, 3H), 6.35 (d, 1 H), 7.3 0 (t, 1 H), 7.3 5 (m, 2H) , 8.06 (d, 1H), 8.21 (dd, 1H), 9. 3 3 (s, 1H); 11.74 (s, 1H).

Example 132 Ethyl 4- (2-amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) butanoate

396 mg (0.86 mmol) 4- (2-amino-6 - {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) Butyric acid (from Example 130) are heated in 20 ml of ethanol after addition of 0.10 ml of sulfuric acid for 20 hours under RF. It is concentrated in vacuo, mixed with dichloromethane and a little methanol and extracted with sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate and the solvent is concentrated in vacuo. The title compound is obtained.
Yield: 379 mg (95% of theory)
LC-MS (method 13): R _t = 1.55 min.
MS (ESI pos.): M / z = 451 (M + H) ^+
1 H NMR (DMSO-d ₆ , 400 MHz): δ = 1.19 (t, 3H), 1.87 (quint., 2H), 2.04 (t, 2H), 2.59 (t, 2H), 4.07 (q, 2H) ), 6.13 (br. S, 1H), 6.25 (dd, 1H), 6.38 (d, 1H), 7.31 - 7.44 (m, 3 H), 8.09 (d, 1 H), 8.22 (br. S, 1 H), 10.51 (br. S, 1 H), 11.79 (s, 1 H), 12.3 3 (br. S, 1 H).

Example 133 4- (2-Amino-6- {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) butane l-ol

300 mg (0.67 mmol) 4- (2-amino-6 - {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4-yl) Butan-l-ol (from Example 132) are suspended in 15 ml of ethanol and 253 mg (6.66 mmol) of sodium borohydride are added in portions at RT. The mixture is stirred at RT for 24 hours, concentrated and treated with ethyl acetate and water. The organic phase is dried over sodium sulfate. It is purified by column chromatography (silica gel 60; gradient column, eluent: DCM: methanol = 9: 1 to 3: 1). 133 mg (27%) of the starting material are obtained. The product fraction is cleaned by preparative HPLC. The title compound is obtained.
Yield: 43 mg (16% of theory)
LC-MS (method 13): R _t = 1.37 min.
MS (ESI neg.): M / z = 407 (MH)
¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 1.45 (tt, 2H), 1.62 (tt, 2H), 2.39 (t, 2H), 3.41 (dt, 2H), 4.37 (t, 1H) ), 5.90 (s, 1 H), 6.24 - 6.26 (m, 1 H), 6.27 (br. S, 2H), 6.34 (d, 1 H), 7.27 (dd, 1 H), 7.34 - 7.37 (m , 2H), 8.06 (d, 1 H), 8.21 (dd, 1 H), 9.31 (s, 1 H), 11.74 (s, 1 H).

Example 134 N ⁴ - [3-Fluoro-4- (1 H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-piperidin-3-ylpyrimidine-2,4-diamine

1.36 g (2.46 mmol) benzyl-3- (2-amino-6 - {[3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] amino} pyrimidin-4- yl) piperidine-1-carboxylate (from Example LXXIV) and 0.4 g of 10% palladium on carbon are stirred in ethanol under a hydrogen atmosphere at room temperature for 24 hours. The suspension is suctioned off through Celite ° and the filtrate is concentrated.
Yield: 0.66 g (60% of theory)
LC-MS (method 13): R _t = 1.37 min.
MS (ESI neg.): M / z = 407 (MH) ^-
1 H-NMR DMSO-d ₆ , 300 MHz): δ = 1.46 - 1.70 (m, 4H), 1.89 (m, 1H), 2.57 (m, 1 H), 2.67 (t, 1 H), 2.97 (m , 1 H), 3 .10 (m, 1 H), 4.07 (br. S, 1 H), 5.90 (s, 1 H), 6.25 (m, 1H), 6.30 (s, 2H), 6.35 (d , 1H), 7.26 (t, 1H), 7.37 (m, 2H), 8.06 (d, 1H), 8.18 (dd, 1 H), 9.3 5 (s, 1 H), 11.71 (s, 1 H).

Beispiel 139 6-(1-Acetylpiperidin-3-yl)-N⁴-[3-fluor-4-(1H-pyrrolo [2,3-b]pyridin-4-yloxy)phenyl]pyrimidin-2,4-diamin

The following are prepared analogously to Example 134:

Example 139 6- (1-Acetylpiperidin-3-yl) -N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine

50 mg (0.119 mmol) N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-piperidin-3-ylpyrimidine-2,4-diamine ( from Example 134) are suspended in ethanol. 0.013 ml (0.146 mmol) of acetic anhydride are added and the mixture is stirred at room temperature for 18 hours. Then it is concentrated. The residue is purified by means of preparative HPLC.

Yield: 24 mg (40% of theory)
HPLC (method 7): R _t = 3.58 min.
MS (ESI pos.): M / z = 462 (M + H) ⁺
1H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.23 - 1.78 (m, 4H), 1.94 (m, 1H), 2.02 (s, 3H), 2.3 2 (m, 1H), 2.5 7 (m, 1H), 2.99 (t, 1H), 3. 84 (t, 1 H), 4.31 (dd, 0.5 H), 4. 5 5 (dd, 0.5H), 5.92 (s, 0.5H), 5.95 (s, 0.5H), 6.25 (m, 1H), 6.30 (s, 2H), 6.35 (d, 1H), 7.26 (t, 1 H), 7.37 (m, 2H), 8.06 (d, 1 H), 8.19 (dd, 1 H), 9.36 (d, 1 H), 11.71 (s, 1H).

Example 140 N ⁴ - [3-Fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6- (1-isopropylpiperidin-3-yl) pyrimidine-2,4-diamine

50 mg (0.119 mmol) N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] -6-piperidin-3-ylpyrimidine-2,4-diamine ( from Example 134) are dissolved in DMF. 0.013 ml (0.143 mmol) of 2-bromopropane and 49 mg (0.358 mmol) of potassium carbonate are added, and the mixture is stirred at room temperature for 18 hours. The suspension is suctioned off and the filtrate is purified by means of preparative HPLC.
Yield: 15 mg (27% of theory)
LC-MS (method 13): R _t = 1.28 min.
MS (ESI neg.): M / z = 460.5 (MH) ^-

Example 141 N ⁴ - [3-Fluoro-4- (1 H -indazol-5-yloxy) phenyl] pyrimidine-2,4-diamine

50 mg (0.135 mmol) of 6-chloro-N ⁴ - [3-fluoro-4- (1H-indazol-5-yloxy) phenyl] pyrimidine-2,4-diamine (from Example 8) are dissolved in ethanol. 50 mg of 10% palladium on carbon are added and the suspension is stirred overnight under a hydrogen atmosphere. The palladium catalyst is suctioned off and the filtrate is concentrated.
Yield: 40 mg (70% of theory)
LC-MS (method 9): R _t = 1.81 min.
MS (ESI pos.): M / z = 337.2 (M + H) ⁺

Example 142 N ⁴ - [3-Fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine-2,4-diamine

Analogously to Example 141, the title compound is obtained by reducing 53 mg (0.14 mmol) 6-chloro-N ⁴ - [3-fluoro-4- (1H-pyrrolo [2,3-b] pyridin-4-yloxy) phenyl] pyrimidine -2,4-diamine (from Example 60).
Yield: 16 mg (32% of theory)
LC-MS (method 16): R _t = 1.30 min.
MS (ESI neg.): M / z = 335 (MH) -
¹ H-NMR DMSO-d ₆ , 300 MHz): δ = 6.02 (d, 1H), 6.25 (dd, 1H), 6.32 (br. S, 2H), 6.35 (d, 1H), 7.27 (t, 1 H), 7.34 - 7.40 (m, 2H), 7.86 (d, 1 H), 8.06 (d, 1 H), 8.21 (dd, 1 H), 9.3 9 (s, 1 H), 11.72 (s, 1 H).

B. Assessment of physiological effectiveness

In an in vitro recombinant assay Rho-Kinase-II is used to study the inhibition of the enzyme. The vasodilator Effect is isolated from phenylephrine-induced contractions Rings of the rabbit artery saphena determined. The suitability of the compounds according to the invention for the treatment of cardiovascular Diseases can be examined by examining the hypotensive effects on anesthetized rats.

Inhibition of recombinant Rho-Kinase II (ROKα)

The activity of the Rho-Kinase is determined by the incorporation of ³³ P-phosphate in a substrate peptide. For this purpose, commercially available Rho-Kinase II (Upstate Biotechnology) is pre-incubated in the presence of the S6 phosphate acceptor peptide with the test substances or a solvent control for 10 min at 37 ° C. The kinase reaction is then started by adding ³³ P-labeled ATP. After 20 min at 37 ° C, the reaction is stopped by adding HP ₃ O ₄ . Aliquots are pipetted onto filters, the filters are washed and then coated with a scintillator. The radioactivity of the ³³ P-labeled peptides bound to the filter is measured in a micro beta counter. The IC ₅₀ value corresponds to the concentration of a test substance at which the Rho-kinase-catalyzed incorporation of ³³ P into the peptide is inhibited by 50% compared to a solvent control. The experimental data are summarized in the following table.

Vascular relaxant effect in vitro

3 mm wide rings of the isolated rabbit artery saphena are placed individually in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution. The vascular tone is recorded isometrically and registered. Contractions are induced by adding 3 × 10 ^-8 g / ml phenylephrine and washed out again after 4 min. After several control cycles, the substance to be examined is preincubated with increasing doses with each further run and the subsequent contraction is compared with the level of the last control contraction. The concentration is calculated that is required to reduce the level of the control value by 50% (IC ₅₀ ). The experimental data are summarized in the following table.

Blood pressure measurement on anesthetized rats

male Wistar rats with a body weight from 300 - 350 g are anesthetized with thiopental (100 mg / kg i.p.). After the tracheotomy a catheter for measuring blood pressure is inserted into the femoral artery. The to be checked Substances are called solutions administered either orally using a pharyngeal tube or intravenously via the femoral vein.

C. working examples for pharmaceutical compositions

The compounds of the invention can be pharmaceutical as follows Preparations are transferred:

Tablet:

Composition:

100 mg of the compound of example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of the compound according to the invention, Lactose and starch is with a 5% solution (m / m) of the PVP granulated in water. The granules will dry after with the magnesium stearate for 5 minute mixed. This mixture is compressed using a conventional tablet press (For the format of the tablet, see above). As a guideline for pressing a press force of 15 kN is used.

Oral suspension:

Composition:

1000 mg of the compound of example 1, 1000 mg ethanol (96%), 400 mg Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g water.

A single dose of 100 mg compound of the invention correspond to 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol the compound of the invention is added to the suspension. With stirring the water is added. Until the swelling of the Rhodigels is stirred for about 6 hours.

Claims (10)

Compounds of the formula

where A is a residue

means what X is N or CH, Y is NR ⁷ , O or S, where R ^{7 is} hydrogen, benzyl, phenyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, where alkyl and cycloalkyl in turn can be substituted by fluorine, hydroxy, amino, carboxyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or morpholinyl, Z represents N or CH, R ^{6 represents} hydrogen, halogen , Trifluoromethyl, (C ₁ -C ₆ ) alkylamino or W-R7 ⁴ , where W is NH, O or a bond, R ^{7 has} the meaning given above and * represents the point of attachment to the phenolic oxygen, R ¹ and R ² independently of one another denote hydrogen, halogen or cyano, R ³ and R ⁴ independently of one another denote hydrogen, fluorine or chlorine, R5 denotes a radical which is selected from the group of: hydrogen, hydroxyl, halogen, trifluoromethyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, where cycloalkyl, alkyl and alkoxy in turn by hydroxy, carboxyl, (C ₁ -C ₆ ) -alkoxy, ( C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) aryl, NR ⁸ R ⁹ or C (= O) NR ⁸ R ⁹ can be substituted, in which R ⁸ and R ^{9 are} independently hydrogen, (C ₁ -C ₈ ) alkyl optionally substituted by (C ₁ -C ₆ ) alkyl (C ₃ -C ₆ ) cycloalkyl, optionally substituted by halogen (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl stand or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further hetero atom O or N in the ring and which is (C ₁ -C ₆ ) - Alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted, (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, 5- to 10- membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heterocyclyl bonded via a carbon atom, whereby aryl, aryloxy, heteroaryl, heteroaryloxy and heterocyclyl in turn by halogen, cyano, nitro, carboxyl, amino, trifluoromethyl, optionally by hydr oxy substituted (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) - Alkoxycarbonyl, (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino or 5- or 6-membered heterocyclyl can be substituted, NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ independently of one another are hydrogen, ( C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₆ -C ₁₀ ) -aryl or 5 to 10-membered heteroaryl, alkyl and cycloalkyl in turn being substituted by hydroxy, (C ₁ - C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl or NR ¹⁵ R ¹⁶ may be substituted, in which R1 ⁵ and R ¹⁶ independently of one another are hydrogen, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₆ -C ₁₀ ) -aryl or 5- or 6-membered heteroaryl or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached, a 5 - Form or 6-membered heterocycle, which may contain a further heteroatom O or N in the ring and which by (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) -alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl, and aryl and heteroaryl in turn by halogen, hydroxy, amino, cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) -Alkoxy, (C ₁ -C ₆ ) -alkylamino or (C ₁ -C ₆ ) -alkanoylamino, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, a 4- to 6- form a heterocycle, which may contain a further heteroatom O or N in the ring and which may contain fluorine, hydroxyl, carboxyl, 5- to 7-membered heterocyclyl and which may contain one or two further heteroatoms N and / or O in the ring, and this in turn can be substituted by (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxy, optionally by hydroxy, (C ₁ -C ₄ ) alkoxy or NR ¹⁷ R ¹⁸ substituted (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl, (C ₁ -C ₄ ) alkoxycarbonyl or NR ¹² R ¹³ can be substituted, where R ¹² and R ^{13 are} independently of one another Hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₄ ) alkanoyl or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- or form a 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl can be substituted, and R ¹⁷ and R ¹⁸ independently of one another for hydrogen, optionally substituted by hydroxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or 5 - or 6-membered heteroaryl or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which is characterized by (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl may be substituted, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, a 7- to 12-membered bicyclic or tricyclic Form heterocycle, which is fused or spirocyclic and can have one or two further heteroatoms from the series N and / or O in the ring and which by fluorine, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl , (C ₁ -C ₄ ) alkanoyl or benzyl may be substituted, and C (= O) R ¹⁴ , wherein R ^{14 represents} (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or one is a 5- to 10-membered mono- or bicyclic heterocycle bonded via a nitrogen atom, which is fused or spirocyclic and can have one or two further heteroatoms from the series N and / or 0 in the ring, alkylamino in turn by a 5- or 6-membered heterocyclyl can be substituted, and their salts, hydrates, hydrates of the salts and solvates. Compounds according to claim 1, wherein A is a radical

where R ^{6 represents} hydrogen, (C ₁ -C ₄ ) -alkyl or NH-R ⁷ , R ^{7 represents} hydrogen or (C ₁ -C ₄ ) -alkyl and * represents the point of attachment to the phenolic oxygen, R ¹ and R ^{2 are} independently hydrogen, fluorine or chlorine, R ³ and R ^{4 are} independently hydrogen or fluorine, R ^{5 represents} a radical which is selected from the group of: hydrogen, chlorine, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, where alkyl and alkoxy in turn can be substituted by hydroxy, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, NR ⁸ R ⁹ or C (= O) NR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another is hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl optionally substituted by (C ₁ -C ₄ ) -alkyl, optionally substituted by halogen-substituted phenyl or 5- or 6- are linked heteroaryl or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, which rings in turn may be substituted by (C ₁ -C ₄ ) alkyl , (C ₆ -C ₁₀ ) -aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl bonded via a carbon atom, aryl, heteroaryl and heterocyclyl in turn being substituted by halogen, cyano, nitro, carboxyl, Amino, trifluoromethyl, optionally substituted by hydroxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) alkanoyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoylamino, (C ₁ -C ₄ ) alkoxycarbonylamino or 6-membered heterocyclyl can be substituted, NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} independently of one another Are hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, phenyl or 5- or 6-membered heteroaryl, alkyl and cycloalkyl in turn being hydroxy, (C ₁ -C ₄ ) alkoxy , Phenyl, 5- or 6-membered heteroaryl or NR ¹⁵ R ¹⁶ can be substituted, in which R ¹⁵ and R ¹⁶ independently of one another are hydrogen, (C ₁ -C ₄ ) -A1ky1, (C ₃ -C ₆ ) cycloalkyl, Are phenyl or 5- or 6-membered heteroaryl or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, the rings themselves being replaced by (C ₁ - C ₄ ) alkyl may be substituted NEN, and phenyl and heteroaryl in turn by fluorine, chlorine, hydroxy, amino, cyano, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylamino or (C ₁ -C ₄ ) -alkanoylamino can be substituted, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which contain a further hetero atom O or N in the ring can and by fluorine, hydroxy, carboxyl, 5- to 7-membered heterocyclyl, which can contain one or two further heteroatoms N and / or O in the ring, which in turn by (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxycarbonyl may be substituted, (C ₁ -C ₄ ) alkoxy optionally substituted by hydroxy, (C ₁ -C ₄ ) alkoxy or NR ¹⁷ R ¹⁸ substituted (C ₁ -C ₄ ) alkyl, ( C ₁ -C ₄ ) alkanoyl, (C ₁ -C ₄ ) alkoxycarbonyl or NR ¹² R ¹³ can be substituted, where R ¹² and R ¹³ independently of one another are hydrogen or (C ₁ -C ₄ ) alkyl or R ¹² and R ¹³ together with the nitrogenate om to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which is substituted by (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) - Alkanoyl or (C ₁ -C ₆ ) alkoxycarbonyl can be substituted, and R ¹⁷ and R ¹⁸ independently of one another represent hydrogen, optionally substituted by hydroxy (C ₁ -C ₄ ) alkyl or phenyl or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a pyrrolidine ring, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic or tricyclic heterocycle which is fused or spirocyclic and a or can have two further heteroatoms from the series N and / or 0 in the ring and that by (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkanoyl or benzyl and C (= O) R ¹⁴ , where R ^{14 is} for (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino or one via a stick 5- to 10-membered mono- or bicyclic heterocycle bonded to the atom, which is fused or spirocyclic and can have one or two further heteroatoms from the series N and / or 0 in the ring, alkylamino in turn being represented by a 5- or 6- membered heterocyclyl may be substituted, and their salts, hydrates, hydrates of the salts and solvates. Compounds according to one of claims 1 or 2, wherein A is a radical

means where R ^{6 is} hydrogen or methyl and * represents the point of attachment to the phenolic oxygen, R ¹ and R ² independently of one another are hydrogen, fluorine or chlorine, R ³ and R ^{4 are} hydrogen, R ^{5 is} a radical which is selected from the group of: hydrogen, chlorine, cyclohexyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, alkyl and alkoxy in turn being hydroxyl, carboxyl, (C ₁ -C ₄ ) -Alkoxy, methyloxycarbonyl, ethyloxycarbonyl, NR ⁸ R ⁹ , or C (= O) NR ⁸ R ⁹ may be substituted, wherein R ⁸ and R ⁹ independently of one another are hydrogen, (C ₁ -C ₈ ) -alkyl, cyclopropyl, if appropriate are methyl-substituted cyclopentyl or optionally fluorine-substituted phenyl or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a piperidine, 2-methylpiperidine or 2,6-dimethylpiperidine ring, phenyl, pyridyl, pyrrolyl, Piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-yl, being phenyl, pyridyl and pyrrolyl may in turn be substituted by fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, methyl, hydroxymethyl, methoxy, dimethylamino or morpholinyl, and piperidin-3-yl, piperidin-4-yl and pynolidin-2-yl in turn by methyl , Ethyl, n-propyl, isopropyl, methylcarbonyl or ethylcarbonyl can be substituted, NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ¹¹ independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, 3-hydroxypropyl, 2- Hydroxycyclohexyl, 2-aminocyclohexyl, phenyl, pyridyl or pyrazolyl, where phenyl and pyridyl can in turn be substituted by chlorine, hydroxy, amino, cyano, methyl or methoxy, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached , a piperazine, 3-methylpiperazine, 3,5-dimethylpiperazine, 4-isobutylpiperazine, morpholine, pyrrolidine, 3-aminopyrrolidine, 3-methylaminopyrrolidine, 3- (NN-dimethylamino) pyrrolidine, 2 Aminomethylpyrrolidine, 3-hydroxypyrrolidine, 2-hydroxymethylpyrrolidine or 2-M ethoxymethylpyrrolidine ring or a residue

form where * represents the point of attachment to the pyrimidine ring, and C (= O) R ¹⁴ , where R ^{14 represents} methoxy, piperidinyl-N-ethylamino, piperidinyl or piperazinyl, and their salts, hydrates, hydrates of the salts and solvates. Process for the preparation of compounds as defined in claim 1, characterized in that either [A] compounds of the formula (II)

wherein A, R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim 1, with compounds of formula (III)

wherein R ^{5 has} the meaning given in claim 1 and X ¹ for hydrogen, B (OH) ₂ or a boronic ester such as

or [B] compounds of the formula (IV)

wherein R ^{5 has} the meaning given in claim 1, with compounds of the formula (V)

wherein A, R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim 1. A compound as in any one of claims 1 to 3 defined, for the treatment and / or prophylaxis of diseases. Use of a compound as in any one of claims 1 to 3 defined, for the manufacture of medicaments for treatment and / or Prophylaxis of cardiovascular Diseases. Use of a compound as in any one of claims 1 to 3 defined, for the manufacture of medicaments for treatment and / or Prevention of erectile dysfunction. Process for the treatment and / or prophylaxis of cardiovascular Diseases, using a cardiovascular effective Amount of a compound as defined in any one of claims 1 to 3. Medicament containing a compound as in a of claims Defined 1 to 3, and another active ingredient. Medicament containing a compound as in one of the claims 1 to 3 defined, in combination with an inert non-toxic, pharmaceutically acceptable excipient.