HK1159099B - Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd - Google Patents

Description

Cyclic pyrimidine-4-carboxamides as CCR2 receptor antagonists for the treatment of inflammation, asthma and COPD

Technical Field

The present invention relates to novel antagonists of CCR2(CC chemokine receptor 2), and their use to provide medicaments for the treatment of the following conditions and diseases: activation of CCR2 is the causative disorder and disease, especially pulmonary diseases such as asthma and COPD; neurological disorders, in particular pain disorders; immune-related diseases, particularly diabetes, including diabetic nephropathy; and cardiovascular diseases, especially atherosclerosis.

Background

Chemokines are a family of small proinflammatory cytokines with strong chemotactic activity. Chemokines are chemotactic cytokines that are released by a variety of cells to attract a variety of cells (e.g., monocytes, macrophages, T cells, eosinophils, basophils, and neutrophils) to sites of inflammation.

Chemokine receptors (e.g. CCR2 or CCR5) have been shown to be important mediators (mediators) of inflammatory and immunoregulatory disorders and diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Thus, agents that modulate chemokine receptors (e.g., the CCR2 and CCR5 receptors) would be useful in these conditions and diseases.

In particular, it is recognized that many conditions and diseases involve inflammatory processes. These inflammations are critically initiated and/or promoted by the activity of macrophages formed by the differentiation of monocytes. It has further been found that monocytes are characterized by a high expression of CCR2, e.g. present in the membrane, while CCR2 expression in macrophages is lower. CCR2 is a key regulator of monocyte migration, which can be described as the movement of monocytes to inflammation along a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2, MCP-3, MCP-4).

Therefore, to reduce macrophage-induced inflammation, it is desirable to block monocyte CCR2 with antagonists so that monocytes are less induced to migrate to the inflamed area and convert to macrophages.

Based on the above, there is a need to provide pharmacologically acceptable potent antagonists of CCR 2.

Disclosure of Invention

It has now been found that these potent CCR2 inhibitors can be provided by the compounds of formula (I) and their acid addition salt forms with pharmacologically acceptable acids and their solvate and/or hydrate forms,

wherein R is₁is-L₁-R₇，

Wherein L is₁Is a linking group selected from a bond or from-C₁-C₂Alkylene and-C₁-C₂-alkenylene (alkenylene) group, -C₁-C₂Alkylene and-C₁-C₂-alkenylene optionally comprising in the chain one or more groups selected from-O-, -C (O) -and-NH-and optionally substituted by a group selected from-OH, -NH₂、-C₁-C₃Alkyl, O-C₁-C₆-alkyl and-CN groups,

wherein R is₇Is selected from-C₃-C₈-cycloalkyl, -C₃-C₈-heterocyclyl, -C₅-C₁₀-aryl and-C₅-C₁₀-a ring of a heteroaryl group,

wherein the ring R₇Optionally substituted by one or more groups selected from-CF₃、-O-CF₃A group of-CN and-halogen,

or wherein the ring R₇Optionally substituted with one or more groups selected from: -C₁-C₆-alkyl, -O-C₁-C₆-alkyl, -C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl, -C₃-C₈-cycloalkyl, -C₃-C₈-heterocyclyl, -C₁-C₆-alkenyl and-C₁-C₆-alkynyl, these radicals optionally further substituted by one or more groups selected from-OH, -NH₂、-C₁-C₃-alkyl, -O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃Halogen and ═ O,

or wherein the ring R₇Optionally further substituted on two adjacent ring atoms by one or more groups selected from-C₁-C₆Alkylene, -C₂-C₆-alkenylene and-C₄-C₆-divalent substitution of the radical of alkynylene (alklylene) to form a fused ring, wherein one or two carbon centres may optionally be replaced by 1 or 2 heteroatoms selected from N, O and S, the divalent radical optionally being substituted by one or more heteroatoms selected from-OH, -NH₂、-C₁-C₃-alkyl, -O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃Halo and ═ O;

R₂selected from-H, -halogen, -CN, -O-C₁-C₄-alkyl, -C₁-C₄-alkyl, -CH ═ CH₂、-C≡CH、-CF₃、-OCF₃、-OCF₂H and-OCFH₂；

R₃Selected from the group consisting of-H, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -OCH₃and-CN;

R₄and R₅Independently selected from the group consisting of electron pair, -H, -C₁-C₆-alkyl, -NH₂、-C₃-C₈-cycloalkyl, -C₃-C₈-heterocyclyl, -C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl and-C (O) -N (R)₈，R_8′) Wherein R is₈And R_8′Independently selected from-H and-C₁-C₆-an alkyl group,

wherein R is₄And R₅If not an electron pair or-H, is optionally independently substituted with one or more groups selected from: -halogen, -OH, -CF₃、-CN、-C₁-C₆-alkyl, -O-C₁-C₆-alkyl, -O-C₃-C₈-cycloalkyl, -O-C₃-C₈-heterocyclyl, -O-C₅-C₁₀-aryl, -O-C₅-C₁₀-heteroaryl, -C₀-C₆alkylene-CN, -C₀-C₄alkylene-O-C₁-C₄-alkyl, -C₀-C₄alkylene-O-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-O-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-O-C₅-C₁₀-aryl, -C₀-C₄alkylene-O-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-Q-C₀-C₄-alkyl-N (R)₉，R_9′)、-C₀-C₄alkylene-N (R)₁₀)-Q-C₁-C₄-alkyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₅-C₁₀-aryl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-Q-N (R)₁₁，R_11′)、-C₀-C₄alkylene-N (R)₁₂)-Q-N(R₁₃，R_13′)、-C₀-C₄-alkylene-R₁₄、-C₀-C₄alkylene-Q-C₁-C₆-alkyl, -C₀-C₄alkylene-Q-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-Q-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-Q-C₅-C₁₀Aryl radical, -C₀-C₄alkylene-Q-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-O-Q-N (R)₁₅，R_15′) and-C₀-C₄alkylene-N (R)₁₆)-Q-O-(R₁₇)，

Wherein Q is selected from the group consisting of-C (O) -and-SO₂-，

Wherein R is₁₂、R₁₆Independently selected from-H, -C₁-C₆-alkyl and-C₃-C₆-a cycloalkyl group,

wherein R is₉、R_9′、R₁₀、R₁₁、R_11′、R₁₃、R_13′、R₁₅、R_15′Independently selected from-H and-C₁-C₆-alkyl and-C₃-C₆-a cycloalkyl group,

or wherein R is₉And R_9′、R₁₁And R_11′、R₁₃And R_13′、R₁₅And R_15′Together form-C₂-C₆Alkylene, preferably-C₅-C₆-an alkylene group,

wherein R is₁₄And R₁₇Independently selected from-H, -C₁-C₆-alkyl, -C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl, -C₃-C₈-cycloalkyl and-C₃-C₈-heterocyclyl, wherein the-C₃-C₈-heterocyclyl optionally containing nitrogen and/or-SO in the ring₂-, and wherein R₁₄And R₁₇Optionally substituted with one or more groups selected from: -OH, -OCH₃、-CF₃、-OCF₃-CN, -halogen, -C₁-C₄-alkyl, ═ O and-SO₂-C₁-C₄-an alkyl group,

or wherein R is₄And/or R₅Independently is structure-L₂-R₁₈The group of (a) or (b),

wherein L is₂Selected from-NH-and-N (C)₁-C₄-alkyl) -,

wherein R is₁₈Is selected from-C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl, -C₃-C₈-cycloalkyl and-C₃-C₈-a heterocyclic group,

wherein R is₁₈Optionally substituted with one or more groups selected from: halogen, -CF₃、-OCF₃、-CN、-OH、-O-C₁-C₄-alkyl, -C₁-C₆-alkyl, -NH-C (O) -C₁-C₆-alkyl, -N (C)₁-C₄-alkyl) -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-alkyl, -S (O)₂-C₁-C₆-alkyl, -NH-S (O)₂-C₁-C₆-alkyl, -N (C)₁-C₄-alkyl) -S (O)₂-C₁-C₆Alkyl and-C (O) -O-C₁-C₆-an alkyl group,

and wherein R₄、R₅And R₁₈Optionally further spiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl substitution thereby reacting with R₄、R₅And/or R₁₈Together form a spiro ring, wherein the spiro-C₃-C₈-heterocyclyl optionally containing in the ring one or more substituents selected from nitrogen, -C (O) -, -SO₂-and-N (SO)₂-C₁-C₄-an alkyl) -group(s),

or wherein R is₄、R₅And R₁₈Optionally further substituted by one or more groups selected from-C₁-C₆Alkylene, -C₂-C₆-alkenylene and-C₄-C₆Divalent substitution of one or two carbon centres by one or two heteroatoms chosen from N, O and S, and the divalent radical being optionally substituted on one or two adjacent ring atoms by one or more atoms chosen from-OH, -NH₂、-C₁-C₃Alkyl, O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃And halogen;

R₆is selected from-H, -C₁-C₄-alkyl, -OH, -O-C₁-C₄-alkyl, -halogen, -CN, -CF₃and-OCF₃；

A is selected from single bond, ═ CH-, -CH₂-, -O-, -S-and-NH-;

n is 1,2 or 3;

z is C or N.

Preferred compounds of formula (I) according to the invention are R₂、R₃、R₄、R₅、R₆、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₂Z, Q and n are as defined above or below, wherein R is₁is-L₁-R₇，

Wherein L is₁Is a linking group selected from a bond or from-C₁-C₂Alkylene and-C₁-C₂A radical of alkenylene, -C₁-C₂Alkylene and-C₁-C₂-alkenylene optionally comprising in the chain one or more groups selected from-O-, -C (O) -and-NH-and optionally substituted by a group selected from-OH, -NH₂、-C₁-C₃Alkyl, O-C₁-C₆-alkyl and-CN groups,

wherein R is₇Is a ring selected from: -C₃-C₈-cycloalkyl, -C₅-C₁₀-aryl, -C comprising 1 or 2 heteroatoms selected from N and O₃-C₈-heterocyclyl and-C comprising 1 or 2 heteroatoms selected from N and O₅-C₁₀-a heteroaryl group,

wherein the ring R₇Optionally substituted by one or more groups selected from-CF₃、-O-CF₃A group of-CN and-halogen,

or wherein the ring R₇Optionally substituted with one or more groups selected from: -C₁-C₆-alkyl, -O-C₁-C₆-alkyl, -C₅-C₁₀-aryl, -C₃-C₈-cycloalkyl, -C₃-C₈-heterocyclyl, -C₁-C₆-alkenyl and-C₁-C₆Alkynyl, these radicals optionally being substituted by one or moreEach is selected from-OH and-NH₂、-C₁-C₃-alkyl, -O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃Halogen and ═ O,

or wherein the ring R₇Optionally further substituted by one or more groups selected from-C₁-C₆Alkylene, -C₂-C₆-alkenylene and-C₄-C₆Divalent substitution of a fused ring-forming group of alkynylene, in which one or two carbon centres may optionally be replaced by 1 or 2 heteroatoms selected from N and O, and in which the divalent radical is optionally substituted by one or more groups selected from-OH, -NH₂、-C₁-C₃-alkyl, -O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃Halo and ═ O;

preferred compounds of formula (I) according to the invention are R₂、R₃、R₄、R₅、R₆、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₂Z, Q and n are as defined above or below, wherein R is₁is-L₁-R₇，

Wherein L is₁Is a linking group selected from the group consisting of a bond, methylene, ethylene, methyleneene and vinylene,

wherein L is₁If not a bond, optionally substituted with one or more groups selected from methyl and ethyl,

wherein R is₇Is a ring selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridinyl, and furanyl,

wherein the ring R₇Optionally substituted with one or more groups selected from: -F, -Cl, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -tert-butyl, -CF₃、-O-CF₃-CN, -O-methyl, -furyl and-phenyl, wherein the furyl and the phenyl are optionally independently substituted with one or more groups selected from-C₁-C₆-alkyl, halogen, -OCH₃、-CF₃and-OCF₃Is substituted with a group (b).

Or wherein R is₇Divalent substitution on two adjacent ring atoms with one or more groups selected from the group consisting of:

preferred compounds of formula (I) according to the invention are R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₂Z, Q and n are as defined above or below, wherein R is₁is-L₁-R₇，

And wherein L₁Is a linking group selected from the group consisting of a bond, methylene, ethylene, methyleneene and vinylene, and wherein L₁Optionally substituted by one or more methyl or ethyl groups, and wherein L₁Optionally containing one or more-O-atoms.

Preferred compounds of formula (I) according to the invention are R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₂Z, Q and n are as defined above or below, wherein R is₁Is selected from

Preferred compounds of formula (I) according to the invention are R₁、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₂Selected from-H, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -butyl, -isobutyl, -tert-butyl, -F, -Cl, -Br, -I, -CN, -CH ═ CH₂-C.ident.CH and-OCH₃More preferably from the group consisting of-H, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl and-OCH₃。

Preferred compounds of formula (I) according to the invention are R₁、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₂Selected from the group consisting of-H, -methyl, -ethyl, -Br and-OCH₃。

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₃Selected from-H and-methyl.

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₆、R₇、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₄And R₅Independently selected from the group consisting of an electron pair, -H, -isopropyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azacyclobutylalkyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and-C (O) -N (R)₈，R_8′) Wherein R is₈And R_8′Independently selected from-H and-C₁-C₆-an alkyl group,

wherein R is₄And R₅Optionally independently substituted with one or more groups selected from: -fluoro, -methyl, -ethyl, -propyl, -isopropyl, -butyl, -isobutyl, -tert-butyl, -hydroxy, -CF₃、-OCF₃、-CN、-O-CH₃、-O-C₂H₅、-O-C₃H₇、-CH₂-CN、-CH₂-O-CH₃、-(CH₂)₂-O-CH₃、-C(O)-CH₃、-C(O)-C₂H₅、-C(O)-C₃H₇、-COOH、-C(O)-NH₂、-C(O)-NH-CH₃、-C(O)-N(CH₃)₂、-NH-C(O)-CH₃、-N(CH₃)C(O)-CH₃、-NH-C(O)-C₂H₅、-N(CH₃)-C(O)-C₂H₅、-NH-C(O)-C₃H₇、-N(CH₃)-C(O)-C₃H₇、-NH-SO₂-CH₃、-N(CH₃)-SO₂-CH₃、-N(C₂H₅)-SO₂-CH₃、-N(C₃H₇)-SO₂-CH₃、-NH-SO₂-C₂H₅、-N(CH₃)-SO₂-C₂H₅、-N(C₂H₅)-SO₂-C₂H₅、-N(C₃H₇)-SO₂-C₂H₅、-NH-SO₂-C₃H₇、-N(CH₃)-SO₂-C₃H₇、-N(C₂H₅)-SO₂-C₃H₇、-N(C₃H₇)-SO₂-C₃H₇、-NH-SO₂-C₃H₅、-N(CH₃)-SO₂-C₃H₅、-N(C₂H₅)-SO₂-C₃H₅、-N(C₃H₇)-SO₂-C₂H₅、-CH₂-NH-SO₂-CH₃、-CH₂-N(CH₃)-SO₂-CH₃、-CH₂-NH-SO₂-C₂H₅、-CH₂-N(CH₃)-SO₂-C₂H₅、-CH₂-NH-SO₂-C₃H₇、-CH₂-N(CH₃)-SO₂-C₃H₇、-CH₂-NH-SO₂-C₃H₅、-CH₂-N(CH₃)-SO₂-C₃H₅、-NH-C(O)-NH₂、-N(CH₃)-C(O)-NH₂、-NH-C(O)-NH-CH₃、-N(CH₃)-C(O)-NH-CH₃、-NH-C(O)-N(CH₃)₂、-N(CH₃)-C(O)-N(CH₃)₂、-SO₂-NH₂、-SO₂-NH(CH₃)、-SO₂-N(CH₃)₂、-C(O)-NH-C₂H₅、-C(O)-N(CH₃)-C₂H₅、-C(O)-N(CH₃)-C₃H₇、-C(O)-N(CH₃)-C₄H₉、-C(O)-NH-CH(CH₃)-C₂H₅、-C(O)-N(CH₃)-CH(CH₃)-C₂H₅、-CH₂-C(O)-NH₂、-CH₂-C(O)-NH-CH₃、-CH₂-C(O)-N(CH₃)₂、-N(CH₃)-SO₂-N(CH₃)₂-phenyl, -pyridin-4-yl, -CH₂-3-methyl-oxetan (oxyethan) -3-yl, -O-1, 2-difluoro-phen-5-yl, -O-pyridin-2-yl, -pyrrolidin-2-one-1-yl, -3, 5-dimethyl- [1,2,4]Triazol-4-yl, -3-methyl- [1,2,4 [ ]]Diazol-5-yl,

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₄And R₅Independently selected from the group consisting of an electron pair, -H, -amino, -piperidinyl, -tetrahydropyranyl and-pyrrolidinyl,

wherein R is₄And R₅Optionally independently substituted with one or more groups selected from: -fluoro, -CF₃-hydroxy, -O-CH₃、-OCF₃、-CN、-NH-SO₂-CH₃、-N(CH₃)-SO₂-CH₃、-N(C₂H₅)-SO₂-CH₃、-N(C₃H₇)-SO₂-CH₃、-NH-SO₂-C₂H₅、-N(CH₃)-SO₂-C₂H₅、-N(C₂H₅)-SO₂-C₂H₅、-N(C₃H₇)-SO₂-C₂H₅、-NH-SO₂-C₃H₇、-N(CH₃)-SO₂-C₃H₇、-N(C₂H₅)-SO₂-C₃H₇、-N(C₃H₇)-SO₂-C₃H₇、-NH-SO₂-C₃H₅、-N(CH₃)-SO₂-C₃H₅、-N(C₂H₅)-SO₂-C₃H₅、-N(C₃H₇)-SO₂-C₂H₅、-CH₂-NH-SO₂-CH₃、-CH₂-N(CH₃)-SO₂-CH₃、-CH₂-NH-SO₂-C₂H₅、-CH₂-N(CH₃)-SO₂-C₂H₅、-CH₂-NH-SO₂-C₃H₇、-CH₂-N(CH₃)-SO₂-C₃H₇、-CH₂-NH-SO₂-C₃H₅、-CH₂-N(CH₃)-SO₂-C₃H₅、-NH-C(O)-NH₂、-N(CH₃)-C(O)-NH₂、-NH-C(O)-NH-CH₃、-N(CH₃)-C(O)-NH-CH₃、-NH-C(O)-N(CH₃)₂、-N(CH₃)-C(O)-N(CH₃)₂、-SO₂-NH₂、-SO₂-NH(CH₃)、-SO₂-N(CH₃)₂、-C(O)-NH-C₂H₅、-C(O)-N(CH₃)-C₂H₅、-C(O)-N(CH₃)-C₃H₇、-C(O)-N(CH₃)-C₄H₉、-C(O)-NH-CH(CH₃)-C₂H₅、-C(O)-N(CH₃)-CH(CH₃)-C₂H₅、-CH₂-C(O)-NH₂、-CH₂-C(O)-NH-CH₃、-CH₂-C(O)-N(CH₃)₂、-N(CH₃)-SO₂-N(CH₃)₂-pyridin-4-yl, -CH₂-3-methyl-oxetan-3-yl, -O-1, 2-difluoro-phen-5-yl, -O-pyridin-2-yl, -pyrrolidin-2-one-1-yl, -3, 5-dimethyl- [1,2,4]Triazol-4-yl, -3-methyl- [1,2,4 [ ]]Diazol-5-yl,

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、A、L₁Z, Q and n are as defined above or below, wherein R is₄And R₅Independently is structure-L₂-R₁₈Wherein L is₂Selected from-NH-, -N (CH)₃) -and-N (C)₂H₅) -, wherein R₁₈Selected from the group consisting of-tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyranopyrrolyl, -octahydro-pyranopyridinyl, -octahydro-pyrano-oxazinyl, -oxaspirodecyl (oxaspirodecanoyl) and-tetrahydro-naphthyridinyl,

wherein R is₁₈Optionally substituted with one or more groups selected from: -F, -CF₃、-OCF₃、-CN、-OH、-O-CH₃、-CH₃、-NH-C(O)-CH₃、-N(CH₃)-C(O)-CH₃、-C(O)-CH₃、-S(O)₂-CH₃、-NH-S(O)₂-CH₃、-N(CH₃)-S(O)₂-CH₃and-C (O) -O-C₂H₅。

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₄、R₅And R₁₈Optionally further divalent substitution on one or two adjacent ring atoms by one or more groups selected fromTo form a spiro or fused ring:

preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₄Is selected from

Preferred compounds of the invention of formula (I) areR₁、R₂、R₃、R₄、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₅Selected from the group consisting of electron pairs, -H and-C (O) -NH₂。

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₄、R₅、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Z, Q and n are as defined above or below, wherein R is₆Is selected from-H, -CH₃、-C₂H₅、-O-CH₃、-O-C₂H₅、-F、-CF₃and-OCF₃And more preferably wherein R₆Selected from H and-O-CH₃And most preferably wherein R₆is-H.

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₃、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、L₁、L₂Z, Q and n are as defined hereinbefore or hereinafter wherein A is selected from the group consisting of single bond, ═ CH-, -CH₂-, -O-and-NH-, and more preferably wherein A is selected from the group consisting of-O-and-NH-, and most preferably itWherein A is-NH-.

Preferred compounds of formula (I) according to the invention are R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_8′、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂Q and N are as defined above or below, wherein Z is selected from C and N, and more preferably wherein Z is C.

All the above embodiments of formula (I) are understood to optionally be present in the following forms: the individual optical isomers thereof, the mixtures thereof or the racemates thereof, as well as the acid addition salts thereof with pharmacologically acceptable acids, and the solvates and/or hydrates thereof.

Definition of

All substituents are independent of each other unless otherwise indicated. For example, if there may be more than one C in a group₁-C₆Alkyl as a substituent, then in three C₁-C₆In the case of an-alkyl substituent, one may represent a methyl group, one may represent an n-propyl group and one may represent a tert-butyl group.

Within the scope of the present application, in the definition of possible substituents, these substituents may also be represented in the form of structural formulae. The asterisk in the structural formula of a substituent is to be understood as the point of attachment to the rest of the molecule.

Further, the substituent atom immediately after the point of attachment is referred to as the atom at position No. 1. Thus, for example, the radicals N-piperidinyl (piperidine-A), 4-piperidinyl (piperidine-B), 2-tolyl (tolyl-C), 3-tolyl (tolyl-D) and 4-tolyl (tolyl-E) are shown below:

a piperidinyl group-A having a structure of a cyclic ether group,a piperidinyl group-B which is a cyclic or cyclic moiety,a tolyl group-C group, which is a phenyl group,

tolyl-D andtolyl-E.

If no asterisk (—) is present in the substituent structural formula, each hydrogen atom can be removed from the substituent and the valency thus released can serve as a binding site for the rest of the molecule. Thus, for example, (tolyl-F) may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl

tolyl-F.

The term "branched or straight chain, saturated or unsaturated C₁-C₆By carbon chain "is meant a chain of carbon atoms consisting of 6 carbon atoms arranged in a row and which may optionally additionally comprise a branch or one or more heteroatoms selected from N, O or S. The carbon chain may be saturated or unsaturated by the inclusion of double or triple bonds.

The term "C₁-C₆Alkyl "(including C as part of another group)₁-C₆-alkyl) refers to branched and straight-chain alkyl groups having 1 to 6 carbon atoms, and the term "C₁-C₄-alkyl "refers to branched and straight-chain alkyl groups having 1 to 4 carbon atoms. Preferably having 1 to 4 carbonsAn alkyl group of atoms. Examples of the alkyl group having 1 to 6 carbon atoms include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl. Optionally, the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be used for the above groups. Unless otherwise indicated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups described. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, sec-butyl, tert-butyl, and the like.

The term "C₁-C₈Alkylene "(including C as part of another group)₁-C₈Alkylene) means branched and straight-chain alkylene having 1 to 8 carbon atoms. The term "C₂-C₈By alkylene is meant both branched and straight chain alkylene groups having from 2 to 8 carbon atoms. The term "C₂-C₆By alkylene is meant both branched and straight chain alkylene groups having 2 to 6 carbon atoms. The term "C₁-C₄By alkylene is meant both branched and straight chain alkylene groups having from 1 to 4 carbon atoms. The term "C₁-C₂By alkylene is meant both branched and straight chain alkylene groups having from 1 to 2 carbon atoms. The term "C₀-C₄By alkylene is meant branched and straight chain alkylene groups having from 0 to 4 carbon atoms and thus also single bonds. The term "C₁-C₃Alkylene "refers to both branched and straight chain alkylene groups having 1 to 3 carbon atoms. C₁-C₈Examples of alkylene groups include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1-dimethylpropylene, 2-dimethylpropylene, 1, 3-dimethylpropylene, hexylene, heptylene or octylene. Unless otherwise indicated, the definitions propylene, butylene, pentylene, hexylene, heptylene and octylene include all possible isomeric forms of the groups described having the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1-Dimethylethylene, 1, 2-dimethylethylene.

If the group of the substituted carbon chain can form, together with one or two carbon atoms of the alkylene chain, a carbocycle having 3,5 or 6 carbon atoms, the carbocycle includes the following ring examples:

the term "C₂-C₆Alkenyl "(including C as part of another group)₂-C₆-alkenyl) means branched and straight chain alkenyl groups having 2 to 6 carbon atoms, and the term "C₂-C₄-alkenyl "means branched and straight chain alkenyl groups having 2 to 4 carbon atoms, provided that they contain at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. C₂-C₆Examples of-alkenyl groups include: ethenyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise indicated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups described. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, and butenyl includes 1-butenyl, 2-butenyl and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, and the like.

The term "methyleneenyl" refers to a group having 1 carbon atom, provided that it is connected by a single bond and the other side is connected by a double bond:

the term "C₂-C₈Alkenylene "(including C as part of another group)₂-C₈-alkenylene) means branched and straight-chain alkenylene having 2 to 8 carbon atoms, and the term "C₂-C₆-alkenylene "means having from 2 to 6 carbon atomsBranched and straight chain alkenylene groups of (4). The term "C₁-C₂-alkenylene "means alkenylene having from 1 to 2 carbon atoms, provided that it has at least one double bond, and the term" C₁-alkenylene "means" methyleneene ". C₂-C₈Examples of the alkenylene group include: vinylidene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1-dimethylvinylene, 1, 2-dimethylvinylene, pentenylene, 1-dimethylpropenylene, 2-dimethylpropenylene, 1, 3-dimethylpropenylene, hexenylene, heptenylene or octenylene. Unless otherwise indicated, the definitions propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the groups having the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene, and butenylene includes 1-methylpropenylene, 1-dimethylethenylene, 1, 2-dimethylethenylene.

The term "C₂-C₆Alkynyl "(including C as part of other groups)₂-C₆-alkynyl) refers to branched and straight chain alkynyl groups having 2 to 6 carbon atoms, and the term "C₂-C₄-alkynyl "means branched and straight chain alkynyl groups having 2 to 4 carbon atoms, provided that they have at least one triple bond. C₂-C₆Examples of-alkynyl groups include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless otherwise indicated, the definitions propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the radicals in question. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-butynyl, 2-butynyl and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl and the like.

The term "C₂-C₈Alkynylene "(including C as part of another group)₂-C₈-alkynylene) means branched and straight chain alkynylene having 2 to 8 carbon atoms, and the term "C₂-C₆-alkynylene "means having 2 to 6 carbon atomsBranched and straight chain alkynylene groups. C₂-C₈Examples of alkynylene groups include: ethynylene, propynyl, 1-methylacetylene, butynyl, 1-methylpropynyl, 1-dimethylethynylene, 1, 2-dimethylethynylene, pentynyl, 1-dimethylpropynyl, 2-dimethylpropynyl, 1, 3-dimethylpropynyl, hexynyl, heptynyl or octynyl. Unless otherwise indicated, the definitions propynylene, butynylene, pentynylene and hexynylene include all possible isomeric forms of the groups having the same number of carbons. Thus, for example, propynyl also includes 1-methylacetylene, and butynyl includes 1-methylpropynyl, 1-dimethylethyleneene, 1, 2-dimethylethyleneene.

The term "ring" refers to a carbocyclic ring that may be saturated, unsaturated, or aromatic and optionally may contain one or more heteroatoms selected from N, O or S.

The term "-C₃-C₈-heterocyclyl "means a 3-, 4-, 5-, 6-or 7-membered saturated or unsaturated heterocyclic ring which may contain one, two or three heteroatoms selected from oxygen, sulphur and nitrogen, while the ring may be attached to the molecule via a carbon atom or via a nitrogen atom, if present. The term "-C₅-C₈-heterocyclyl "means a 5-, 6-or 7-membered saturated or unsaturated heterocyclic ring which may contain one, two or three heteroatoms selected from oxygen, sulphur and nitrogen, while the ring may be attached to the molecule via a carbon atom or via a nitrogen atom, if present. Examples include:

unless otherwise specified, the heterocycle may have a keto group. Examples include:

the term "C₃-C₈Cycloalkyl "(including C as part of another group)₃-C₈-cycloalkyl) means a cyclic alkyl group having 3 to 8 carbon atoms. Also, the term "C₃-C₆-cycloalkyl "refers to a cyclic alkyl group having 3 to 6 carbon atoms. C₃-C₈Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Unless otherwise specified, a cycloalkyl group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo, and iodo.

The term "aryl" (including aryl groups that are part of other groups) refers to aromatic ring systems. The term "C₅-C₁₀Aryl "(including C as part of another group)₅-C₁₀-aryl) means an aromatic ring system having 5 to 10 carbon atoms. Preferably "C₆-C₁₀-aryl ", wherein aromatic ring means having 6 to 10 carbon atoms. Examples include: phenyl or naphthyl. Also preferred is "C₅-C₆Aryl ", wherein aromatic ring means having 5 to 6 carbon atoms. Unless otherwise indicated, the aromatic ring system may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "C₅-C₁₀Heteroaryl "(including C as part of another group)₅-C₁₀Heteroaryl) means a 5-or 6-membered heterocyclic aromatic group or a 5-10 membered bicyclic heteroaryl ring which may contain one, two or three heteroatoms selected from oxygen, sulphur and nitrogen, and which contains a number of conjugated double bonds to form an aromatic system. The following are examples of 5-or 6-or 9-membered heterocyclic aromatic groups:

preference is given to“C₅-C₆Heteroaryl ", wherein aromatic ring means a 5-or 6-membered heterocyclic aromatic group. Unless otherwise specified, these heteroaryl groups may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo, and iodo.

When a general combination of groups (e.g. -X-C) is used₁-C₄-alkyl-, wherein X is a functional group such as-CO-, -NH-, -C (OH) -or the like), the functional group X may be located at-C₁-C₄Either end of the alkyl chain.

The term "spiro-C₃-C₈Cycloalkyl "(spiro) means a 3-8 membered spiro ring, with the ring being attached to the molecule via a carbon atom. The term "spiro-C₃-C₈Heterocyclyl "(spiro) means a 3-8 membered spiro ring which may contain one, two or three heteroatoms selected from oxygen, sulphur and nitrogen, while the ring may be attached to the molecule via a carbon atom or via a nitrogen atom, if present.

Unless otherwise specified, a spiro ring may have oxo, methyl or ethyl. Examples include:

in the context of the present invention, "halogen" denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are considered as preferred halogens.

In the context of the present invention, "linker" denotes a divalent group or a chemical bond. The groups and residues listed above may be combined to form more complex structures consisting of carbon chains, rings, and the like.

The compounds of the general formula (I) can have acidic groups, predominantly carboxyl groups, and/or basic groups, for example amino functions. Thus, the compounds of general formula (I) may exist in the form: internal salt; salts with pharmaceutically acceptable inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid) or organic acids (e.g. maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid); or with a pharmaceutically acceptable base such as an alkali or alkaline earth metal hydroxide or carbonate, zinc hydroxide or ammonium hydroxide or an organic amine such as diethylamine, triethylamine, triethanolamine.

As mentioned above, the compounds of formula (I) can be converted into their salts, in particular into their physiologically and pharmacologically acceptable salts for medical use. In one aspect, these salts may be in the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, if R is hydrogen, the compounds of the formula (I) can also be converted into physiologically and pharmacologically acceptable salts by reaction with inorganic bases, with alkali metal or alkaline earth metal cations as counterions. Acid addition salts can be prepared, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Mixtures of the above acids may also be used. The alkali metal and alkaline earth metal salts of the compounds of the formula (I) are preferably prepared using alkali metal and alkaline earth metal hydroxides and hydrides thereof, of which the hydroxides and hydrides of alkaline earth metals, in particular of sodium and potassium, are preferred and sodium hydroxide and potassium hydroxide are particularly preferred.

If desired, the compounds of the general formula (I) can be converted into their salts, in particular with inorganic or organic acids, into pharmacologically acceptable acid addition salts for medical use. Suitable acids include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid, or citric acid. Mixtures of the above acids may also be used.

The invention relates to said compounds optionally in the form of: individual optical isomers, mixtures of individual enantiomers or racemates, tautomers and also the free bases or the corresponding acid addition salts with pharmacologically acceptable acids, for example with hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or organic acids, such as oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid.

The compounds of the invention may optionally be present in racemic form, but they may also be obtained in pure enantiomeric/diastereomeric form.

The invention relates to said compounds optionally in the form of: individual optical isomers, mixtures of individual enantiomers or racemates, tautomers and also the free bases or the corresponding acid addition salts with pharmacologically acceptable acids, for example with hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or organic acids, such as oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid.

The compounds of formula (I) according to the invention have the above meaning, in particular, where R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R_9′、R₁₀、R₁₁、R_11′、R₁₂、R₁₃、R_13′、R₁₄、R₁₅、R_15′、R₁₆、R₁₇、R₁₈、A、L₁、L₂The preferred embodiments defined by Z, Q and n are in each case selected independently of one another.

Therapeutic applications

The above exemplary materials were tested for binding to CCR2 using the binding assay described below:

cell culture:

at 37 ℃ and 5% CO under standard conditions₂Next, THP-1 cells (human acute monocytic leukemia cells) were cultured in a humidified incubator. THP-1 cells were cultured in RPMI 1640 medium (Gibco21875) containing 1% MEM-NEAA (Gibso 11140), 2mM L-glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 10mM HEPES and 1.0mM sodium pyruvate (90%); 10% fetal calf serum (FCS Gibco 10500-064).

Preparing THP-1 cell membrane. Centrifugation of THP-1 at 300Xg at 4 deg.CCells were run for 10 minutes. The cell pellet (pellet) was resuspended in Phosphate buffered saline (Phosphate BufferSaline) (PBS, containing 10. mu.M Pefabloc and a "complete" protease inhibitor cocktail (Boehringer Mannheim) (1 pellet/50 ml)) to a concentration of 80 cells per ml. Membranes were prepared by dividing cells by Nitrogen decomposition (at 50 bar for 1 hour) from a "Nitrogen bomb (Nitrogen bomber)" (Parr Instrument). Cell debris was removed by centrifugation (800Xg, at 4 ℃ C., 1 min). The supernatant was centrifuged at 80000Xg for 30 minutes at 4 ℃ to pellet the cell membranes. 1 × 10E9 cells typically produced 50mg of protein (Bradford assay). To achieve a concentration of 25mM HEPES, 25mM MgCl₂、1mM CaCl₂Aliquots of 10% glycerol were stored at-80 ℃ and membranes resuspended in 25mM HEPES, 25mM MgCl₂、1mM CaCl₂10% glycerol and stored at-80 ℃.

Receptor membrane binding assay:

perkin Elmer NEX 332Jod 125MCP-1, stock solution: 2200Ci/mmol, dissolved in 2000. mu.l assay buffer and stored at-20 ℃. With 25mM HEPES (pH 7.2); 5mM MgCl₂；0.5mM CaCl₂(ii) a The concentration of THP-1 membrane was adjusted to 2.5. mu.g/15. mu.l with 0.2% BSA assay buffer. The concentration of Amersham Biosciences PVT-WGA beads (RPNQ0001) was adjusted to 0.24 mg/30. mu.l with assay buffer. To prepare the membrane-bead-suspension, the membrane and beads were incubated at room temperature for 30 minutes at a ratio of 1: 2 under rotation (60 rpm). Test compounds were dissolved in 100% DMSO to give a concentration of 10mM, and further diluted to 1mM with 100% DMSO. All other compound dilutions were obtained in assay buffer (final 1% DMSO). Incubation compound, membrane-bead suspension and¹²⁵I]MCP-1 (approximately 25000 cpm/10. mu.l). After 8 hours, bound radioactivity was determined by scintillation counting. Affinity determinations (dissociation constants hKi) for test compounds were calculated by iterative fitting of experimental data using the "easy sys" program based on the law of mass action (Schittkowski K. (1994), Numerische Mathemmatik, Vol.68, 129-142).

All of the above examples have been found to be active at 10. mu.M or less than 10. mu.M in this assay.

Based on the ability of the agents of formula (I) to effectively bind CCR2, a variety of therapeutic applications are contemplated. The present invention provides a method of modulating or treating at least one MCP-1 associated disease known in the art or described herein using at least one CCR2 antagonist of the present invention in a cell, tissue, organ, animal or patient. The present invention also provides a method of modulating or treating at least one MCP-1 associated disease in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: malignant diseases, metabolic diseases, immune or inflammatory related diseases, cardiovascular diseases, infectious diseases or neurological diseases. These conditions are selected from (but not limited to) diseases or conditions mediated by cell adhesion and/or angiogenesis. Such diseases or disorders include immune disorders or diseases; a cardiovascular disorder or disease; infectious, malignant, and/or neurological disorder or disease; or other known or specific MCP-1 associated disorders. In particular, CCR2 antagonists are useful in the treatment of the following diseases: diseases involving inflammation, such as COPD; diseases involving angiogenesis, such as ocular diseases and neoplastic diseases; diseases involving tissue remodeling, such as restenosis; and diseases involving proliferation of specific cell types, particularly epithelial and squamous cell carcinomas. Specific indications include use in the treatment of atherosclerosis, restenosis, cancer metastasis, rheumatoid arthritis, diabetic retinopathy and macular degeneration. These antagonists may also be useful in the treatment of a variety of fibrotic diseases, such as idiopathic pulmonary fibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Accordingly, the present invention provides a method of modulating or treating at least one CCR2 associated disease known in the art or described herein, using at least one CCR2 antagonist of the present invention in a cell, tissue, organ, animal or patient. Specific indications are as follows:

pulmonary diseases

The present invention also provides a method of modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: pneumonia; lung abscess; occupational lung disease caused by substances in the form of dust, gas or mist; asthma, obstructive fibrositis, respiratory failure, allergic lung diseases (including allergic pneumonia (exogenous allergic alveolitis), allergic bronchopulmonary aspergillosis, and drug reactions); adult Respiratory Distress Syndrome (ARDS), Goodpasture's syndrome, chronic obstructive airway disorder (COPD), idiopathic interstitial lung disease (e.g., idiopathic pulmonary fibrosis and sarcoidosis), desquamative interstitial pneumonia, acute interstitial pneumonia, interstitial lung disease associated with respiratory bronchiolitis, idiopathic obstructive bronchiolitis complicated by pneumonia (organonizing pneumoconia), lymphocytic interstitial pneumonia, Langerhans' cell granulomatosis, idiopathic pulmonary hemochromatosis; acute bronchitis, alveolar proteinosis, bronchiectasis, pleural disorders, atelectasis, cystic fibrosis and lung tumors and pulmonary embolisms.

Malignant disease

The present invention also provides a method of modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: leukemia, Acute Lymphoblastic Leukemia (ALL), B-cell ALL, T-cell ALL or FAB ALL, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), chronic lymphocytic leukemia (ClL), hairy cell leukemia, myelodysplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal cancer, pancreatic cancer, renal cell carcinoma, breast cancer, nasopharyngeal cancer, malignant histiocytosis, malignant paraneoplastic syndrome/hypercalcemia of malignant disease, solid tumors, adenocarcinoma, squamous cell carcinoma, sarcoma, malignant melanoma (especially metastatic melanoma), hemangioma, melanoma, and malignant leukemia, Metastatic disease, cancer-related bone resorption, cancer-related bone pain, and the like.

Immune related diseases

The present invention also provides a method of modulating or treating at least one immune-related disorder in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathy, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis (iridococyclitis luteitis neuronitis), idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vas deferens recision, allergic/ectopic disease, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, allergic pneumonia, transplantation, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome (sepsis syndrome), Gram-positive sepsis, gram-negative sepsis, culture-negative sepsis (culture negative sepsis), fungal sepsis, neutropenic fever (neutropenic fever), urinary tract sepsis, meningococcemia, traumatic hemorrhage, burn injury, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory disorders, sarcoidosis, Crohn's disease, sickle cell anemia, diabetes, nephritis, atopic disorders, allergic reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, transplant rejection of any organ or tissue, kidney transplant rejection, liver cancer, kidney cancer, liver cancer, kidney cancer, liver cancer, kidney cancer, Heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, Bone Marrow Transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone transplant rejection, small intestine transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity, Graves disease, Raynaud's disease, insulin-resistant diabetes B, asthma, myasthenia gravis, antibody-mediated cytotoxicity, IU-type hypersensitivity, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, orgamegaly disease), endocrinopathy, monoClonal gammopathy (monoClonal), and cutaneous change syndrome), polyneuropathy, organ megaly disease, endocrinopathy, monoClonal gammopathy, pathological change syndrome, multiple neuropathy, bone marrow transplantation rejection, bone marrow transplant rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small intestine transplant rejection, fetal thymus implant rejection, fetal thymus graft rejection, kidney disease rejection, kidney-thyroid graft rejection, bone marrow transplant rejection, bone graft rejection, Graves rejection, cutaneous change syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes, chronic active hepatitis, primary biliary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, anaphylaxis type IV, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granuloma due to intracellular organisms, drug allergy, metabolism/idiopathic diseases, Wilson's disease, hemochromatosis, J-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis assessment, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, primary biliary cirrhosis, thyroiditis, and primary biliary cirrhosis, Chronic lung disease in neonates, Chronic Obstructive Pulmonary Disease (COPD), familial hemolymphoblastic lymphocytosis (familial hemotoposis), skin disorders, psoriasis, hair loss, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, hemodialysis, uremia, poisoning, preeclampsia, OKT3 therapy, anti-CD 3 therapy, cytokine therapy, chemotherapy, radiation therapy (including, but not limited to, asthenia (astemia), anemia, cachexia, etc.), chronic salicylic acidosis, and the like.

Cardiovascular diseases

The present invention also provides a method of modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: cardiac arrest syndrome (cardiac 25stun syndrome), myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic atherosclerosis, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, pulmonary heart disease, primary pulmonary hypertension, arrhythmia, atrial ectopic beat, atrial flutter, atrial fibrillation (persistent or paroxysmal), post-perfusion syndrome, cardiopulmonary bypass inflammatory response (cardiac by perfusion response), turbulent or multifocal atrial beat tachycardia, regular narrow wave QRS tachycardia, specific arrhythmia, ventricular fibrillation, bundle qrasys arrhythmia (His), atrial ventricular block, bundle branch block, cardiac conduction block, cardiac shock, stroke, ischemic stroke, hemorrhage, arterial sclerosis, atherosclerosis, heart failure, pulmonary embolism, atrial fibrillation, cardiac arrhythmia, Myocardial ischemia, coronary artery disease, angina, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial disease, cardiac tumors, aortic and peripheral aneurysms, aortic dissection, inflammation of the aorta, obstruction of the abdominal aorta and its branches, peripheral vascular disorders, obstructive arterial disease, peripheral atherosclerosis, thromboangiitis obliterans, functional peripheral arterial disease, Raynaud's phenomen and disease, cyanosis of the extremities, erythromelalgia, venous disease, venous thrombosis, varicose veins, arteriovenous fistulas, lymphedema, fatty edema (lipedema), unstable angina, reperfusion injury, post-pump syndrome (post pump syndrome), post-ischemic reperfusion injury, and the like. The method may optionally comprise administering to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist.

Neurological diseases

The present invention also provides a method of modulating or treating at least one neurological disorder in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: neuropathic pain, such as lower back pain, hip pain (hip pain), leg pain, non-herpetic neuralgia, postherpetic neuralgia, diabetic neuropathy, pain induced by nerve injury, neuropathic pain associated with acquired immunodeficiency syndrome (AIDS), nerve injury caused by head trauma, toxins and chemotherapy, phantom limb pain, multiple sclerosis, nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome (thalamic pain syndrome), pain following stroke, central nervous system injury, postoperative pain, carpal tunnel syndrome (carpal tunnel syndrome), trigeminal neuralgia, post-mastectomy syndrome, post-thoracotomy syndrome (post-thoracotomy syndrome), residual limb pain (stump pain), recurrent pain (recurrence pain), neuropathic pain, pain-related hypersensitivity and allodynia, Alcoholism and other drug-induced pain; neurodegenerative diseases, multiple sclerosis, migraine, AIDS dementia complex, demyelinating diseases (e.g., multiple sclerosis and acute transverse myelitis); extrapyramidal and cerebellar diseases, such as corticospinal lesions; basal ganglia disorders or cerebellar disease; hyperkinetic movement disorders (hyperkinetic movement disorders), such as Huntington's Chorea and senile Chorea; drug-induced dyskinesias, such as drug-induced dyskinesias that block CNS dopamine receptors; hypokinetic movement disorders (hypokinetic movement disorders), such as Parkinson's disease; progressive supranuclear palsy (progressive supra-nuclear palsy); structural lesions of the cerebellum; spinocerebellar degenerative disorders, such as, for example, spinocerebellar ataxia, Friedreich's ataxia, cerebellar cortical degeneration, multiple system degeneration (Mencel, dejilin-Thomas), schlaguerung's disease (Shi-Drager), and macchado-Joseph disease (Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multisystemic disorders); demyelinating core disorders (demyelinating core disorders), such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit, such as neuromuscular atrophy (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, spinal muscular atrophy in infants and juvenile spinal muscular atrophy); alzheimer's disease; middle-aged Down syndrome (Down's syndrome in middle age); diffuse Lewy body disease (diffuis Lewy body disease); senile dementia with lewy bodies; Wernike-Korsakoff syndrome (Wernicke-Korsakoff syndrome); chronic alcoholism; Creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease); subacute sclerosing panencephalititis (subacute sclerosing panencephatis), Hallowerdon-Schlemt's disease (Hallerrorden-Spatz disease); and dementia pugilistica, and the like.

Fibrotic disorders

In addition to the conditions and diseases described above, the present invention also provides a method of modulating or treating fibrotic disorders of various etiologies, such as liver fibrosis (including, but not limited to, alcohol-induced cirrhosis, virus-induced cirrhosis, autoimmune-induced hepatitis); pulmonary fibrosis (including but not limited to scleroderma, idiopathic pulmonary fibrosis); renal fibrosis (including, but not limited to, scleroderma, diabetic nephritis, glomerulonephritis, lupus nephritis); skin fibrosis (including, but not limited to, scleroderma, hypertrophic scars (hypertrophic scars) and keloids (keloid scars), burns); myelofibrosis; neurofibromatosis multiplex; fibroids; intestinal fibrosis; and fibrous adhesions resulting from surgery (fibroshese).

The present invention also provides a method of modulating or treating at least one wound, wound or tissue injury or chronic conditions caused by or associated with it in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following conditions: physical injury or trauma associated with surgery (including thoracic, abdominal, cranial, or oral surgery); or wherein the wound is selected from: aseptic wound (aseptic wound), contusion (structured wound), incisional wound (incisional wound), lacerated wound (lacerated wound), non-penetrating wound (non-penetrating wound), open wound, penetrating wound (penetrating wound), perforating wound (penetrating wound), stab wound (penetrating wound), septic wound (septic wound), infarction and subcutaneous wound; or wherein the wound is selected from ischemic ulcers, decubitus ulcers (pressure sore), fistulas (fistulae), severe bites, thermal burns and donor site wounds; or wherein the wound is an aphthous, traumatic or herpes-associated wound. Donor site wounds arise in connection with, for example, moving hard tissue from one part of the body to another part of the body, such as in connection with transplantation. The wounds resulting from these procedures are extremely painful and therefore improved healing is of paramount importance. Wound fibrosis is also controlled by CCR2 antagonist therapy, as the first cells to invade the wound area are neutrophils, followed by monocytes activated by macrophages. Macrophages are thought to be essential for effective wound healing because they are also responsible for phagocytosis of pathogenic organisms and clearance of tissue debris. In addition, many of the factors it releases are involved in the subsequent events of the healing process. Macrophages attract fibroblasts to begin collagen production. Almost all tissue repair processes include early connective tissue formation, stimulation of which and subsequent processes can improve tissue healing, whereas overproduction of connective tissue and collagen can produce fibrotic tissue characterized by inelasticity and hypoxia. The CCR2 antagonists of the present invention are useful in methods of modulating, treating, or preventing the sequelae of wound healing.

Additional therapeutic uses of CCR2 antagonists

The present invention also provides a method of modulating or treating at least one infectious disease in a cell, tissue, organ, animal or patient, including (but not limited to) at least one of the following: acute or chronic bacterial infections, acute and chronic parasitic or infectious processes (infectious processes) including bacterial, viral and fungal infections, HIV infection, HIV neuropathy, meningitis, hepatitis (type A, type B or type C, etc.), septic arthritis, peritonitis, pneumonia, epiglottitis, E.coli 0157: h7, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever (denguehemorrhhagic farm), leishmaniasis (leishmaniasis), leprosy, toxic shock syndrome, streptococcal myositis (streptococcal myositis), gas gangrene, Mycobacterium tuberculosis (mycobacteriosis), intracellular Mycobacterium avium (mycobacteriophagularis), pneumocystis (pneumocystis), pelvic inflammatory disease (pelvic inflammatory disease), infectious bronchitis/epidermitis), epidemic influenza (epidemic influenza A), infectious bronchitis (pelvic inflammatory disease), chronic infectious diseases (epidermitis), and infectious diseases of the kidney, and infectious diseases (epidermitis), and the like, Viral associated hemophagocytic syndrome, viral encephalitis/septic meningitis (viral encephalititisic meningitis), and the like.

Any of the methods of the present invention may comprise administering to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist.

In addition to being useful for human therapy, these compounds are also useful in veterinary medicine for the treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like.

Combination of

The compounds of formula I can be used alone or in combination with other active substances of formula I according to the invention. If desired, the compounds of the formula I can also be used in combination with other pharmacologically active substances. For this purpose, preference is given to using active substances selected from the following: e.g., betamimetics (betamimetics), anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, MRP4 inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists, and PI3 kinase inhibitors, or combinations of two or three thereof, e.g., a compound of formula I in combination with one or two compounds selected from:

-beta mimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists,

-anticholinergics, beta mimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists,

PDE4 inhibitors, corticosteroids, EGFR inhibitors and LTD4 antagonists

EGFR inhibitors, PDE4 inhibitors and LTD4 antagonists

EGFR inhibitors and LTD4 antagonists

-CCR3 inhibitors, iNOS inhibitors (inducible nitric oxide synthase inhibitors), the (6R) -L-erythro-5, 6, 7, 8-tetrahydrobiopterin described in WO2006/120176 (hereinafter referred to as "BH 4") and derivatives thereof, and SYK inhibitors (spleen tyrosine kinase inhibitors)

Anticholinergics, beta mimetics, corticosteroids, PDE4 inhibitors and MRP4 inhibitors.

The invention also comprises combinations of three active substances, each selected from one of the above classes of compounds.

The beta mimetics used are preferably compounds selected from the group consisting of: salbutamol, bambuterol, bitolterol, bromsalterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol (arformoterol), clenbuterol, hexoprenaline, ibuterol, isoproterenol, isoprenaline, levosalbutamol, mabuterol, meluadrine (meluadrine), metaproterenol, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, soterel (solenol), salfenarol, tiaramide, terbutaline, tobuterol (tolibuterol), CHF-1035, HOKU-81, KUL-1248, 3- (4- {6- [ 2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino]-hexyloxy } -butyl) -benzyl-sulfonamide, 5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] l]Sulfonyl } ethyl]-amino } ethyl]-2(3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzo (b)Oxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1,2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoOxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [1, 1-dimethyl-2- (2, 4, 6-trimethylphenyl) -ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylAmino group]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethyl-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 4- (4- {2- [ 2-hydroxy-2- (6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-8-yl) -ethylamino]-2-methyl-propyl } -phenoxy) -butyric acid, 8- {2- [2- (3, 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one and 1- (4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Preferably the betamimetic agent is selected from: bambuterol, bitolterol, carbbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, salfenprotol, terbutaline, tulobuterol, 3- (4- {6- [ 2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino]-alreadyAryloxy } -butyl) -benzenesulfonamide, 5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl]-8-hydroxy-1-quinolin-2-one, 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] e]Sulfonyl } ethyl]-amino } ethyl]-2(3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1,2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoOxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [1, 1-dimethyl-2- (2, 4, 6-trimethylphenyl) -ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1 dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethyl-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 4- (4- {2- [ 2-hydroxy-2- (6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-8-yl) -ethylamino]-2-methyl-propyl } -phenoxy) -butyric acid, 8- {2- [2- (3, 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Particularly preferred betamimetics are selected from: fenoterol, formoterol, salmeterol, 3- (4- {6- [ 2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino]-hexyloxy } -butyl) -benzenesulfonamide, 5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino]Ethanol, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylAmino group]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [1, 1-dimethyl-2- (2, 4, 6-trimethylphenyl) -ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1 dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethyl-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 4- (4- {2- [ 2-hydroxy-2- (6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-8-yl) -ethylamino]-2-methyl-propyl } -phenoxy) -butyric acid, 8- {2- [2- (3, 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-ones and 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoOxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1,2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, optionally in the form of its racemate, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates or hydrates.

According to the invention, particularly preferred ones of these betamimetics are: formoterol, salmeterol, 3- (4- {6- [ 2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino]-hexyloxy } -butyl) -benzenesulfonamide, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [1, 1-dimethyl-2- (2, 4, 6-trimethylphenyl) -ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-one, 6-hydroxy-8- { 1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1 dimethyl-ethylamino]-ethyl } -4H-benzo [1, 4]]Oxazin-3-ones, 8- {2- [2-(4-Ethyl-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-one, 4- (4- {2- [ 2-hydroxy-2- (6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-8-yl) -ethylamino]-2-methyl-propyl } -phenoxy) -butyric acid, 8- {2- [2- (3, 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4]]Oxazin-3-ones and 5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, optionally in the form of its racemate, enantiomers, diastereomers and optionally in the form of a pharmacologically acceptable acid addition salt, solvate or hydrate thereof.

According to the invention, the acid addition salts of the betamimetics are preferably selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate salts, preferably the hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate salts. Of the above acid addition salts, the hydrochloride, methanesulfonate, benzoate and acetate salts are particularly preferred according to the invention.

The anticholinergic used is preferably a compound selected from the group consisting of: tiotropium (tiotropium) salt, oxitropium (oxitropium) salt, flutropium (flutropium) salt, ipratropium (ipratropium) salt, glycopyrronium (glycopyrronium) salt, trospium (trospium) salt, tropine (tropenol)2, 2-diphenylpropionate methylbromide, scopolamine (scopine)2, 2-diphenylpropionate methylbromide, scopolamine 2-fluoro-2, 2-diphenylpropionate methylbromide, tropine 2-fluoro-2, 2-diphenylpcetate methylbromide, tropine 3, 3 ', 4, 4' -tetrafluorobenzilate methylbromide, scopolamine 3, 3 ', 4, 4' -tetrafluorobenzilate methylbromide, tropine 4, 4 '-difluorobenzilate methylbromide, scopolamine 4, 4' -difluorobenzilate formate, flutolanilide methylbromide, flutolanilide, tiotropium (flutropium) salt, ipratrotropium (ipratropium) salt, ipratropium (ipratropium) salt, glycopyrronium (ipratropium) salt, tropine 3, 3 '-difluorobenzilic acid ester methylbromide, scopine 3, 3' -difluorobenzilic acid ester methylbromide, tropine 9-hydroxy-fluorene-9-formate methylbromide, tropine 9-fluoro-fluorene-9-formate methylbromide, scopine 9-hydroxy-fluorene-9-formate methylbromide, scopine 9-fluoro-fluorene-9-formate methylbromide, tropine 9-methyl-fluorene-9-formate methylbromide, scopine 9-methyl-fluorene-9-formate methylbromide, cyclopropyl tropine (cyclopropylpyrophylline) benzilic acid ester methylbromide, cyclopropyl tropine 2, 2-diphenylpropionate methylbromide, pseudoephedrine, and pseudoephedrine, Cyclopropyl tropine 9-hydroxy-xanthene-9-carboxylate methyl bromide, cyclopropyl tropine 9-methyl-fluorene-9-carboxylate methyl bromide, cyclopropyl tropine 9-methyl-xanthene-9-carboxylate methyl bromide, cyclopropyl tropine 9-hydroxy-fluorene-9-carboxylate methyl bromide, methyl cyclopropyl tropine 4, 4' -difluorobenzilate methyl bromide, tropine 9-hydroxy-xanthene-9-carboxylate methyl bromide, scopoletin 9-hydroxy-xanthene-9-carboxylate methyl bromide, tropine 9-methyl-xanthene-9-carboxylate methyl bromide, scopoletin 9-methyl-xanthene-9-carboxylate methyl bromide, scopoletin, scop, Tropine 9-ethyl-xanthene-9-carboxylate methylbromide, tropine 9-difluoromethyl-xanthene-9-carboxylate methylbromide, scopoletin 9-hydroxymethyl-xanthene-9-carboxylate methylbromide, optionally in the form of solvates or hydrates thereof.

In the above salts, the cation tiotropium ion, oxitropium ion, flutolonium ion, ipratropium ion, glycopyrronium ion and trospium ion is a pharmacologically active ingredient. For the anion, the above-mentioned salt preferably may contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as the counter ion. Of all salts, chloride, bromide, iodide and methanesulfonate are particularly preferred.

Tiotropium bromide is particularly important. In the case of tiotropium bromide, the pharmaceutical combination of the invention preferably contains tiotropium bromide in the form of crystalline tiotropium bromide monohydrate, which form is known from WO 02/30928. If tiotropium bromide is used in the pharmaceutical combination according to the invention in anhydrous form, it is preferred to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.

The corticosteroid used herein is preferably a compound selected from the group consisting of: prednisolone, prednisone, butocortexolone propionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, (S) -6, 9-difluoro-17- [ (2-furylcarbonyl) oxy ] -11-hydroxy-16-methyl-3-oxo-androst-1, 4-diene-17-thiocarbonate fluoromethyl ester and (S) -6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1, 4-diene-17-thiocarbonate (2-oxo-tetrahydro-furan-3S-yl) ester, these compounds are optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, solvates and/or hydrates.

Particularly preferred are steroids selected from the group consisting of: flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, (S) -6, 9-difluoro-17- [ (2-furanylcarbonyl) oxy ] -11-hydroxy-16-methyl-3-oxo-androsta-1, 4-diene-17-thiocarbonate fluoromethyl ester and (S) -6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1, 4-diene-17-thiocarbonate (2-oxo-tetrahydro-furan-3S-yl) ester, optionally as racemates thereof, Enantiomers or diastereomers and optionally in the form of salts and derivatives, solvates and/or hydrates thereof.

Particularly preferred are steroids selected from the group consisting of: budesonide, fluticasone, mometasone, ciclesonide and (S) -6, 9-difluoro-17- [ (2-furanylcarbonyl) oxy ] -11-hydroxy-16-methyl-3-oxo-androsta-1, 4-diene-17-thiocarbonate, optionally in the form of the racemate, enantiomers or diastereomers thereof and optionally in the form of salts and derivatives, solvates and/or hydrates thereof.

Each reference to a steroid includes a reference to any salt or derivative, hydrate or solvate thereof which may be present. Examples of possible salts and derivatives of steroids may be their alkali metal salts, such as sodium or potassium salts; a sulfobenzoate salt; a phosphate salt; isonicotinate; an acetate salt; a propionate salt; a dihydric phosphate salt; a palmitate salt; pivalate or furoate.

Other PDE4 inhibitors that may be used are preferably compounds selected from the group consisting of: enprophylline, theophylline, roflumilast, ariflulol (ariflo) (cilomilast), tuofet, pramafungin, limaster, arocrine, atizolium, D-4396(Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N- (3, 5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (-) p- [ (4aR (-) p^*，10bS^*) -9-ethoxy-1, 2, 3, 4, 4a, 10 b-hexahydro-8-methoxy-2-methylbenzo [ s ]][1，6]Naphthyridin-6-yl]-N, N-diisopropylbenzamide, (R) - (+) -1- (4-bromobenzyl) -4- [ (3-cyclopentyloxy) -4-methoxyphenyl]-2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N' - [ N-2-cyano-S-methyl-isothioureido]Benzyl) -2-pyrrolidone, cis [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]2-methoxycarbonyl (carbome)thoxy) -4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohex-1-one, cis [ 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohex-1-ol](R) - (+) - [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene]Ethyl acetate, (S) - (-) - [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene]Ethyl acetate, 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3, 4-c]-1,2, 4-triazolo [4, 3-a]Pyridine and 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3, 4-c]-1,2, 4-triazolo [4, 3-a]Pyridine, optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates.

The PDE4 inhibitor is particularly preferably selected from: enpropenaphthalene, roflumilast, aclofluoro (cilomilast), aronacine, aciconazole, AWD-12-281(GW-842470), T-440, T-2585, PD-168787, V-11294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370, N- (3, 5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid ], 2-methoxycarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohex-1-one, Cis [ 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol ], 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3, 4-c ] -1,2, 4-triazolo [4, 3-a ] pyridine and 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3, 4-c ] -1,2, 4-triazolo [4, 3-a ] pyridine, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, the use of such compounds as pharmaceutical preparations, pharmaceutical compositions and pharmaceutical compositions, Solvate and/or hydrate forms.

The acid addition salts which the above PDE4 inhibitors are able to form with pharmacologically acceptable acids are meant to be, for example, salts selected from the following: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate.

LTD4 antagonists which may be used are preferably compounds selected from the group consisting of: montelukast, pranlukast, zafirlukast, MCC-847(ZD-3523), MN-001, MEN-91507(LM-1507), VUF-5078, VUF-K-8707, L-733321, 1- (((R) - (3- (2- (6, 7-difluoro-2-quinolyl) vinyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid, 1- (((1(R) -3(3- (2- (2, 3-dichlorothieno [3, 2-b ] pyridin-5-yl) - (E) -vinyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane-acetic acid, and [2- [ [2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl ] oxymethyl ] phenyl ] acetic acid, optionally in the form of its racemate, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts thereof, and optionally in the form of salts and derivatives, solvates and/or hydrates thereof.

The LTD4 antagonist is preferably selected from: montelukast, pranlukast, zafirlukast, MCC-847(ZD-3523), MN-001, MEN-91507(LM-1507), VUF-5078, VUF-K-8707, and L-733321, optionally in the form of their racemates, enantiomers, or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, and optionally in the form of their salts and derivatives, solvates, and/or hydrates.

LTD4 antagonists are particularly preferably selected from: montelukast, pranlukast, zafirlukast, MCC-847(ZD-3523), MN-001, and MEN-91507(LM-1507), optionally in the form of their racemates, enantiomers, or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, and optionally in the form of their salts and derivatives, solvates, and/or hydrates.

An acid addition salt of an LTD4 antagonist, which is capable of forming with a pharmacologically acceptable acid, refers to a salt selected, for example, from the following: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate. Salts or derivatives which LTD4 antagonists are able to form are meant, for example: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts; a sulfobenzoate salt; a phosphate salt; isonicotinate; an acetate salt; a propionate salt; a dihydric phosphate salt; a palmitate salt; pivalate or furoate.

The EGFR inhibitor used is preferably a compound selected from the group consisting of: 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-diethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- Cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) - 6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- ((S) -6-methyl-2-oxo -morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (N, N-bis- (2-methoxy-ethyl) -amino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-ethyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (tetrahydropyran-4-yl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline - ((R) -tetrahydrofuran-3-yloxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopentyloxy-quinazoline, a pharmaceutically acceptable salt thereof, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, n-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6, 7-bis- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -7- [3- (morpholin-4-yl) -propoxy ] -6- [ (vinylcarbonyl) amino ] -quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2, 3-d ] pyrimidine, 3-cyano-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-ethoxy-quinoline, 4- { [ 3-chloro-4- (3-fluoro-benzyloxy) -phenyl ] amino } -6- (5- { [ (2-methanesulfonyl-ethyl) amino ] methyl } -furan-2-yl) quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -oxo-2-buten-1-yl ] amino } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N, N-bis- (2-methoxy-ethyl) -amino ] -1-oxo-2-buten-1-yl } amino) -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, a, 4- [ (3-ethynyl-phenyl) amino ] -6- { [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -6- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl ] -ethoxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-Butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier thereof, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidine- 3-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholine-4-yl) -yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (piperidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7- Methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (tetrahydropyran-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } - Cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) sulfonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidine-4-carboxylic acid Benzyloxy) -7-ethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy- Quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (piperidin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (4-methyl-piperazin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-isopropoxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-methylamino- Cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ N- (2-methoxy-acetyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid or salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (S, S) - (2-oxa-5-aza-bicyclo [2, 2, 1] hept-5-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (N-methyl-N-2-methoxyethyl-amino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-ethyl-piperidin-4-yloxy) - 7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methoxyethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (3-methoxypropyl-amino) -carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline -methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline -methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -quinazoline -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and maicr-62, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, pharmaceutically acceptable salts of the acids, pharmaceutically acceptable salts of the salts, and pharmaceutically acceptable salts thereof, Solvate and/or hydrate forms.

Preferably, the EGFR inhibitor is selected from: 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-diethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- Cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) - 6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- ((S) -6-methyl-2-oxo -morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (N, N-bis- (2-methoxy-ethyl) -amino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-ethyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (tetrahydropyran-4-yl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline - ((R) -tetrahydrofuran-3-yloxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopentyloxy-quinazoline, a pharmaceutically acceptable salt thereof, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, n-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6, 7-bis- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -7- [3- (morpholin-4-yl) -propoxy ] -6- [ (vinylcarbonyl) amino ] -quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2, 3-d ] pyrimidine, 3-cyano-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7-ethoxy-quinoline, 4- { [ 3-chloro-4- (3-fluoro-benzyloxy) -phenyl ] amino } -6- (5- { [ (2-methanesulfonyl-ethyl) amino ] methyl } -furan-2-yl) quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -oxo-2-buten-1-yl ] amino } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N, N-bis- (2-methoxy-ethyl) -amino ] -1-oxo-2-buten-1-yl } amino) -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, a, 4- [ (3-ethynyl-phenyl) amino ] -6- { [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -6- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl ] -ethoxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-Butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier thereof, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidine- 3-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholine-4-yl) -yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (piperidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7- Methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (tetrahydropyran-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } - Cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) sulfonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidine-4-carboxylic acid Benzyloxy) -7-ethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy- Quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (piperidin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (4-methyl-piperazin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-isopropoxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-methylamino- Cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ N- (2-methoxy-acetyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid or salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acid, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (S, S) - (2-oxa-5-aza-bicyclo [2, 2, 1] hept-5-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (N-methyl-N-2-methoxyethyl-amino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-ethyl-piperidin-4-yloxy) - 7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methoxyethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (3-methoxypropyl-amino) -carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline -methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline -methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -quinazoline Yl ] -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, and cetuximab, these compounds are optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, solvates and/or hydrates.

Within the scope of the present invention, it is particularly preferred to use EGFR inhibitors selected from the group consisting of: 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo- 2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (tetrahydropyran-4-yl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopentyloxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, n-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6, 7-bis- (2-methoxy-ethoxy) -quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2, 3-d ] pyrimidine, 3-cyano-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl -yl ] amino } -7-ethoxy-quinoline, 4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- { [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl ] -ethoxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-3-yl Oxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (piperidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-form -4- { N- [ (piperidin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy-quinazoline ) -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (N-methyl-N-2-methoxyethyl-amino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7 -methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, and 4-, [2 ] (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methoxyethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, optionally in the form of its racemate, enantiomers or diastereomers, optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates.

Particularly preferred EGFR inhibitors of the present invention are compounds selected from the group consisting of: 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -7- [ (S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6, 7-bis- (2-methoxy-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-yl ] -quinazoline -oxo-2-buten-1-yl ] amino } -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- { [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino } -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-in-yl) -3-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier thereof, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methoxyethyl) carbonyl ] -piperidine-4-carboxylic acid Aryloxy } -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexane-1- Aryloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, optionally in the form of its racemate, enantiomers or diastereomers, optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates.

An acid addition salt of an EGFR inhibitor capable of forming with a pharmacologically acceptable acid is for example a salt selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate.

Examples of dopamine agonists that can be used preferably include compounds selected from the group consisting of: bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxylindole, ropinirole, talipexole, terguride and vesuvin (viozan). Within the scope of the present invention, each reference to the aforementioned dopamine agonist includes reference to any pharmacologically acceptable acid addition salt and optionally hydrate thereof, if any. The physiologically acceptable acid addition salts which the aforementioned dopamine agonists can form refer to, for example, pharmaceutically acceptable salts selected from: hydrochloride, hydrobromide, sulphate, phosphate, methanesulphonate, acetate, fumarate, succinate, lactate, citrate, tartrate and maleate.

Examples of H1 antihistamines preferably include compounds selected from the group consisting of: epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedasine, dimetinden, clemastine, pamirine, dexchlorphenamine, pheniramine, doxylamine, chlorphenxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine (desloratidine), and meclizine. Within the scope of the present invention, each reference to the aforementioned H1 antihistamine includes a reference to any pharmacologically acceptable acid addition salt thereof that may be present.

Examples of PAF antagonists preferably include compounds selected from the group consisting of: 4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanon-1-yl]-6H-thieno [3, 2-f]-[1，2，4]Triazolo [4, 3-a][1，4]Diaza derivatives6- (2-chlorophenyl) -8, 9-dihydro-1-methyl-8- [ (4-morpholinyl) carbonyl]-4H, 7H-cyclopenta [4, 5 ]]Thieno [3, 2-f][1，2，4]Triazolo [4, 3-a][1，4]Diaza derivatives

The MRP4 inhibitor used is preferably a compound selected from the group consisting of: n-acetyl-dinitrophenyl cysteine, cGMP, cholate, diclofenac, 3-glucuronic acid dehydroepiandrosterone (dehydroepiandrosterone 3-glucuronide), 3-sulfuric acid dehydroepiandrosterone (dehydroepiandrosterone 3-sulphate), delazipride, dinitrophenyl-s-glutathione, 17- β -glucuronic acid estradiol, 3, 17-hydrogen-sulfuric acid estradiol (estradiol 3, 17-disulphate), 3-glucuronic acid estradiol, 3-sulfuric acid estrone, flurbiprofen, folic acid, N5-formyl-tetrahydrofolic acid, glycocholate (glycocholate), glycolithocholic acid (glycolithocholic acid), ibuprofen, indomethacin, indoprofen, ketoprofen, sulfuric acid, methotrexate, MK ((E) -3- [ [ [3- [2- (7-chloro-2-quinolinyl) ethylene-3-quinolinyl ] vinyl acetate, ibuprofen, indomethacin, ketoprofen, lithospermum, MK Phenyl ] - [ [ 3-dimethylamino ] -3-oxopropyl ] thio ] methyl ] thio ] -propionic acid), alpha-naphthyl-beta-D-glucuronic acid, nitrobenzyl mercaptopurine glycoside (nitrobenzyl mercaptopurine glycoside), probenecid, PSC833, sildenafil (sildenafil), sulpirone, taurochenodeoxycholate (taurochenodeoxycholate), taurocholate, taurodeoxycholate, taurocholic sulfate, topotecan, ququizacin and zaprinast, dipyridamole, optionally in the form of their racemates, enantiomers, diastereomers and pharmacologically acceptable acid addition salts and hydrates.

The present invention preferably relates to the use of an MRP4 inhibitor for the preparation of a pharmaceutical composition for the treatment of a respiratory disorder, the pharmaceutical composition contains a PDE4B inhibitor and an MRP4 inhibitor, the MRP4 inhibitor is preferably selected from N-acetyl-dinitrophenyl-cysteine, 3-dehydroepiandrosterone sulfate, delazipu, dinitrophenyl-S-glutathione, 3, 17-estradiol hydrogen sulfate, flurbiprofen, glycocholate, glycocholic acid sulfate, ibuprofen, indomethacin, indoprofen, lithocholic acid sulfate, MK571, PSC833, sildenafil, taurocholate, taurocholic acid sulfate, trequizaline and zaprinast, dipyridamole, these compounds are optionally in the form of their racemates, enantiomers, diastereomers and pharmacologically acceptable acid addition salts and hydrates.

More preferably, the present invention relates to the use of an MRP 4-inhibitor for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, comprising a PDE4B inhibitor and an MRP4 inhibitor according to the invention, the MRP4 inhibitor being preferably selected from the group consisting of dehydroepiandrosterone 3-sulphate, estradiol 3, 17-sulphate, flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionally in the form of their racemates, enantiomers, diastereomers and pharmacologically acceptable acid addition salts and hydrates. Enantiomers can be separated from racemates using methods known in the art (e.g., chiral phase chromatography, etc.).

Acid addition salts with pharmacologically acceptable acids mean, for example, salts selected from the following: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate.

The invention also relates to pharmaceutical preparations containing a combination of a PDE4B inhibitor, an MRP4 inhibitor and another active substance according to the invention (e.g. an anticholinergic, a steroid, an LTD4 antagonist or a beta mimetic), and to the production and use thereof for the treatment of respiratory diseases.

The iNOS inhibitors used are preferably compounds selected from the group consisting of: s- (2-aminoethyl) isothiourea, aminoguanidine (aminoguanidinine), 2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, S-methylthiocitrulline, S-ethylthiocitrulline, L-NA (N^ω-nitro-L-arginine), L-NAME (N)^ω-nitro-L-arginine methyl ester), L-NMMA (N)^Gmonomethyl-L-arginine), L-NIO (N)^ω-iminoethyl-L-ornithine), L-NIL (N)^ω-iminoethyl-lysine), (S) -6-iminoethyl (ethylimidoyl) amino-2-amino-hexanoic acid (1H-tetrazol-5-yl) -amide (SC-51) (J.Med.chem.2002, 45, 1686-]-3H-imidazo [4, 5-b]Pyridine (BYK191023) (mol. Pharmacol.2006, 69, 328-337), 2- ((R) -3-amino-1-phenyl-propoxy) -4-chloro-5-fluorobenzonitrile (WO 01/62704), 2- ((1R, 3S) -3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -6-trifluoromethyl-nicotinonitrile (nicotinonitril) (WO2004/041794), 2- ((1R, 3S) -3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -4-chloro-benzonitrile (WO2004/041794), 2- ((1R, 3S) -3-amino-4-hydroxy-1-thiazole.-5-yl-butylsulfanyl) -5-chloro-benzonitrile (WO2004/041794), (2S, 4R) -2-amino-4- (2-chloro-5-trifluoromethyl-phenylsulfanyl) -4-thiazol-5-yl-butan-1-ol (WO2004/041794), 2- ((1R, 3S) -3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -5-chloro-nicotinonitrile (WO2004/041794), 4- ((S) -3-amino-4-hydroxy-1-phenyl-butylsulfanyl) -6-methoxy-nicotinonitrile (WO 02/090332), Substituted 3-phenyl-3, 4-dihydro-1-isoquinolinamines (e.g. AR-C102222) (J.Med.chem.2003, 46, 913-) 916), (1S, 5S, 6R) -7-chloro-5-methyl-2-aza-bicyclo [4.1.0]Hept-2-en-3-ylamine (ONO-1714) (biochem. Biophys. Res. Commun.2000, 270, 663-), (4R, 5R) -5-ethyl-4-methyl-thiazolidin-2-ylideneamine (bioorg. Med. chem.2004, 12, 4101), (4R, 5R) -5-ethyl-4-methyl-selenazolidine) -2-ylideneamine (bioorg. Med. chem. Lett.2005, 15, 1361), 4-aminotetrahydrobiopterin (curr. DrugMetabol.2002, 3, 119- -121), (E) -3- (4-chloro-phenyl) -N- (1- { 2-oxo-2- [4- (6-trifluoromethyl-pyrimidin-4-yloxy) -piperidin-1-yl-piperidine]-ethylcarbamoyl } -2-pyridin-2-yl-ethyl) -acrylamide (FR260330) (eur.j. pharmacol.2005, 509, 71-76), 3- (2, 4-difluoro-phenyl) -6- [2- (4-imidazol-1-ylmethyl-phenoxy) -ethoxy]-2-phenyl-pyridine (PPA250) (j. pharmacol. exp. ther.2002, 303, 52-57), 3- { [ (benzo [ 1.3)]Dioxolen-5-ylmethyl) -carbamoyl]-methyl } -4- (2-imidazol-1-yl-pyrimidin-4-yl) -piperazine-1-carboxylic acid methyl ester (BBS-1) (Drugs Future2004, 29, 45-52), (R) -1- (2-imidazol-1-yl-6-methyl-pyrimidin-4-yl) -pyrrolidine-2-carboxylic acid (2-benzo [ 1.3)]Dioxol-5-yl-ethyl) -amide (BBS-2) (Drugs Future2004, 29, 45-52) and pharmaceutically salts, prodrugs or solvates thereof.

Other iNOS inhibitors that can be used within the scope of the present invention are antisense oligonucleotides, particularly antisense oligonucleotides that bind to nucleic acids encoding iNOS. For example, WO01/52902 discloses antisense oligonucleotides for modulating expression of iNOS, in particular antisense oligonucleotides that bind to nucleic acids encoding iNOS. These iNOS antisense oligonucleotides (disclosed in particular in WO 01/52902) can therefore also be combined with the PDE4 inhibitors of the present invention, based on their activity similar to that of iNOS inhibitors.

Compounds useful as SYK inhibitors are preferably selected from R343 or R788.

Pharmaceutical preparation

Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. In each case, the amount of pharmaceutically effective compound should be in the range of 0.1% to 90%, preferably 0.5% to 50% by weight of the total composition, i.e. an amount sufficient to achieve the dosage range specified below.

The formulations may be administered orally in the form of tablets, powders in capsules (e.g., hard gelatin capsules), solutions or suspensions. When administered by inhalation, the active substance combination may be provided in the form of a powder, an aqueous solution or an aqueous ethanol solution or using a propellant gas formulation.

Preferred pharmaceutical preparations are therefore characterized in that they contain one or more compounds of the formula I of the preferred embodiments described above.

It is particularly preferred to administer the compounds of formula I orally, and it is also particularly preferred to administer them once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose; disintegrating agents, such as corn starch or alginic acid; binders, such as starch or gelatin; lubricants, such as magnesium stearate or talc; and/or a release-delaying agent, such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise multiple layers.

Coated tablets may accordingly be prepared by coating cores prepared analogously to tablets with substances customarily used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or to prevent incompatibilities, the core may also be composed of multiple layers. Similarly, the tablet coating may be composed of multiple layers to achieve delayed release, which may be achieved using the excipients described above for the tablets.

Syrups containing the active substances of the invention or combinations thereof may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar; and taste enhancers, such as flavoring agents (e.g., vanillin or orange extract). It may also contain suspension adjuvants or thickeners (e.g. sodium carboxymethylcellulose), wetting agents (e.g. condensation products of fatty alcohols with ethylene oxide) or preservatives (e.g. parabens).

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and filling them in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing with carriers provided for this purpose, such as neutral lipids or polyethylene glycols or derivatives thereof.

Excipients that may be used include, for example, water; pharmaceutically acceptable organic solvents, for example paraffins (e.g. petroleum fractions), vegetable oils (e.g. arachis oil or sesame oil), mono-or polyhydric alcohols (e.g. ethanol or glycerol); carriers, for example, natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

For oral administration, the tablets may of course contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and calcium hydrogen phosphate, and various additives such as starch (preferably potato starch), gelatin and the like. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance may be combined with various taste enhancers or colorants in addition to the excipients mentioned above.

It is also preferred to administer the compounds of formula I by inhalation, particularly preferably once or twice daily. For this purpose, the compounds of the formula I must be brought into a form suitable for inhalation. Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable solutions, optionally in admixture with physiologically acceptable well-known excipients.

Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The formulations that can be used according to the invention are described in more detail in the next part of the description.

Inhalable powder

If the active substance of the formula I is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the preparation of the inhalable powders according to the invention: monosaccharides (such as glucose or arabinose), disaccharides (such as lactose, sucrose, maltose), oligo-and polysaccharides (such as polydextrose), polyols (such as sorbitol, mannitol, xylitol), salts (such as sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Preferably, mono-or disaccharides are used, wherein lactose or glucose are preferably used, especially (but not limited to) in their hydrate form. For the purposes of the present invention, lactose is a particularly preferred excipient, with lactose monohydrate being particularly most preferred. Methods for preparing inhalable powders by grinding and micronization and finally mixing the components together are known from the prior art.

Inhalable aerosols containing propellant

The propellant-containing inhalable aerosols which can be used according to the invention can contain 1 dissolved in the propellant gas or in dispersed form. Propellant gases which can be used for the preparation of the inhalation aerosols of the invention are known from the prior art. Suitable propellant gases are selected from hydrocarbons, such as n-propane, n-butane or isobutane; and halocarbons, preferably fluorinated derivatives such as methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases may be used individually or in mixtures. Particularly preferred propellant gases are fluorinated alkane derivatives selected from the group consisting of TG134a (1, 1, 1, 2-tetrafluoroethane), TG227(1, 1, 1,2, 3, 3, 3-hexafluoropropane) and mixtures thereof. The propellant-driven inhalation aerosol used in the context of the use according to the invention may also contain other ingredients, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH regulators. All of these ingredients are known in the art.

Propellant-free inhalable solutions

The compounds of the formula I according to the invention are preferably used for the preparation of propellant-free inhalable solutions and inhalable suspensions. Solvents for this purpose include aqueous or alcoholic solutions, preferably alcoholic solutions. The solvent may be water alone or a mixture of water and ethanol. The solution or suspension may be adjusted to a pH of 2 to 7, preferably 2 to 5, using a suitable acid. The pH can be adjusted using an acid selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid, and the like. Preferred mineral acids are hydrochloric acid and sulfuric acid. Acids which have formed an acid addition salt with one of the active substances can also be used. Among the organic acids, preferred are. Ascorbic, fumaric and citric acids mixtures of the above acids may also be used if desired, for example especially if the acids have other properties than acidifying properties (for example as flavouring, antioxidant or complexing agent, for example citric acid or ascorbic acid). According to the invention, hydrochloric acid is particularly preferably used for adjusting the pH value.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions for the purposes of the present invention. Preferred cosolvents are cosolvents containing hydroxyl groups or other polar groups, such as alcohols (especially isopropanol), glycols (especially propylene glycol), polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In the present context, the terms excipient and additive mean an active substance which is not active, but which can be formulated with the active substance in a pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulationAny pharmacologically acceptable substance of matter. Preferably, these substances have no pharmacological effect, or, when combined with the desired therapy, no significant pharmacological effect or at least no undesirable pharmacological effect. Such excipients and additives include, for example, surfactants (e.g., soy lecithin, oleic acid, sorbitan esters (e.g., polysorbates), polyvinylpyrrolidone), other stabilizers, complexing agents, antioxidants and/or preservatives that ensure or extend the shelf life of the finished pharmaceutical formulation, flavoring agents, vitamins, and/or other additives known in the art. The additive also includes a pharmacologically acceptable salt (e.g., sodium chloride) as an isotonic agent. Preferred excipients include antioxidants such as ascorbic acid (provided that it has not been used to adjust the pH), vitamin a, vitamin E, tocopherol, and similar vitamins or provitamins present in the human body. Preservatives can be used to protect the formulation from pathogen contamination. Suitable preservatives are those known in the art, especially cetylpyridinium chloride(cetylpyridinium chloride), benzalkonium chloride or benzoic acid or benzoate, for example in concentrations known from the prior art. For the above treatment forms, a ready-to-use pharmaceutical package for the treatment of respiratory diseases is provided, containing packaged instructions, including for example the following text: respiratory diseases, COPD or asthma, pteridine and one or more combination drugs (combination partner) selected from the group consisting of the above.

Experimental methods and Synthesis examples

List of abbreviations

CAN acetonitrile

APCI atmospheric pressure chemical ionization (MS)

Ctrl control

DAD diode array detector

DMA N, N-dimethylacetamide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EI electronic impact (MS)

ESI electrospray ionization (MS)

ex examples

GC/MS gas chromatography-mass spectrometry combined detection

h hours

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphoric acid

Salt (salt)

HPLC high performance liquid chromatography

HPLC/MS high performance liquid chromatography mass spectrometry combination

min for

MS Mass Spectrometry

NMR nuclear magnetic resonance

R_tRetention time (HPLC)

sec second, sec

TBTU O- (1H-benzo-1, 2, 3-triazol-1-yl) -N, N, N ', N' -tetramethylureaBoron tetra-fluoride

Acid salts

tert

TFA trifluoroacetic acid

TLC thin layer chromatography

UV absorption

Analytical method

HPLC method

The method comprises the following steps:

·1A

column: sunfire MS-C8, 5 μm, 4.6X 100mm

Mobile phase: a ═ 10nM NH₄Aqueous COOH solution) + 10% ACN;

B＝ACN+10％(10nM NH₄aqueous COOH solution).

Flow rate: 1500 mul/min

Gradient: A/B (95/5%) was held for 1 minute and then reached A/B within 10 minutes

(5/95%) and held for 2 minutes.

·1E

Column: symmetry C8, 5 μm, 3X 150mm

Mobile phase: a ═ 10nM NH₄Aqueous COOH solution) + 10% ACN;

B＝ACN+10％(10nM NH₄aqueous COOH solution).

Flow rate: 1200 mu L/min

Gradient: a (100%) was held for 1.5 minutes and then reached B (100%) in 10 minutes

And kept for 3 minutes

·1E(Fusion)

Column: synergy Fusion RP80A, 4 μm, 4.6X 100mm

Mobile phase: a ═ 10nM NH₄Aqueous COOH solution) + 10% ACN;

B＝ACN+10％(10nM NH₄aqueous COOH solution).

Flow rate: 1200 mu L/min

Gradient: a (100%) was held for 1.5 minutes and then reached B (100%) in 10 minutes

And kept for 3 minutes

·1E(Hydro)

Column: synergy Hydro RP80A, 4 μm, 4.6X 100mm

Mobile phase: a ═ 10nM NH₄Aqueous COOH solution) + 10% ACN;

B＝ACN+10％(10nM NH₄aqueous COOH solution).

Flow rate: 1200 mu L/min

Gradient: a (100%) was held for 1.5 minutes and then reached B (100%) in 10 minutes

And kept for 3 minutes

Equipment:

the instrument comprises the following steps: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,

and (3) detection: UV at 254nm

And (3) detection: finnigan MSQ (four-pole)

An ion source: APCI

The method comprises the following steps:

·1F

column: xterra MS-C8, 3.5 μm, 4.6X 50mm

Mobile phase: a ═ H₂O+0.1％TFA)+10％ACN；B＝ACN

Flow rate: 1300 mu L/min

Gradient: a (100%), then A/B (10/90%) was achieved within 3.25 minutes and was preserved

For 0.75 minute

·1Fa

Column: xterra MS-C18, 5 μm, 4.6X 50mm

Mobile phase: a ═ H₂O+0.1％NH₄COOH)+10％ACN；

B＝ACN

Flow rate: 1300 mu L/min

Gradient: a (100%), followed by 3.25 min to A/B (10/90%) and hold

0.75 min

Equipment:

the instrument comprises the following steps: HPLC/MS Waters, Hplc Alliance 2695DAD, ZQ (quadrupole)

And (3) detection: UV at 254nm

And (3) detection: waters ZQ (quadrupole);

an ion source: ESI

The method comprises the following steps:

·2A

column: X-Terra MS C184.6X 50mm, 3.5 μm;

column temperature: 40.0 deg.C

Mobile phase: a ═ H₂O+0.1％TFA；B＝ACN+0.1％TFA

Flow rate: 1500 mul/min

Gradient:

·2B

column: X-Terra MS C184.6X 50mm, 3.5 μm;

column temperature: 40.0 deg.C

Mobile phase: a ═ H₂O+0.1％TFA；B＝ACN+0.1％TFA

Flow rate: 1000 uL/min

Gradient:

·2C

column: sunfire C184.6X 50mm, 3.5 μm;

column temperature: 40.0 deg.C

Mobile phase: a ═ H₂O+0.1％TFA；B＝ACN+0.1％TFA

Flow rate: 1500 mul/min

Gradient:

device

The instrument comprises the following steps: waters ZQ2000 mass spectrometer

And (3) detection: HP1100HPLC + DAD (wavelength range: 210 to 500nM) + Gilson

215 auto-sampler

An ion source: ESI +

The method comprises the following steps:

·2Ca

column: MERCK; chromolith Flash; RP18 e; 25X 4.6mm

Mobile phase: a + water + 0.1% HCOOH; b ═ ACN + 0.1% HCOOH

Flow rate: 1.6ml/min

Gradient:

·2Cb

column: MERCK; chromolith Flash; RP18 e; 25X 4.6mm

Mobile phase: a + water + 0.1% HCOOH; MeOH ═ B

Flow rate: 1.6ml/min

Gradient:

device

The instrument comprises the following steps: agilent Technology; HP 1200 series, DAD SL

And (3) detection: UV 240-

And (3) detection: waters ZQ (Single quadrupole)

An ion source: ESI +

The method comprises the following steps:

·2F

column: symmetry Shield RP8, 5 μm, 4.6X 150mm

Mobile phase: a ═ H₂O+HCOOH 0.1％)+10％ACN

B＝ACN+10％(H₂O+0.1％HCOOH)

Flow rate: 1000 uL/min

Gradient: A/B (95/5%) was held for 1.5 minutes and then reached within 10 minutes

A/B (5/95%) and hold for 1.5 minutes

·2M

Column: symmetry Shield RP8, 5 μm, 4.6X 150mm

Mobile phase: a ═ H₂O+HCOOH 0.1％)+10％ACN

B＝ACN+10％(H₂O+0.1％HCOOH)

Flow rate: 1200 mu L/min

Gradient: A/B (90/10%) was held for 1.5 minutes and then reached within 10 minutes

(5/95%) and held for 2 minutes

Equipment:

the instrument comprises the following steps: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,

LCQduo ion trap

And (3) detection: UV lambda 254nm

And (3) detection: finnigan LCQDuo ion trap

An ion source: ESI

The method comprises the following steps:

·2G

eluent: a ═ H₂O+0.05％TFA；B＝ACN

Column: waters SunAire C1830X 100mm 5 μm

Gradient: slope: 5%/min

The operation was stopped after 12 minutes; the pre-operation method comprises the following steps: in initial conditions 3

Minute (min)

Equipment:

the method comprises the following steps:

·2Ga

column: BEH C18, 1.8 μm, 2.1X 100mm

Mobile phase: a ═ H₂O+NH₄COOH 0.1％)

B＝ACN+10％H₂O

Flow rate: 450 mu L/min

Gradient: 100% A for 1.5 min, followed by 100% B in 2.2 min

·2Gb

Column: BEH C18, 1.7 μm, 2.1X 50mm

Mobile phase: a ═ H₂O 90％+0.1％TFA+10％ACN

B＝ACN+10％H₂O

Flow rate: 480 mu L/min

Gradient: A/B (90: 10) was then achieved and maintained within 1.2 minutes

0.46 minute

Equipment:

the instrument comprises the following steps: UPLC/MS Acquity Waters

And (3) detection: UV lambda 254nm

And (3) detection: waters SQD (four poles)

An ion source: ESI

The method comprises the following steps:

2H (isocratic)

Column: DAICEL (IC)5 μm, 4.6X 250mm

Mobile phase: a ═ hexane + 0.2% diethylamine; b ═ MeOH/EtOH 50/50%.

A/B＝50/50％

Flow rate: 1ml/min

2I (equal gradient)

Column: DAICEL AS-H5 μm, 4.6X 250mm

Mobile phase: a ═ hexane; B-EtOH (con AS-H), IPA (con AD-H)

A/B＝98/2％

Flow rate: 1ml/min

Device

The instrument comprises the following steps: LC Agilent technologies hplc 1100 series, DAD form a.

And (3) detection: UV 220-300nm

GC-MS method:

the method comprises the following steps:

·3A

column: agilent DB-5MS, 25 m.times.0.25 mm.times.0.25 μm

Carrier gas: helium, constant flow rate of 1ml/min

Oven procedure: 50 deg.C (holding for 1 min), 10 deg.C/min to 100 deg.C, 20 deg.C/min

Reaching 200 deg.C, and reaching 300 deg.C at 30 deg.C/min

Device

The instrument comprises the following steps: GC/MS Finnigan TRACE GC, TRACE MS (quadrupole)

And (3) detection: TRACE MS (quadrupole)

An ion source: EI (El)

Microwave heating:

equipped with 10mL and 35mL containersA CEM instrument.

Synthesis of intermediates

Intermediate 1a

Potassium hydroxide (37.9g, 0.67mol) was suspended in 200ml of anhydrous ethanol, formamidine acetate (28.1g, 0.27mol) and diethyl oxalopropionate (50ml, 0.27mol) were added, and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature, and the formed precipitate was filtered, washed with ethanol and ether, dissolved in 200ml of water, and the resulting solution was acidified with 37% aqueous hydrochloric acid until pH 2. The acidic aqueous solution was concentrated under vacuum and the resulting residue was suspended in 100ml of methanol and stirred. The insoluble inorganic salts are filtered off. The solution was concentrated. 15g (97.4mmol) of the desired compound are obtained.

Intermediate 1b

The synthesis was carried out analogously to intermediate 1a starting with acetamidine hydrochloride.

Intermediate 1c

Potassium tert-butoxide (185.4g, 1.65mol) was dissolved in 650ml of anhydrous ethanol and slowly added to a suspension of diethyl 2-ethyl-3-oxo-succinate (274.3g, 1.27mol) and formamidine acetate (171.4g, 1.65mol) at-10 ℃. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and ice water was added. The mixture was acidified with 37% aqueous hydrochloric acid until pH 5, and extracted with chloroform. After drying the organic layer, the solvent was evaporated in vacuo and crystallized from ethyl acetate/hexane (2: 3) to give 38g (0.19mol) of the desired compound.

Intermediate 1d

A suspension of sodium tert-butoxide (3.9g, 40.5mmol) in 25ml of absolute ethanol was added to a solution of diethyl oxaloacetate (3.0ml, 16.2mmol) and O-methylisourea hydrochloride (2.15g, 19.5mmol) in 25ml of absolute ethanol and the reaction mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC to give the desired product (752mg, 3.5 mmol).

Intermediate 1e

Intermediate 1d (550mg, 2.6mmol) was dissolved in 4M aqueous sodium hydroxide (3.0ml, 12.0mmol) and stirred at room temperature for 3 hours. The reaction mixture was acidified with concentrated hydrochloric acid to give the desired product as a precipitate (443mg, 2.4 mmol).

Intermediate 2a

Intermediate 1a (7.0g, 45.4mmol) was suspended in 35ml thionyl chloride (0.45mol), 0.10ml DMF was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated in vacuo. 8.6g (45mmol) of the desired product are obtained and used in the next step without further purification.

Intermediate 2b

The synthesis was carried out analogously to intermediate 2a starting from intermediate 1 b.

Intermediate 2c

The synthesis was carried out analogously to intermediate 2a starting from intermediate 1 e.

Intermediate 3a

Potassium carbonate (43.34g, 0.31mol) was suspended in 350ml of anhydrous ethanol. A solution of intermediate 2a (20g, 0.10mol) in 10ml of dichloromethane was slowly added at 0 ℃. The reaction mixture was brought to room temperature and stirred for 1 hour. The potassium carbonate was filtered off and the solvent was removed under vacuum. The crude product was purified by flash chromatography (BIOTAGESP 1; silica gel column: 65 i; eluent dichloromethane/ethyl acetate 95/5%). 5.3g (26mmol) of the desired compound are obtained.

Intermediate 3b

The synthesis was carried out analogously to intermediate 3a starting from intermediate 2 b.

Intermediate 3c

Intermediate 1c (38g, 0.19mol) was added to a mixture of phosphorus pentachloride (40.3g, 0.19mol) in 240ml of phosphorus oxychloride. The reaction mixture was refluxed until a clear solution was observed. The reaction mixture was concentrated in vacuo. The resulting crude product was purified by distillation in vacuo. 12g (94.5mmol) of the desired compound are obtained and used in the next step without further purification.

Intermediate 3d

Ethyl 5-bromo-6-hydroxy-pyrimidine-4-carboxylate (63g, 0.26mol) was suspended in 140ml of phosphorus oxychloride. Phosphorus pentachloride (54g, 0.26mmol) was added and the reaction mixture was refluxed for 72 hours. The reaction mixture was concentrated in vacuo and the crude product was suspended in warmed hexane (50 ℃) and stirred; a precipitate formed and was filtered off. The filtrate was concentrated in vacuo to give 64g (243mmol) of the desired product, which was used in the next step without further purification.

Intermediate 4a

10ml of 1, 2-dimethoxyethane containing 3-phenylcyclohexanone (500mg, 2.87mmol) and 1-isocyanomethylsulfonyl-4-methyl-benzene (750mg, 3.84mmol) were stirred at 0 ℃. A solution of potassium tert-butoxide (650mg, 5.79mmol) in 10ml of 1, 2-dimethoxyethane and 20ml of tert-butanol was added dropwise and the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was diluted with ether and washed with ice water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. 439mg (2.3mmol) of the desired product are obtained.

Intermediate 4b

The synthesis was carried out analogously to intermediate 4a starting from (R) -3-phenylcyclohexanone.

GC/MS (method 3A) R_t11.52 min and 11.68 min (mixture of diastereomers)

[M]⁺＝185

Intermediate 4c

The synthesis was carried out analogously to intermediate 4a starting from (S) -3-phenylcyclohexanone.

GC/MS (method 3A) R_t11.50 min and 11.65 min (mixture of diastereomers)

[M]⁺＝185

The following intermediates were synthesized analogously to intermediate 4 a.

Intermediate 4n

Intermediate 4j (400mg, 2.11mmol) was purified by flash chromatography (Biotage SP1 column 25 g; eluent: cyclohexane/ethyl acetate 99/1%). 60mg (0.22mmol) of the diastereomerically pure cis intermediate are eluted as a second fraction (relative stereochemical configuration determined by NMR).

GC/MS (method 3A) R_t9.62 minutes.

[M]⁺＝189。

Intermediate 4o

Intermediate 4n (120mg, 4.22mmol) was isolated by chiral semi-preparative HPLC. 20mg of enantiomerically pure intermediate 4o (unknown absolute stereochemical configuration) are obtained.

Chiral HPLC (method 2I (isocratic)) R_t6.94 min.

Intermediate 4p

Further elution of the column gave 20mg of enantiomerically pure intermediate 4p (unknown absolute stereochemical configuration).

Chiral HPLC (method 2I (isocratic)) R_t＝7.27。

Intermediate 5

Intermediate 4b (2.1g, 11.28mmol) was stirred in 20ml of 96% sulfuric acid and 20ml of water under reflux overnight. The reaction mixture was cooled, treated with 30% aqueous sodium hydroxide and ice, and washed with dichloromethane. The aqueous alkaline phase was treated with 37% aqueous hydrochloric acid. The aqueous acidic solution was extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. 1.85g (9.1mmol) of the desired compound are obtained as a mixture of diastereomers and are used in the next step without further purification.

Intermediate 6a

Intermediate 5(1.85g, 9.06mmol, mixture of 2 diastereomers) and triethylamine (2.02ml, 14mmol) were stirred in 10ml of tetrahydrofuran at 0 ℃. A solution of ethyl chloroformate (1.29ml, 13.58mmol) in 5ml of tetrahydrofuran was added dropwise, and the reaction mixture was stirred at 0 ℃ for 1 hour. Subsequently, 10ml of 30% aqueous ammonium hydroxide solution was added dropwise, and the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, dissolved with dichloromethane, washed with 1M aqueous sodium hydroxide, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel column 70 g; eluent dichloromethane/methanol 99/1%). 145mg (0.71mmol) of diastereoisomerically pure (1R, 3R) -3-phenyl-cyclohexanecarboxamide are obtained (relative stereochemical configuration determined by NMR).

GC/MS (method 3A) R_t12.88 min.

[M]⁺＝203。

Intermediate 6b

The column was further eluted, yielding 230mg (1.13mmol) of diastereomerically pure (1S, 3R) -3-phenyl-cyclohexanecarboxamide (relative stereochemical configuration determined by NMR).

GC/MS (method 3A) Rt 13.03 min.

[M]⁺＝203。

Intermediate 6c

Intermediate 4c (300mg, 1.61mmol) was stirred in 2ml of 96% sulfuric acid and 2ml of water under reflux for 3 hours. The reaction mixture was cooled, treated with 30% aqueous sodium hydroxide solution and ice, and washed with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute silica gel column 20 g; eluent dichloromethane/methanol 99/1%). 37mg (0.18mmol) of diastereoisomerically pure (1S, 3S) -3-phenyl-cyclohexanecarboxamide are obtained (relative stereochemical configuration determined by NMR).

GC/MS (method 3A) R_t12.88 min.

[M]⁺＝203。

Intermediate 6d

The column was further eluted to give 40mg (0.2mmol) of diastereoisomerically pure (1R, 3S) -3-phenyl-cyclohexanecarboxamide (relative stereochemical configuration determined by NMR).

GC/MS (method 3A) R_t13.03 min.

[M]⁺＝203。

Intermediate 6e

5-bromo-3-furancarboxylic acid (1.0g, 5.23mmol), phenylboronic acid (0.77g, 6.28mmol), tetrakis (triphenylphosphine) palladium (0) (1.21g, 1.04mmol) and 2M sodium carbonate solution (6.28ml, 12.57mmol) were dissolved in 12ml of 1, 2-dimethoxy-ethane and the reaction mixture was stirred at 80 ℃ under nitrogen atmosphere for 18 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and treated with 1M aqueous hydrochloric acid until pH 1. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The carboxylic acid was obtained and used without further purification for the synthesis of intermediate 6e analogously to intermediate 6 a.

Intermediate 6f

Intermediate 6f was synthesized analogous to intermediate 6a starting from trans 3- (4-chlorophenyl) -cyclobutanecarboxylic acid (prepared according to Wiberg, K.B., Dailey, W.P., Walker, F.H., Waddell, S.T., Crocker, L.S., Newton, M.journal of the American Chemical Society; 1985, 107, 7247-.

Intermediate 6g

Intermediate 6g was synthesized analogous to intermediate 6a starting from cis 3- (4-chlorophenyl) -cyclobutanecarboxylic acid (prepared according to Wiberg, K.B., Dailey, W.P., Walker, F.H., Waddell, S.T., Crocker, L.S., Newton, M.journal of the American Chemical Society; 1985, 107, 7247-.

Intermediate 7a

Intermediate 4a (390mg, 2.10mmol) and Raney Nickel (Raney-Nickel) (10mg) were stirred under hydrogen atmosphere (4 bar) in 10ml of a 1M solution of ammonia in ethanol overnight. The reaction mixture was filtered through a pad of celite and concentrated under vacuum. By flash chromatography (dichloromethane/methanol/NH)₃The crude product was purified (30% aqueous solution) ═ 95/5/0.1%) to give 217mg (1.15mmol) of the desired product.

Intermediate 7b

2.85ml of a 1M solution of lithium aluminum hydride (2.85mmol) in tetrahydrofuran were dissolved in 10ml of tetrahydrofuran and stirred at 0 ℃ under a nitrogen atmosphere. A solution of intermediate 6a (145mg, 0.71mmol) in 10ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at 0 ℃ for 2 hours, and then quenched with water and ice. The reaction mixture was extracted with dichloromethane. The organic phase was washed with 1M aqueous sodium hydroxide, brine, dried over sodium sulfate and concentrated in vacuo. 100mg (0.55mmol) of the desired product are obtained.

GC/MS (method 3A) R_t11.53 min.

[M]⁺＝189。

Intermediate 7c

The synthesis was performed analogously to intermediate 7b starting from intermediate 6 b.

GC/MS (method 3A) R_tAfter 11.47 minutes.

[M]⁺＝189。

Intermediate 7d

The synthesis was performed analogously to intermediate 7b starting from intermediate 6 c.

GC/MS (method 3A) R_t11.53 min.

[M]⁺＝189。

Intermediate 7e

The synthesis was performed analogously to intermediate 7b starting from intermediate 6 d.

GC/MS (method 3A) R_t13.03 min.

[M]⁺＝189。

The following intermediates were synthesized analogously to intermediate 7 a.

Intermediate 7r

The synthesis was performed analogously to intermediate 7b starting from intermediate 6 e.

Intermediate 7s

The synthesis was performed analogously to intermediate 7b starting from intermediate 6 f.

Intermediate 7t

Obtained and isolated as a by-product in the preparation of intermediate 7 s.

Intermediate 7u

The synthesis was carried out analogously to intermediate 7b starting from intermediate 6 g.

Intermediate 7v

Obtained and isolated as a by-product in the preparation of intermediate 7 u.

Intermediate 8a

Tri (dibenzylideneacetone) dipalladium (1.71g, 1.87mmol) and 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (2.32g, 3.72mmol) were stirred in 30ml of toluene under an argon atmosphere for 10 minutes.

Piperidin-3-yl-methyl-carbamic acid tert-butyl ester (2g, 9.33mmol), bromobenzene (1.27ml, 0.01mol) and sodium tert-butoxide (1.43g, 14.93mmol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was filtered through a pad of celite. The organic phase was washed with saturated aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was dissolved in methanol and loaded on an SCX column (25 g). After washing with methanol, the product was eluted with 2M ammonia in methanol. 1.17g (4.03mmol) of the desired product are obtained and used in the next step without any further purification.

Intermediate 9a

To intermediate 8a (1.1g, 3.79mmol) in 10ml1, 4-bis1, 4-Di-1, 4M hydrochloric acid added dropwise to a solution in an alkaneAlkane solution (15ml, 60 mmol); the reaction mixture was stirred at room temperature overnight and then concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica column: 50 g; eluent: dichloromethane/methanol-95/5%). 250mg (1.31mmol) of the desired compound are obtained.

The following intermediates were synthesized analogously to intermediates 8a and 9 a.

Intermediate 10

Piperidin-3-yl-methyl-carbamic acid tert-butyl ester (100mg, 0.47mmol), 2-chloro-4-fluoro-benzonitrile (72.5mg, 0.47mmol) and N, N-diisopropylethylamine (0.160ml, 1.23mmol) were dissolved in 10ml DMF and the reaction mixture was stirred at 125 ℃ overnight. The reaction mixture was concentrated in vacuo, and the crude product was purified by flash chromatography (Isolute silica gel column: 5 g; eluent: ethyl acetate). 125mg (0.36mmol) of the desired compound are obtained.

Intermediate 11

To intermediate 10(125mg, 0.36mmol) in 5ml 1, 4-bis1, 4-Di-1, 4M hydrochloric acid added dropwise to a solution in an alkaneAlkane solution (0.12ml, 480 mmol); the reaction mixture was stirred at room temperature overnight and then concentrated under vacuum. 102mg (0.36mmol) of the desired compound are obtained.

Intermediate 12

Cooling a solution of tert-butyl 4-methanesulfonylamino-piperidine-1-carboxylate (500 mg; 1.79mmol) in 5ml acetonitrile to-5 deg.C, iodoethane (308mg, 1.79mmol) and sodium hydride (96mg, 3.59mmol) were added; the reaction mixture was warmed to room temperature and stirred for 72 hours.

The reaction mixture was concentrated under vacuum; the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with water.

The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel column: 10g, eluent: dichloromethane) to give 332mg (1.1mmol) of the desired compound.

Intermediate 13

To intermediate 12(330mg, 1.1mmol) in 20ml 1, 4-bis1, 4-Di-1, 4M hydrochloric acid added dropwise to a solution in an alkaneAlkane solution (4.06ml, 16 mmol); the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 262mg (1.1mmol) of the desired compound.

Intermediate 14

Trans-4-azido-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (1.6g, 6.24mmol), Pd/C10% (200mg) and acetic acid (1.6ml) were dissolved in 25ml of methanol and the reaction mixture was stirred under a hydrogen atmosphere (4 bar) for 3 hours. The reaction mixture was filtered through a pad of celite and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP1 column 65i, eluent: dichloromethane/methanol 95/5%). 900mg (3.91mol) of the desired compound are obtained.

Intermediate 15a

Intermediate 14(900mg, 3.91mmol) and N, N-diisopropylethylamine (0.86ml, 5mmol) were dissolved in 25ml dichloromethane. The reaction mixture was cooled to 0 ℃ and methanesulfonyl chloride (0.33ml, 4.30mmol) was added. The reaction mixture was stirred at 0 ℃ for 20 minutes, followed by addition of water. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute silica gel column: 10g, eluent: hexane/ethyl acetate 50/50%). 170mg (0.55mol) of the desired compound are obtained.

Intermediate 15b

Intermediate 15a (350mg, 1.l3mmol) and potassium carbonate (157mg, 1.13mmol) were dissolved in 15ml acetonitrile and stirred. A solution of iodomethane (0.071ml, 1.13mmol) in 5ml of acetonitrile was added dropwise and the reaction mixture was warmed to 60 ℃ overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, separated, dried over sodium sulfate and concentrated in vacuo. 300mg (0.93mmol) of the desired compound are obtained and used in the next step without further purification.

Intermediate 16a

Intermediate 15a (170mg, 0.55mmol) was stirred at 10 ℃ in 2ml 1, 4-bisSolution in an alkane. 1, 4-bis with dropwise addition of 4M hydrochloric acidAlkane solution (8ml, 32mmol) and the reaction mixture stirred at room temperatureCompound 5 hours. The reaction mixture was concentrated in vacuo to give 115mg (0.55mmol) of the desired compound.

Intermediate 16b

The synthesis was carried out analogously to intermediate 16a starting from intermediate 15 b.

Intermediate 17

The synthesis was performed analogously to intermediate 15a starting from (3S, 4R) -4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester.

Intermediate 18

Intermediate 17(660mg, 2.14mmol) was stirred at 10 ℃ in 10ml1, 4-bisSolution in an alkane. Trifluoroacetic acid (2ml, 26mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give 600mg (1.86mmol) of the desired compound, which was used in the next step without further purification.

Intermediate 19a

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11g, 47.91mmol) was suspended in 200ml1, 2-dichloroethane, N-diisopropylethylamine (17.12ml, 96.17mmol) and 1- (tert-butyloxycarbonyl) -piperidin-4-one (9.58g, 48.08mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (12.23g, 57.50mmol) was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate.

The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP 1; silica gel column: 65 i; eluent: ethyl acetate/methanol 50/50%) to yield 7.2g (19.2mmol) of the desired compound.

Intermediate 20a

Intermediate 19a (7.2g, 19.2mmol) was suspended in 20ml of 1, 4-bisTo the alkane, 4M hydrochloric acid in 1, 4-bisAlkane solution (48ml, 192 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. 6.3g (18mmol) of the desired compound are obtained.

The following intermediates were synthesized analogously to intermediates 19a and 20 a.

Intermediate 19la

4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (500mg, 1.87mmol) was suspended in 10ml of 1, 2-dichloroethane. Tetrahydro-pyran-4-one (0.17ml, 1.87mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (593mg, 2.80mol) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate.

The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel column 10 g; eluent dichloromethane/methanol 94/6%). 240mg (0.80mmol) of the desired compound are obtained.

Intermediate 20la

Intermediate 19la (240mg, 0.80mmol) was suspended in 10ml of 1, 4-bisTo the alkane, 1, 4-bis containing 4M hydrochloric acid was added dropwiseAlkane solution (2.0ml, 8.0 mmol). Stirring at room temperatureThe reaction mixture was allowed to react for 18 hours. The reaction mixture was concentrated under vacuum. 200mg (0.74mmol) of the desired compound are obtained.

The following intermediates were synthesized analogously to intermediates 19la and 20la

Intermediate 19m

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (1.13g, 4.95mmol) was suspended in 10ml1, 2-dichloroethane, N-diisopropylethylamine (2.6ml, 14.9mmol) and N-ethoxycarbonyl-3-methoxy-piperidin-4-one (1g, 4.95mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.16g, 14.85mol) was added, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate.

The organic phase was dried over sodium sulfate and concentrated under vacuum. 1.5g (3.97mmol) of the desired compound are obtained and used without further purification.

Intermediate 20m

Intermediate 19m (1.5g, 3.97mmol) and potassium hydroxide (4.46g, 7.94mmol) were suspended in 25ml ethanol and the reaction mixture was stirred under reflux overnight. The reaction mixture was concentrated in vacuo and the crude product was loaded onto an SCX column (25g) and eluted with 2M ammonia in methanol. 1.2g (3.97mmol) of the desired compound are obtained.

Intermediate 21

Piperidin-4-yl-carbamic acid tert-butyl ester (6g, 30mmol) and 1- (benzyloxycarbonyl) -4-oxopiperidine (9.6g, 48mmol) are dissolved in 50ml dichloromethane and the reaction mixture is stirred at room temperature for 30 minutes; sodium triacetoxyborohydride (12.23g, 57.5mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was treated with acetone/isopropyl ether and the precipitate was filtered off. 8.4g (20mmol) of the desired product are obtained.

Intermediate 22

Intermediate 21(8.4g, 20mmol) pre-cooled to 0 ℃ was added to 150ml 1, 4-bisTo the solution in alkane was added 12.6ml (50mmol) of 1, 4-bis-hydrochloric acid 4M dropwiseAn alkane solution; the reaction mixture was warmed to room temperature and stirred at this temperature overnight. The solid precipitated from the reaction mixture was filtered off and dried under vacuum at 50 ℃ to give 6g (15mmol) of the desired compound.

Intermediate 23

Intermediate 22(6.0g, 15mmol) was suspended in 55ml dichloromethane; triethylamine (6.43ml, 46mmol) was added and the reaction mixture was cooled to 0 ℃ and stirred at this temperature for 30 min. Methanesulfonyl chloride (1.43ml, 18mmol) was added dropwise to a solution of 5ml dichloromethane. The reaction mixture was stirred at 0 ℃ for 1 hour; water was then added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was treated with diisopropyl ether and the precipitate was filtered off and dried to yield 5g (13mmol) of the desired product.

Intermediate 24

Intermediate 23(5g, 13mmol) was dissolved in 50ml methanol; acetic acid (1.5ml, 25.3mmol) and Pd/C10% (500mg) were added successively and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (3 bar) for 5 days. The reaction mixture was filtered through a pad of celite and the organic phase was loaded onto an SCX column (10 g). After washing with methanol, the desired compound was eluted with 2M ammonia in methanol. 3.7g (4.6mmol) of the title compound are obtained.

Intermediate 25a

Intermediate 24(1.1g, 4.21mmol) was suspended in 20ml of anhydrous dichloromethane, N-diisopropylethylamine (1.47ml, 8.42mmol) and DMF (137 μ l, 1.67mmol) were added and the reaction mixture was stirred under nitrogen atmosphere and cooled to 0 ℃. Intermediate 2a (812mg, 4.21mmol) was added dropwise to a solution of 5ml dichloromethane and the reaction mixture was warmed to room temperature and stirred for 1.5 hours; the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (isolute silica gel column: 10 g; eluent dichloromethane/methanol-95/5%). 1.0g (2.41mmol) of the title compound are obtained.

The following intermediates were synthesized analogously to intermediate 25 a.

Intermediate 26a

Intermediate 3a (10g, 49.35mmol) and N, N-diisopropylethylamine (17ml, 99mmol) were dissolved in 20ml anhydrous DMF; a solution of 2- (3, 4-dichloro-phenyl) -ethylamine (9.57g, 49.35mmol) in 10ml anhydrous DMF was added and the reaction mixture was stirred at 90 ℃ for 2 h. Cooling the reaction mixture to room temperature, adding water and extracting the reaction mixture with dichloromethane; the organic phase is concentrated under vacuum, the crude product is suspended in diethyl ether and stirred, and the precipitate is filtered off and dried. 10.2g (28.8mmol) of the desired compound are obtained.

Intermediate 27a

Intermediate 26a (10.0g, 28.25mmol) was dissolved in 70ml ethanol and a solution of LiOH (3.52g, 83.88mmol) in 70ml water was added. The reaction mixture was stirred at 70 ℃ for 1 hour, concentrated under vacuum and the residual aqueous solution was taken up with 20ml of 4M hydrochloric acid 1, 4-bisAcidifying the alkane solution; the precipitate formed is filtered off and dried. 8.6g (26.37mmol) of the desired product are obtained.

The following intermediates were synthesized analogously to intermediates 26a and 27 a.

Intermediate 26i

Intermediate 3d (2g, 7.53mmol) and N, N-diisopropylethylamine (1.97ml, 11.3mmol) were dissolved in 15ml anhydrous DMF; 4-tert-butyl-benzylamine (1.6ml, 9.04mmol) was added and the reaction mixture was stirred at 60 ℃ for 18 h. Cooling the reaction mixture to room temperature, adding water, and extracting the reaction mixture with dichloromethane; the organic phase was concentrated under vacuum and the crude product was purified by flash chromatography (BIOTAGE SP 1; silica gel column: 65 i; eluent: hexane/ethyl acetate 70/30%). 1.5g (3.82mmol) of the desired compound are obtained.

Intermediate 26ib

Intermediate 26hb (75mg, 179. mu. mol), tributyl (vinyl) tin (200. mu.l, 685. mu. mol) and bis (triphenylphosphine) palladium chloride (13mg, 18. mu. mol) were added to 3ml 1, 2-dichloroethane. The reaction mixture was heated at 120 ℃ in a microwave for 4 hours. Subsequently, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give the desired product (56mg, 117 mmol).

Intermediate 26ic

The synthesis was carried out analogously to intermediate 26ib starting from intermediate 26hb and tributyl (ethynyl) tin.

Intermediate 27i

Intermediate 26i (500mg, 1.27mmol) and CuCN (114mg, 1.27mmol) were dissolved in 5ml DMA and the reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was cooled, diluted with dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. 30mg (0.1mmol) of the crude product are obtained and used in the next step without purification.

Intermediate 27ib

The synthesis was carried out analogously to 27a starting from intermediate 26 ib.

Intermediate 27ic

The synthesis was carried out analogously to 27a starting from intermediate 26 ic.

Intermediate 28a

Intermediate 27a (4g, 12.14mmol), TBTU (3.9g, 12.14mmol) and N, N-diisopropylethylamine (5.34ml, 30.35mmol) were dissolved in 25ml DMF. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes; piperidin-4-one hydrochloride (1.66g, 12.14mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, 1M aqueous sodium hydroxide, brine, then dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (BIOTAGE SP 1; silica gel column: 65 i; eluent dichloromethane/methanol 95/5%). 2.2g (5.4mmol) of the desired compound are obtained.

The following intermediates were synthesized analogously to intermediate 28 a.

Intermediate 29

Intermediate 28a (500mg, 1.22mmol), piperazine-1-carboxylic acid tert-butyl ester (228mg, 1.23mmol) and 2-methylpyridine borane complex (131.3mg, 1.22mmol) in 15ml of methanol were stirred at room temperature for 72 h; the reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica column: 20 g; eluent: dichloromethane/methanol-98/2%). 280mg (0.48mmol) of the desired compound are obtained.

Intermediate 30

Intermediate 29(280mg, 0.48mmol) was dissolved in 6ml 1, 4-bisIn an alkane; 4ml (16mmol) of 4M hydrochloric acid in 1, 4-bis (tert-butyl) solution were added dropwiseAlkane solution, and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum. 240mg (0.46mmol) of the desired compound are obtained.

Intermediate 31

Intermediate 27c (500mg, 1.67mmol), TBTU (643mg, 2mmol) and N, N-diisopropylethylamine (0.29ml, 1.67mmol) were dissolved in 5ml DMF. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes; tert-butyl [1, 4] diazepane-1-carboxylate (334mg, 1.67mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The crude product was suspended in diisopropyl ether and stirred, the resulting solid was filtered and dried. 700mg (1.45mmol) of the desired compound are obtained.

Intermediate 32

Intermediate 31(600 mg; 1.24mmol) was suspended in 5ml of diethyl ether, 5ml of a 1M solution of hydrochloric acid in diethyl ether was added dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum and the crude product was loaded onto an SCX column (10g) and eluted with 2M ammonia in methanol. 470mg (1.23mmol) of the title compound are obtained.

Intermediate 33

Intermediate 3a (1.5g, 7.47mmol) and tetrakis (triphenylphosphine) palladium (143.9mg, 0.12mmol) were suspended in 40ml toluene under a nitrogen atmosphere; 4-tert-butyl-benzylzinc bromide (29.9ml, 15mmol) was added dropwise and the reaction mixture was subsequently stirred at 20 ℃ for 8 hours. 5ml of methanol, 40ml of water and 100ml of dichloromethane are added. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The resulting crude product was purified by flash chromatography (Biotage column 40M +; eluent dichloromethane/ethyl acetate ═ 95/5%). 230mg (0.74mmol) of the desired compound are obtained.

Intermediate 34

To a solution of 4-tert-butylphenyl acetylene (5ml, 28mmol) in 20ml of anhydrous tetrahydrofuran was added dropwise a solution of catecholborane (3.41ml, 31mmol) in 20ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours and then concentrated under vacuum; the resulting crude product was dissolved in ethyl acetate and the organic phase was washed with 2M aqueous hydrochloric acid. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by flash chromatography (Biotage column 40M +; eluent dichloromethane/ethyl acetate ═ 95/5%). 230mg (0.82mmol) of the desired compound are obtained.

Intermediate 35

Intermediate 3a (600mg, 3mmol), intermediate 34 and tetrakis (triphenylphosphine) palladium (347mg, 0.3mmol) were dissolved in 3.6ml of 2M aqueous sodium carbonate and 40ml of 1, 2-dimethoxyethane. The reaction mixture was stirred at 80 ℃ overnight. Water was added and the reaction mixture was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The resulting crude product was purified by flash chromatography (Biotage column 40M +; eluent dichloromethane/ethyl acetate ═ 95/5%). 550mg (1.60mmol) of the desired compound are obtained.

Intermediate 36

Intermediate 35(250mg, 0.77mmol) was dissolved in 5ml ethanol and 5ml tetrahydrofuran. Pd/C (35mg) was added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. The reaction mixture was filtered through a pad of celite and concentrated under vacuum. 170mg (0.52mmol) of the desired compound are obtained.

Intermediate 37

Palladium acetate (170mg, 0.75mmol) and 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (936mg, 1.5mmol) were dissolved in 25ml of 1, 4-bisIn an alkane and stirred at 40 ℃ for 30 minutes. Ethyl 2-chloro-3-methylpyridine-4-carboxylate (500mg, 2.5mmol), 3, 4-dichlorobenzylamine (680mg, 5mmol) and cesium carbonate (715.5mg, 3.76mmol) were added and the reaction mixture was refluxed for 48 hours. The solvent was concentrated under vacuum and the crude product was loaded onto an SCX column (10g) and eluted with 2M ammonia in methanol. The solvent was concentrated in vacuo and the resulting crude product was purified by flash chromatography (Biotage column 25M +; eluent: ethyl acetate). 250mg (0.73mmol) of the desired compound are obtained.

Intermediate body 38

3- (bromomethyl) biphenyl (150mg, 0.58mmol), sodium carbonate (188mg, 1.75mmol) and ethyl 3-amino-2-methyl-benzoate (0.1ml, 0.58mmol) were combined in 2ml DMF and stirred at 100 ℃ for 2 h. The solvent was concentrated under vacuum and the crude product was purified by reverse phase preparative HPLC. 131mg (0.37mmol) of the desired compound are obtained.

Intermediate 39a

Intermediate 35(300mg, 0.92mmol) was dissolved in 4ml ethanol and 4ml water. Lithium hydroxide (194mg, 4.7mmol) was added and the reaction mixture was stirred at 70 ℃ for 2h, concentrated under vacuum and the residual aqueous solution was taken up with 10ml of 4M hydrochloric acid in 1, 4-bisThe alkane solution was acidified and extracted with dichloromethane; the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. 250mg (0.84mmol) of the desired product are obtained.

The following intermediates were synthesized analogously to intermediate 39 a.

Intermediate 40a

Intermediate 27c (660mg, 2.20mmol), TBTU (849mg, 2.65mmol) and N, N-diisopropylethylamine (0.57ml, 3.31mmol) were dissolved in 25ml DMF. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes; tert-butyl piperidin-4-ylcarbamate (441mg, 2.20mmol) was then added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SNAP column 50 g; eluent dichloromethane/methanol 90/10%). 990mg (2.05mmol) of the desired compound were obtained.

Intermediate 41a

Intermediate 40a (990mg, 2.05mmol) was suspended in 50ml of 1, 4-bisTo the alkane, 4M hydrochloric acid in 1, 4-bisAlkane solution (8.5ml, 34 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum. 780mg (18mmol) of the desired compound are obtained.

The following intermediates were synthesized analogously to intermediates 40a and 41 a.

Intermediate body 42

4, 4-Difluorocyclohexanone (500mg, 3.73mmol) and potassium hydroxide (502mg, 8.95mmol) were dissolved in 10ml of methanol. The reaction mixture was cooled to 0 ℃ and a solution of iodine (1.04g, 4.10mmol) in 20ml of methanol was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under vacuum. The crude product is stirred in 10ml of dichloromethane and the precipitate is filtered off. The filtrate was concentrated in vacuo and 480mg of the desired product (2.45mmol) were obtained as an oil.

Intermediate 43

Sodium hydride (196mg, 4.89mmol) was suspended in 10ml of tetrahydrofuran. The reaction mixture was cooled to 0 ℃ and a solution of intermediate 42(480mg, 4.45mmol) in 5ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at 0 ℃ for 1h, followed by the addition of methyl iodide (0.305ml, 4.89 mmol). The reaction mixture was stirred at room temperature for 4 hours. 0.1ml of 37% aqueous hydrochloric acid and 0.1ml of water were added, followed by 0.3ml of 37% aqueous hydrochloric acid. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and 400mg (2.44mmol) of the desired product were obtained as an oil.

Intermediate 44

Methyl iodide (3.48ml, 55.88mmol) was dissolved in 250ml tetrahydrofuran, the reaction mixture was stirred at 0 ℃ under nitrogen and sodium hydride (60% in mineral oil, 2.23mg, 5.88mmol) was added. After 15 min, trans 4-azido-tetrahydropyran-3-ol (4.0g, 27.94mmol) was added and the reaction mixture was brought to room temperature and stirred for 18 h. 50ml of water are added, the organic phase is separated, dried over sodium sulfate and concentrated in vacuo. The crude oil was purified by flash chromatography (Biotage SNAP column 100 g; eluent dichloromethane/ethyl acetate 80/20%). 200mg (1.27mmol) of the desired regioisomer (regioisomer) are obtained in the form of the trans racemate (relative configuration determined by NMR).

Intermediate 45

Intermediate 44(200mg, 1.27mmol) was dissolved in 250ml methanol, Pd/C (50mg) was added and the reaction mixture was stirred under hydrogen atmosphere (4 bar) for 18 h. The reaction mixture was filtered through a pad of celite and the organic phase was concentrated under vacuum. 110mg (0.84mmol) of the incorporated product are obtained in the form of the trans racemate.

Intermediate 46a

3-methoxy-tetrahydro-pyran-4-one (500mg, 3.84mmol), benzylamine (0.42ml, 3.84mmol) and Raney nickel (100mg) were suspended in 20ml of anhydrous ethanol, and the reaction mixture was stirred under a hydrogen atmosphere (4.5 bar) for 3 days. The reaction mixture was filtered through a pad of celite and the organic phase was concentrated under vacuum. The resulting crude product was dissolved in 10ml methanol, loaded onto an SCX column (10g) and eluted with 2M ammonia in methanol. The solvent was concentrated in vacuo and the resulting crude product was purified by flash chromatography (Isolute column 10 g; eluent: dichloromethane/methanol-96/4%). 163mg (0.73mmol) of the desired product are obtained in the form of the cis racemate (relative configuration determined by NMR).

Intermediate 46b

Under an atmosphere of hydrogen (5 bar), 3-methoxy-tetrahydro-pyran-4-one (1g, 7.68mmol), (R) - (+) -1-phenylethylamine (0.99ml, 7.68mmol) and Raney nickel (200mg) were stirred in 10ml of anhydrous ethanol for 15 days. The reaction mixture was diluted with 20ml methanol and 20ml tetrahydrofuran, stirred for 15 minutes, filtered through a pad of celite and concentrated under vacuum. The crude product was loaded onto an SCX column (50 g). The SCX column was washed with methanol and the desired product was eluted with 7M ammonia in methanol. The basic organic phase was concentrated under vacuum and the resulting crude product was purified by flash chromatography (dichloromethane/methanol-98/2%) to yield 710mg (3.02mmol) of the desired product in the form of a single stereoisomer (diastereomeric purity determined by NMR and relative cis stereochemical configuration determined by NMR).

Intermediate 46c

The synthesis was performed analogously to intermediate 46b, starting from 3-methoxy-tetrahydro-pyran-4-one and (S) - (-) -1-phenylethylamine (diastereomeric purity determined by NMR and relative cis stereochemical configuration determined by NMR).

Intermediate 47a

Intermediate 46a (163mg, 0.73mmol) was dissolved in 10ml methanol, Pd/C (50mg) was added, and the reaction mixture was stirred under hydrogen atmosphere (4.5 bar) for 18 h. The reaction mixture was filtered through a pad of celite and the organic phase was concentrated under vacuum. 80mg (0.61mmol) of the incorporated product are obtained in the form of the cis-racemate.

Intermediate 47b

Intermediate 46b (1.18g, 5.01mmol), Pd/C10% (200mg) and acetic acid (0.3ml, 5.01mmol) were stirred in 20ml methanol under hydrogen atmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20ml of methanol, stirred for 15 minutes, filtered through a pad of celite and concentrated under vacuum. The crude product was loaded onto an SCX column (50 g). The SCX column was washed with methanol and the desired product was eluted with 7M ammonia in methanol. The basic organic phase was concentrated under vacuum and 513mg (3.91mmol) of the desired product were obtained as a single stereoisomer.

Intermediate 47c

The synthesis was performed analogously to intermediate 47b starting from intermediate 46 c.

Intermediate 48b

Intermediate 47b was stirred in ether and a 2M solution of hydrochloric acid in ether was added dropwise until a white solid was formed. The reaction mixture was concentrated under vacuum, the crude product was suspended in methanol and the reaction mixture was concentrated under vacuum to give the desired hydrochloride salt.

Intermediate 48c

The synthesis was performed analogously to intermediate 48b starting from intermediate 47 c.

Intermediate 49a

3- (trifluoromethyl) benzaldehyde (6.46ml, 48.24mmol) was dissolved in 80ml of anhydrous tetrahydrofuran, the reaction mixture was cooled to-78 ℃ and a 0.5M solution of 3-butenyl magnesium bromide in tetrahydrofuran (106.13ml, 53.06mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at-78 ℃ for 30 minutes. The reaction mixture was then brought to room temperature and stirred for 18 hours. 100ml of saturated aqueous ammonium chloride solution and 200ml of ethyl acetate are subsequently added. The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. 7.75g (33.69mmol) of the desired product are obtained.

Intermediate 50a

Intermediate 49a was dissolved in 70ml of anhydrous dichloromethane, the reaction mixture was stirred at 0 ℃ under nitrogen atmosphere and N-bromosuccinimide was added. The reaction mixture was brought to room temperature and stirred for 48 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography (Isolera column; eluent: hexane/ethyl acetate 90/10%) to afford the desired product as a mixture of diastereomers.

Intermediate 51a

Intermediate 50a was purified by flash chromatography (Isolera column; eluent: hexane/ethyl acetate 98/2%). 2.3g (7.44mmol) of the trans diastereomer are obtained in the form of a racemic mixture (relative stereochemical configuration determined by NMR).

Intermediate body 52a

The column was further eluted, yielding 1.05g (3.39mmol) of the cis diastereomer as a racemic mixture (relative stereochemical configuration determined by NMR).

The following intermediates were synthesized analogously to intermediates 49a, 50a, 51a and 52 a.

Intermediate 53a

Intermediate 50a (1.7g, 5.49mmol) was dissolved in 5ml DMSO and the reaction mixture was stirred at room temperature under nitrogen atmosphere. Potassium phthalimide salt (2.54g, 13.75mmol) and sodium iodide (240mg, 1.60mmol) were added, and the reaction mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was cooled to room temperature and diluted with 40ml of saturated aqueous sodium bicarbonate and 100ml of ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolera column; eluent: hexane/ethyl acetate 85/15%) to yield 1.2g (3.2mmol) of the phthalimido intermediate. The phthalimido intermediate (1.2g, 3.2mmol) was dissolved in 15ml of methanol. Hydrazine hydrate (1.24ml, 25.60mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated under vacuum. The crude product was dissolved in 10ml dichloromethane and the organic layer was washed with water, separated, dried over sodium sulfate and concentrated in vacuo. 474mg (1.93mmol) of the desired product are obtained.

Intermediate 54a

The synthesis was performed analogously to intermediate 53a starting from intermediate 51 a.

Intermediate 55a

The synthesis was performed analogously to intermediate 53a starting from intermediate 52 a.

The following intermediates were synthesized analogously to intermediates 53a, 54a and 55 a.

Intermediate 56

2, 3-dihydro-pyrano [3, 2-b ] pyridin-4-one (250mg, 1.7mmol) and Raney nickel (25mg) were added to an ethanol solution of ammonia (10ml), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (3 bar) for 18 hours. Subsequently, the catalyst was removed by filtration through a pad of celite and the mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to give the desired product (129mg, 600 μmol).

Synthetic examples

In the context of the present invention, E and G represent C or N, preferably nitrogen.

The examples of the invention were synthesized according to the following general synthetic method:

the synthesis method A comprises the following steps:

example (b): 1-159 gc; 289-302

The synthesis method B comprises the following steps:

example (b): 160-247; 228a, and 228 b; 228ga-228 gn; 229-247

Example (b): 286-288

Example (b): 228b to 228 g; 228 go; 228gp

The synthesis method C comprises the following steps:

example (b): 248-283; 275a-275dj

Example 1

Intermediate 25b (70mg, 0.16mmol), 4-tert-butyl-benzylamine (32mg, 0.19mmol) and N, N-diisopropylethylamine (0.042ml, 0.24mmol) were added to 2ml dry 1, 4-bis-ethylamine at 70 deg.CThe mixture was stirred in an alkane overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel Isolute column 5 g; eluent ethyl acetate/methanol 90/10%). 16mg (0.027mmol) of the desired product are obtained.

HPLC (method 2F): r_t(minute) ═ 7.59

[M+H]⁺＝557

The following examples were synthesized analogously to the preparation of example 1.

Example 99

Intermediate 2a (200mg, 1.047mmol) was dissolved in 30ml dichloromethane. Add [1, 4' ] bipiperidin-4-ol (192mg, 1.047mmol) and stir the reaction mixture at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the crude product was dissolved in 1ml DMSO. Phenethylamine (0.6ml, 4.73mmol) and N, N-diisopropylethylamine (0.013ml, 0.075mmol) were added and the reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 331mg (0.616mmol) of the desired product are obtained.

HPLC (method C): r_t.(minute) ═ 1.34

[M+H]⁺＝424

The following examples were synthesized in analogy to the preparation of example 99.

Example 104

Intermediate 25i (17mg, 0.05mmol), 3-fluoro-4-methyl-benzylamine (10mg, 0.075mmol) and diisopropylethylamine (0.013ml, 0.075mmol) were stirred in 1ml anhydrous DMSO at 80 ℃ overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 20mg (0.047mmol) of the desired product are obtained.

HPLC (method C): r_t.(minute) ═ 1.45

[M+H]⁺＝426

The following examples were synthesized in analogy to the preparation of example 104.

Example 146

Intermediate 25b (80mg, 0.18mmol), intermediate 7c (40mg, 0.21mmol) and N, N-diisopropylethylamine (0.046ml, 0.26mmol) were placed in a microwave vial in 0.2ml of anhydrous 1, 4-bisMixed in an alkane and reacted under the following conditions: the power is 100, the Ramp (Ramp) is 5 minutes, the temperature is 150 ℃, the pressure is 150 ℃, and the stirring is carried out. The reaction mixture was concentrated under vacuum and diluted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. 36mg (0.06mmol) of the desired product are obtained.

HPLC (method 1e (hydro)): r_t.(minute) ═ 9.52

[M+H]⁺＝583

The following examples were synthesized in analogy to the preparation of example 146.

Example 160

Intermediate 28b (80mg, 0.20mmol), intermediate 13(74mg, 0.30mmol) and N, N-diisopropylethylamine (0.087ml, 0.51mmol) were stirred in 2ml dichloromethane for 10 min at room temperature. Sodium triacetoxyborohydride (129mg, 0.61mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. 39mg (0.06mmol) of the desired product are obtained.

HPLC (method 2F): r_t.(minute) ═ 7.25

[M+H]⁺＝583

The following examples were synthesized in analogy to the preparation of example 160.

Example 228h

Example 228b (22mg, 0.032mmol), formaldehyde (0.003ml, 0.096mmol), N-diisopropylethylamine (0.008ml, 0.048mmol) and trifluoroacetic acid (0.005ml) were stirred in 1.5ml methanol at room temperature for 5 minutes. Sodium cyanoborohydride (10mg, 0.160mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel column 5g, eluent ethyl acetate/methanol 7: 3%). 8.4mg (0.016mmol) of the desired product are obtained.

The following examples were synthesized in analogy to the preparation of example 228 h.

Example 229

Intermediate 28a (100mg, 0.25mmol), (S) -3-hydroxypiperidine (67mg, 0.49mmol) and trimethyl orthoformate (1.07ml, 9.82mmol) were stirred in 5ml methanol at 60 ℃ for 1 hour. 2-methylpyridine borane complex (26mg, 0.25mmol) was added and the reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 64mg (0.13mmol) of the desired product are obtained.

HPLC (method 1E): r_t.(minute) ═ 7.18

[M+H]⁺＝492

The following examples were synthesized in analogy to the preparation of example 229.

Example 234

Intermediate 28d (20mg, 0.05mmol), 2-methyl-morpholine (0.012ml, 0.10mmol), sodium triacetoxyborohydride (43mg, 0.20mmol), acetic acid (0.05ml) and trimethyl orthoformate (0.05ml) were stirred in 0.9ml DMA at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 3mg (0.006mmol) of the desired product are obtained.

HPLC (method a): r_t.(minute) ═ 1.74

[M+H]⁺＝486

The following examples were synthesized in analogy to the preparation of example 234.

Example 248

Intermediate 27e (105mg, 0.33mmol), TBTU (215mg, 0.67mmol) and N, N-diisopropylethylamine (0.12ml, 0.67mmol) were stirred in 2ml DMF at room temperature for 5 min. Intermediate 20f (100mg, 0.33mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si Isolute column (5 g); eluent ethyl acetate/methanol 90/10%). 30mg (0.057mmol) of the desired product are obtained.

HPLC (method 1e (hydro)): r_t.(minute) ═ 9.2

[M+H]⁺＝521

The following examples were synthesized in analogy to the preparation of example 248.

Example 276

Intermediate 27g (50mg, 0.14mmol), HATU (55mg, 0.14mmol) and N, N-diisopropylethylamine (0.05ml, 0.28mmol) were stirred in 2ml DMF at room temperature for 5 min. 4-piperidin-4-yl-morpholine (24mg, 0.14mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. 80mg (0.13mmol) of the desired product are obtained.

HPLC (method C): r_t.(minute) ═ 1.57

[M+H]⁺＝486

The following examples were synthesized in analogy to the preparation of example 276.

Example 284

Intermediate 30(45mg, 0.088mmol) and N, N-diisopropylethylamine (0.05ml, 0.27mmol) were dissolved in 5ml dichloromethane. The reaction mixture was stirred at 0 ℃ and isobutyryl chloride (0.01ml, 0.09mmol) was added. The reaction mixture was stirred at 0 ℃ for 20 minutes, then washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product is suspended in diisopropyl ether and stirred, and the solid is filtered off to yield 30mg (0.05mmol) of the desired compound.

HPLC (method 1E): r_t.(minute) ═ 7.02

[M+H]⁺＝547

The following examples were synthesized in analogy to the preparation of example 284.

Example 286

Intermediate 32(100mg, 0.26mmol) and cyclopentanone (0.02ml, 0.26mmol) were stirred in 2ml dichloromethane for 10 min at room temperature. Sodium triacetoxyborohydride (132mg, 0.62mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. 31mg (0.07mmol) of the desired product are obtained.

HPLC (method 2F): r_t.(minute) ═ 7.52

[M+H]⁺＝450

The following examples were synthesized in analogy to the preparation of example 286.

Example 289

Intermediate 25b (200mg, 0.46mmol), 4-tert-butylphenyl boronic acid (99mg, 0.56mmol), tetrakis (triphenylphosphine) palladium (53mg, 0.05mmol) and 0.56ml of 2M aqueous sodium carbonate solution are stirred in 2ml of 1, 2-dimethoxyethane at 80 ℃ overnight. After cooling to room temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si Isolute column (5 g); eluent ethyl acetate/methanol 95/5%). 41mg (0.08mmol) of the desired product are obtained.

HPLC (method 1e (hydro)): r_t.(minute) ═ 9.93

[M+H]⁺＝528

Example 290

Intermediate 25b (60mg, 0.14mmol) and 4-chlorophenol (0.014ml, 0.14mmol) were dissolved in 2ml DMF. Cesium carbonate (45mg, 0.14mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo, the crude product was dissolved in dichloromethane, and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si Isolute column (5 g); eluent dichloromethane/ethyl acetate 90/1%). 50mg (0.09mmol) of the desired product are obtained.

HPLC (method 1e (hydro)): r_t.(minute) ═ 8.9

[M+H]⁺＝522

The following examples were synthesized in analogy to the preparation of example 290.

Example 292

Sodium hydride (19mg, 0.46mmol) and 4-chloro-3-methylbenzyl alcohol (44mg, 0.28mmol) were suspended in 5ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 min, followed by the addition of intermediate 25b (100mg, 0.23 mmol). The reaction mixture was stirred at 50 ℃ overnight. The solvent was concentrated in vacuo, the crude product was dissolved in dichloromethane, and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si Isolute column (5 g); eluent dichloromethane/methanol 95/5%). 40mg (0.07mmol) of the desired product are obtained.

HPLC (method 1e (hydro)): r_t.(minute) ═ 9.95

[M+H]⁺＝550

The following examples were synthesized in analogy to the preparation of example 292.

Claims (15)

1. A compound of the formula (I),

wherein

R₁is-L₁-R₇，

And wherein L₁Is a chemical bond or a group selected from methylene, ethylene and vinylene,

and wherein R₇Is a ring selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridinyl, and furanyl,

wherein L is₁If not a bond, optionally substituted with one or more groups selected from methyl and ethyl,

wherein the ring R₇Optionally substituted by one or more groups selected from-F, -Cl, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -tert-butyl, -CF₃、-O-CF₃-CN, -O-methyl, furyl and phenyl, wherein the furyl and the phenyl are optionally independently substituted with one or more groups selected from-C₁-C₃-alkyl, halogen, -OCH₃、-CF₃and-OCF₃Is substituted with a group (b) of (a),

or wherein the ring R₇Divalent substitution on two adjacent ring atoms with one or more groups selected from the group consisting of:

wherein R is₂Selected from-H, -halogen, -CN, -O-C₁-C₄-alkyl, -C₁-C₄-alkyl, -CH = CH₂、-C≡CH、-CF₃、-OCF₃、-OCF₂H and-OCFH₂；

Wherein R is₃Selected from the group consisting of-H, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -OCH₃and-CN;

wherein R is₄And R₅Independently selected from the group consisting of an electron pair, -H, and a group selected from: -C₁-C₆-alkyl, -NH₂、-C₃-C₈-cycloalkyl, -C₃-C₈-heterocyclyl, -C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl and-C (O) -N (R)₈,R_8') Wherein R is₈And R_8'Independently selected from-H and-C₁-C₆-an alkyl group,

and wherein R₄And R₅If not an electron pair or-H, is optionally independently substituted with one or more groups selected from: -halogen, -OH, -CF₃、-CN、-C₁-C₆-alkyl, -O-C₁-C₆-alkyl, -O-C₃-C₈-cycloalkyl, -O-C₃-C₈-heterocyclyl, -O-C₅-C₁₀-aryl, -O-C₅-C₁₀-heteroaryl, -C₀-C₆alkylene-CN, -C₀-C₄alkylene-O-C₁-C₄-alkyl, -C₀-C₄alkylene-O-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-O-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-O-C₅-C₁₀-aryl, -C₀-C₄alkylene-O-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-Q-C₀-C₄-alkyl-N (R)₉,R_9')、-C₀-C₄alkylene-N (R)₁₀)-Q-C₁-C₄-alkyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₅-C₁₀-aryl, -C₀-C₄alkylene-N (R)₁₀)-Q-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-Q-N (R)₁₁,R_11')、-C₀-C₄alkylene-N (R)₁₂)-Q-N(R₁₃,R_13')、-C₀-C₄-alkylene-R₁₄、-C₀-C₄alkylene-Q-C₁-C₆-alkyl, -C₀-C₄alkylene-Q-C₃-C₈-cycloalkyl, -C₀-C₄alkylene-Q-C₃-C₈-heterocyclyl, -C₀-C₄alkylene-Q-C₅-C₁₀-aryl, -C₀-C₄alkylene-Q-C₅-C₁₀-heteroaryl, -C₀-C₄alkylene-O-Q-N (R)₁₅,R_15') and-C₀-C₄alkylene-N (R)₁₆)-Q-O-(R₁₇)，

Wherein Q is selected from the group consisting of-C (O) -and-SO₂-，

Wherein R is₁₂、R₁₆Independently selected from-H, -C₁-C₆-alkyl and-C₃-C₆-a cycloalkyl group,

wherein R is₉、R_9'、R₁₀、R₁₁、R_11'、R₁₃、R_13'、R₁₅、R_15'Independently selected from-H, -C₁-C₆-alkyl and-C₃-C₆-a cycloalkyl group,

or wherein R is₉And R_9'、R₁₁And R_11'、R₁₃And R_13'、R₁₅And R_15'Together form-C₂-C₆-an alkylene group,

wherein R is₁₄And R₁₇Independently selected from-H, -C₁-C₆-alkyl, -C₅-C₁₀-aryl, -C₅-C₁₀-heteroaryl, -C₃-C₈-cycloalkyl and-C₃-C₈-heterocyclyl, wherein the-C₃-C₈-heterocyclyl optionally containing nitrogen and/or-SO in the ring₂-, and wherein R₁₄And R₁₇Optionally substituted with one or more groups selected from: -OH, -OCH₃、-CF₃、-OCF₃-CN, -halogen, -C₁-C₄-alkyl, = O and-SO₂-C₁-C₄-an alkyl group,

or wherein R is₄And/or R₅Independently is structure-L₂-R₁₈The group of (a) or (b),

wherein L is₂Selected from-NH-and-N (C)₁-C₄-alkyl) -,

wherein R is₁₈Is selected from-C₅-C₁₀-aryl, -C₅-C₁₀-a heteroaryl group,-C₃-C₈-cycloalkyl and-C₃-C₈-a heterocyclic group,

wherein R is₁₈Optionally substituted with one or more groups selected from: halogen, -CF₃、-OCF₃、-CN、-OH、-O-C₁-C₄-alkyl, -C₁-C₆-alkyl, -NH-C (O) -C₁-C₆-alkyl, -N (C)₁-C₄-alkyl) -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-alkyl, -S (O)₂-C₁-C₆-alkyl, -NH-S (O)₂-C₁-C₆-alkyl, -N (C)₁-C₄-alkyl) -S (O)₂-C₁-C₆Alkyl and-C (O) -O-C₁-C₆-an alkyl group,

and wherein R₄、R₅And R₁₈Optionally further spiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl substitution thereby reacting with R₄、R₅And/or R₁₈Together form a spiro ring, wherein the spiro-C₃-C₈-heterocyclyl optionally containing in the ring one or more substituents selected from nitrogen, -C (O) -, -SO₂-and-N (SO)₂-C₁-C₄-an alkyl) -group(s),

or wherein R is₄、R₅And R₁₈Optionally further substituted by one or more groups selected from-C₁-C₆Alkylene, -C₂-C₆-alkenylene and-C₄-C₆Divalent substitution of one or two carbon centres by one or two heteroatoms selected from N, O and S, and the divalent radical being optionally substituted on one or two adjacent ring atoms by one or more groups selected from-OH, -NH₂、-C₁-C₃Alkyl, O-C₁-C₆-alkyl, -CN, -CF₃、-OCF₃And halogen;

wherein R is₆Is selected from-H, -C₁-C₄-alkyl, -OH, -O-C₁-C₄-alkyl, -halogen, -CN, -CF₃and-OCF₃；

Wherein A is selected from the group consisting of a single bond, -CH₂-, -O-, -S-and-NH-;

wherein n is 1,2 or 3;

wherein Z is C or N.

And acid addition salt forms thereof with pharmacologically acceptable acids.

2. The compound of claim 1, wherein R₁Is selected from

3. The compound of claim 1, wherein R₂Selected from-H, -methyl, -ethyl, -propyl, -isopropyl, -cyclopropyl, -butyl, -isobutyl, -tert-butyl, -F, -Cl, -Br, -I, -CN, -CH = CH₂-C.ident.CH and-OCH₃。

4. The compound of claim 1, wherein R₂Selected from the group consisting of-H, -methyl, -ethyl, -Br and-OCH₃。

5. The compound of claim 1, wherein R₃Selected from-H and-methyl.

6. The compound of claim 1, wherein R₄And R₅Independently selected from the group consisting of an electron pair, -H, and a group selected from: -isopropyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and-c (o) -N (R)₈,R_8') Wherein R is₈And R_8'Independently selected from-H and-C₁-C₆-an alkyl group,

wherein R is₄And R₅If not an electron pair and-H, is optionally independently substituted with one or more groups selected from: -fluoro, -methyl, -ethyl, propyl, -isopropyl, -butyl, -isobutyl, -tert-butyl, -hydroxy, -CF₃、-CN、-O-CH₃、-O-C₂H₅、-O-C₃H₇、-CH₂-CN、-CH₂-O-CH₃、-(CH₂)₂-O-CH₃、-C(O)-CH₃、-C(O)-C₂H₅、-C(O)-C₃H₇、-COOH、-C(O)-NH₂、-C(O)-NH-CH₃、-C(O)-N(CH₃)₂、-NH-C(O)-CH₃、-N(CH₃)C(O)-CH₃、-NH-C(O)-C₂H₅、-N(CH₃)-C(O)-C₂H₅、-NH-C(O)-C₃H₇、-N(CH₃)-C(O)-C₃H₇、-NH-SO₂-CH₃、-N(CH₃)-SO₂-CH₃、-N(C₂H₅)-SO₂-CH₃、-N(C₃H₇)-SO₂-CH₃、-NH-SO₂-C₂H₅、-N(CH₃)-SO₂-C₂H₅、-N(C₂H₅)-SO₂-C₂H₅、-N(C₃H₇)-SO₂-C₂H₅、-NH-SO₂-C₃H₇、-N(CH₃)-SO₂-C₃H₇、-N(C₂H₅)-SO₂-C₃H₇、-N(C₃H₇)-SO₂-C₃H₇、-NH-SO₂-C₃H₅、-N(CH₃)-SO₂-C₃H₅、-N(C₂H₅)-SO₂-C₃H₅、-N(C₃H₇)-SO₂-C₂H₅、-CH₂-NH-SO₂-CH₃、-CH₂-N(CH₃)-SO₂-CH₃、-CH₂-NH-SO₂-C₂H₅、-CH₂-N(CH₃)-SO₂-C₂H₅、-CH₂-NH-SO₂-C₃H₇、-CH₂-N(CH₃)-SO₂-C₃H₇、-CH₂-NH-SO₂-C₃H₅、-CH₂-N(CH₃)-SO₂-C₃H₅、-NH-C(O)-NH₂、-N(CH₃)-C(O)-NH₂、-NH-C(O)-NH-CH₃、-N(CH₃)-C(O)-NH-CH₃、-NH-C(O)-N(CH₃)₂、-N(CH₃)-C(O)-N(CH₃)₂、-SO₂-NH₂、-SO₂-NH(CH₃)、-SO₂-N(CH₃)₂、-C(O)-NH-C₂H₅、-C(O)-N(CH₃)-C₂H₅、-C(O)-N(CH₃)-C₃H₇、-C(O)-N(CH₃)-C₄H₉、-C(O)-NH-CH(CH₃)-C₂H₅、-C(O)-N(CH₃)-CH(CH₃)-C₂H₅、-CH₂-C(O)-NH₂、-CH₂-C(O)-NH-CH₃、-CH₂-C(O)-N(CH₃)₂、–N(CH₃)-SO₂-N(CH₃)₂-phenyl, -pyridin-4-yl, -CH₂-3-methyl-oxetan-3-yl, -O-1, 2-difluoro-phen-5-yl, -O-pyridin-2-yl, -pyrrolidin-2-one-1-yl, -3, 5-dimethyl- [1,2,4]Triazol-4-yl, 3-methyl- [1,2, 4]]Diazol-5-yl,

Or wherein R is₄And R₅Independently is structure-L₂-R₁₈The group of (a) or (b),

wherein L is₂Selected from-NH-, -N (CH)₃) -and-N (C)₂H₅)-，

And wherein R₁₈Selected from the group consisting of-tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyranopyrrolyl, -octahydro-pyranopyridinyl, -octahydro-pyrano-azinyl, -oxaspirodecyl and-tetrahydro-naphthyridinyl,

wherein R is₁₈Optionally substituted with one or more groups selected from: -F, -CF₃、-OCF₃、-CN、-OH、-O-CH₃、-CH₃、-NH-C(O)-CH₃、-N(CH₃)-C(O)-CH₃、-C(O)-CH₃、-S(O)₂-CH₃、-NH-S(O)₂-CH₃、-N(CH₃)-S(O)₂-CH₃and-C (O) -O-C₂H₅,

And wherein R₄、R₅And R₁₈Optionally further divalent substituted on one or two adjacent ring atoms with one or more groups selected from the group consisting of:

7. the compound of claim 1, wherein R₄Is selected from

8. The compound of claim 1, wherein R₅Selected from the group consisting of electron pairs, -H and-C (O) -NH₂。

9. The compound of claim 1, wherein R₆Is selected from-H, -CH₃、-C₂H₅、-O-CH₃、-O-C₂H₅、-F、-CF₃and-OCF₃。

10. The compound of claim 1, wherein R₆Is H or-O-CH₃。

11. The compound of claim 1, wherein a is-O-or-NH-.

12. The compound of claim 1, which is a compound of formula (I),

wherein

R₁Is selected from

R₂Selected from the group consisting of-H, -methyl, -ethyl, -Br and-OCH₃；

R₃Is selected from-H and-methyl;

R₄is selected from

R₅Selected from the group consisting of electron pairs, -H and-C (O) -NH₂；

R₆Is H or-O-CH₃；

A is-O-or-NH-.

13. Use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for the inhibition of the CCR2 receptor.

14. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of osteoarthritis, diabetic nephropathy or a pain disorder.

15. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of lower back pain or neuropathic pain.