WO2010097373A1

WO2010097373A1 - Compounds for use as bradykinin b1 antagonists

Info

Publication number: WO2010097373A1
Application number: PCT/EP2010/052235
Authority: WO
Inventors: Ingo Konetzki; Angelo Ceci; Henri Doods; Norbert Hauel; Jürgen Mack; Henning Priepke; Annette Schuler-Metz; Rainer Walter
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2009-02-26
Filing date: 2010-02-23
Publication date: 2010-09-02

Abstract

The invention relates to the compounds of the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, X1, X2 and X3 are defined as described below, to enantiomers thereof, to diastereomers thereof, to mixtures and salts thereof, in particular physiologically compatible salts thereof having organic or inorganic acids or bases having valuable properties, to the production thereof, to pharmaceuticals comprising the pharmacologically effective compounds thereof, to the production and to the use thereof.

Description

COMPOUNDS AS BRADYKININ B1 ANTAGONISTS

The present invention relates to the compounds of general formula I.

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ are defined as described below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I, in one embodiment 1_

R ¹ is (a) optionally substituted with a radical R ^1-1 substituted Ci _-6 alkyl group,

(b) d-3-alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

a optionally substituted with one radical R ¹ is ^{2-substituted} C3 _-6 cycloalkyl group, can be a -CH ₂ moiety replaced by a -C (O) group (c),

(d) optionally substituted by 1, 2 or 3 radicals R ^{1 3} alkylene substituted aryl-Co _2,

(e) a five-membered heteroaryl-co- _2- alkylene radical optionally substituted by 1, 2 or 3 radicals R ^{1 4 and} containing at least one N, O or S atom and optionally additionally one, two or three further radicals Contains N atoms and may additionally be benzo-fused,

(f) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} six-membered _{heteroaryl-Co-2} alkylene group containing one, two or three N atoms and which may be benzo-fused, in addition, (g) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} nine- or ten-membered heteroaryl radical containing one, two or three N atoms,

(h) a 5- or 6-membered optionally substituted by 1 or 2 R ^{1 4} radicals

Heterocycle which contains at least one N, O or S atom and in which additionally a -CH ₂ unit can be replaced by a -C (O) group,

(i) -OR ¹ - ¹ - ¹ ,

C) -NR ^{1 1 3} R ¹ - ^{1 4} or

(k) -C (= NR ¹ - ⁵ ) -CN,

R ¹ - ¹ halogen, -CN, C ₃ - ₆ -cycloalkyl, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -C (O) R ^{1 1 1} , -S (O) ₂ -R ¹ - ^{1 2} ,

-CO ₂ R ¹ - ^{1 1} , -O-C (O) -R ¹ - ¹ - ¹ , -NR ^{1 1 3} R ¹ - ^{1 4} , -NR ^{1 / l} - ³ -C (O) -R ¹ - ¹ - ¹ , -NR ^{1 / l} - ³ -C (O) -R ¹ - ¹ - ¹ , -NR ^{1 / l} - ³ -CO ₂ -R ¹ - ¹ - ¹ or -C (O) -NR ^{1 1 3} R ¹ - ^{1 4} ,

R ¹ - ¹ - ¹ (a) H, (b) Ci- ₄ alkyl,

(c) C _1-3 -alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

(d) a phenyl group which is optionally substituted by 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ¹ ,

(e) C _3-6 -cycloalkyl or (f) a pyridyl group which is optionally substituted by 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ² ,

p ⁱ . ¹ . ¹ . ¹ independently

(a) halogen, -CN, -OH, -O-Ci _-4 alkyl, C ₃ - ₆ cycloalkyl, d _-4 alkyl or

(b) d- _3- alkyl, in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

R ¹ - ¹ - ¹ - ² are independently halogen or Ci _-4 alkyl,

R ¹ - ¹ - ² (a) Ci- ₄ alkyl, (b) _d-C3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each

Methyl group may be substituted by 1, 2 or 3 fluorine atoms, or

(c) a phenyl group which is optionally substituted by 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ¹ ,

₁₃ 1.1.3, ₁ R ₃ 1.1.4 independent of each other (a) H,

(b) optionally substituted with 1, 2 or 3 radicals R ¹ - ¹ - ⁴ - substituted ¹ Ci kylgruppe _-4-Al,

(d) C _3-6 cycloalkyl, or

R ^{1 "1" 3} and R ^{1 "1" 4} together with the N-atom to which they are attached form a 5- or 6-membered heterocyclic ring which additionally contains one further heteroatom selected from N, O and S. can, or

p ⁱ . ¹ . ⁴ . ¹ _una epending another are halogen, -NH _2, -NH (Ci _-4 alkyl), -N (d _-4 alkyl) ₂ or -SO ₂ -R ¹ - ^{1 2,}

R ¹ - ² halogen, -CN, OH, -O-CH ₃ or phenyl,

R ¹ - ³ (a) halogen, -CN, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -CO ₂ R ¹ - ^{1 1} , C _1-6 alkyl or

(b) C-ι- ₃ alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted,

R ¹ - ⁴ independently

(a) halogen, -CN, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -S (O) -R ¹ - ^{1 2} , -S (O) ₂ -R ¹ - ^{1 2} , - NR ^{1 1 3} R ^{1 1 4,} -N (R ¹ - ⁴ - ¹⁾ -C (O) -C _-4 alkyl, d _-6 alkyl,

(b) d- _3- alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, or

(c) an oxo group,

R ¹ - ⁴ - ¹ H or d _-4 -alkyl,

R ¹ - ⁵ -OH or -Ods-alkyl,

R ² and R ³ together with the carbon atom to which they are attached, an optionally substituted by a radical R ^{2 1} substituted Cs ^ -Cycloalkylengruppe in which a - A -

-CH ₂ unit can be replaced by a heteroatom O, N, S or by a group CO, SO or SO ₂ ,

R ² - ¹ H, -OH,

R ⁴ (a) H,

(b) C _1-4 alkyl,

(c) C-ι- ₃ alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted,

R ⁵ (a) H, halogen, -CN, -OH,

(b) C _1-6 alkyl,

(c) _d-C3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted,

(d) C _3-7 cycloalkyl,

(e) -OC _1-6 -alkyl,

(f) -O-Cs- _T- cycloalkyl,

(g) -NH ₂ , -NH (C _1-3 -alkyl), -N (C _1-3 -alkyl) ₂ , (h) -C (O) -R ^{5 1} ,

(i) -S-Ci ₄ alkyl, -SO ₂ -R ^52,

(j) optionally substituted with one or two Ci _-3 alkyl five-membered heteroaryl group which is selected from the group consisting of pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or

(k) optionally substituted with one or two Ci _-3 alkyl six-membered heteroaryl group which is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,

R ⁵ - ¹ -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / -piperidinyl, Λ / -morpholinyl, - OH, -O-Ci _-8- alkyl or -OC _3-7 -cycloalkyl,

R ⁵ - ² -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / Λ piperidinyl or / and -morpholinyl R ⁶ (a) H, halogen, -CN, -OH,

(b) C _1-6 alkyl,

(d) C _3-7 cycloalkyl,

(e) C _{_2-4} alkynyl,

(f) -OC _1-6 -alkyl, (g) -O-Cs-r-cycloalkyl,

(h) -NH _2, -NH (Ci _-3 alkyl), -N (Ci _-3 alkyl) _2,

(i) -C (O) -R ^{6 1} ,

C) -S-Ci- ₄ alkyl, -SO-Ci ₄ alkyl, -SO ₂ -C _-4 alkyl,

R ⁶ - ¹ -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / -piperidinyl, Λ / -morpholinyl, - OH, -O-Ci _-8 alkyl, or -OC _{_3-7} cycloalkyl,

R ⁷ (a) H, halogen, -CN, -OH,

(b) C _1-6 alkyl, (c) Ci _-3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted .

(d) C _3-7 cycloalkyl,

(e) -OC _1-6 -alkyl, (f) -O-Cs- _T- cycloalkyl,

(g) -NH ₂ , -NH (C _1-3 -alkyl), -N (C _1-3 -alkyl) ₂ , (h) -C (O) -R ^{7 1} ,

(i) -S-Ci _-3 alkyl, -SO ₂ -R ^72,

(j) optionally substituted with one or two Ci _-3 alkyl five-membered heteroaryl group which is selected from the group consisting of pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or (k) a six-membered heteroaryl group which is optionally substituted by one or two C 1-3 -alkyl groups and is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,

R ⁷ - ¹ -NH ₂ , -NH (C 1-6 -alkyl) _! -N (C 1-6 -alkyl) _2! / V-azetidinyl, / V-pyrrolidinyl, / V-piperidinyl, / V-morpholinyl, -OH, -O-Ci _-8-alkyl or -O-Cs-r-cycloalkyl,

R ⁷ - ² -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / Λ piperidinyl or / -morpholinyl,

X ¹ N or CR ⁸ ,

R ^{8 is} H, F, Cl, CH ₃ ,

X ² N or CH and

X ³ N or CH,

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerated salts with organic or inorganic acids or bases.

An embodiment 2 of the present invention consists in the compounds of the above general formula I in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as described above under the embodiment λ_ mentioned are defined and

R ¹ is (a) optionally substituted with a radical R ¹ is substituted C ¹ _-6 alkyl group,

(b) d- _3- alkyl in which any methylene group containing 1 or 2 fluorine atoms and each

(C) a C 3-6 -cycloalkyl group optionally substituted by an R ^1-2 radical in which a -CH ₂ - moiety may be replaced by a -C (O) -group, (d) a phenyl group optionally substituted by 1, 2 or 3 radicals R ^{1 3} , (e) a five-membered heteroaryl radical which is optionally substituted by 1, 2 or 3 radicals R ^{1 4} and contains at least one N, O or S atom and which, if appropriate, additionally contains one, two or three further N atoms,

(f) a six-membered heteroaryl radical which is optionally substituted by 1 or 2 radicals R ^{1 4} and contains one, two or three N atoms,

(g) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} nine- or ten-membered heteroaryl radical containing one, two or three N atoms,

(h) a 5- or 6-membered optionally substituted by 1 or 2 R ^{1 4} radicals

(i) -OR ¹ - ¹ - ¹ or C) -NR ^{1 1 3} R ¹ - ^{1 4} ,

R ¹ - ¹ (a) -CN, C _3- 6 cycloalkyl, -OR ¹ - ¹ - ^1, -NR ¹ R ^{3 1} ¹ - ^{1 4,} or (b) d-3-alkyl, wherein each methylene group with 1 or 2 fluorine atoms and each

Methyl group may be substituted by 1, 2 or 3 fluorine atoms,

R ¹ - ¹ - ¹ (a) H,

(b) C _1-4 alkyl, (c) d- ₃ alkyl in which any methylene group having 1 or 2 fluorine atoms and each

Methyl group may be substituted by 1, 2 or 3 fluorine atoms,

R ¹ - ¹ - ³ , R ¹ - ¹ - ⁴ independently

(a) H, (b) d- _4- alkyl,

(c) C _3-6 -CyCl or I ky I, or

R ¹ - ¹ - ³ and R ¹ - ¹ - ⁴ form, together with the N-atom to which they are attached, a 5- or 6-membered heterocyclic ring which additionally contains a further heteroatom selected from N, O and S. can, or

R ¹ - ² halogen, -CN, -OH, -O-CH ₃ or phenyl,

R ¹ - ³ independently (a) halogen, -CN, -OR ¹ - ¹ - ¹ , d _-6- alkyl or

(b) C _1-3 -alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

R ^{1 4} independently

(a) halogen, -CN, -OR ¹ - ¹ - ¹ , -NR ¹ - ¹ - ³ R ¹ - ¹ - ⁴ , -N (R ¹ - ⁴ - ¹ ) -C (O) -d ₄ - Alkyl, d _-6- alkyl, or

(b) d- _3- alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, and

R ¹ - ⁴ - ¹ H or d- ₄ alkyl, mean

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

An embodiment 3 of the present invention consists in the compounds of the above general formula I, in which R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 mentioned} above under the embodiment 1_ or 2 are defined and

R ² and R ³ together with the carbon atom to which they are attached, a

C ₃ _ ₆ -cycloalkylene group in which a -CH ₂ unit may be replaced by an oxygen atom, mean

An embodiment 4 of the present invention consists in the compounds of the above general formula I, in which R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as described above under the embodiment I -, 2 or 3 mentioned are defined and

(a) H, (b) methyl or ethyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and the methyl group by 1, 2 or 3 fluorine atoms,

An embodiment 5 of the present invention consists in the compounds of the above general formula I, in which R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as described above under the embodiment I , 2, 3 or 4 mentioned are defined and

R ⁵ (a) H, halogen, -CN or

(b) d-s-alkyl,

An embodiment 6 of the present invention consists in the compounds of the above general formula I, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , X ¹ , X ² and X ³ as described above under the embodiment I -, 2, 3, 4 or 5 mentioned are defined and

R ⁶ is (a) H, halogen, -CN, -OH, (b) Ci _-3 alkyl,

(c) _d-C3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms can be substituted,

(d) C _{_2-4} alkynyl, (e) -OC _3-6 cycloalkyl,

(f) -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ ,

(g) _-S-CH3, _-SO-CH3, -SO ₂ -CH _3, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

An embodiment 7 of the present invention consists in the compounds of the above general formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ , X ² and X ³ as described above under the embodiment I -, 2, 3, 4, 5 or 6 mentioned are defined and

R ⁷ (a) H, halogen, -CN, (b) _d-C3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms could be,

(c) C _3-5 cycloalkyl,

(d) -NH _2, -NH (Ci _-3 alkyl), -N (d _-3 alkyl) ₂ means

An embodiment 8 of the present invention consists in the compounds of the above general formula I, in which R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as described above in the embodiment I -, 2, 3, 5, 6 or 7 mentioned are defined and

R ⁴ H means

An embodiment 9 of the present invention consists in the compounds of general formula Ia

wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and X ^{1 are} as defined above in the embodiment I, 2, 3, 6, or 7,

An embodiment W of the present invention consists in the compounds of general formula Ib

in which R ¹ , R ⁶ , R ⁷ and X ^{1 are defined} as mentioned above under the embodiment I, 2, 6, 7 or 8,

An embodiment λ λ_ of the present invention consists in the compounds of the general formula I, Ia or Ib, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and X ³ as described above under the embodiment I, 2, 3, 4, 5, or 8 mentioned are defined and

-Ods-alkyl and R ^{7 is} -CN, -CF ₃ , Cl or Br,

One embodiment of the present invention consists in the compounds of general formula I, Ia or Ib above in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 are} as are defined above in the embodiment I, 3, 4, 5, 6, 7, 8, 9, W or 1_1_ mentioned and

(b) a phenyl group which is optionally substituted by 1, 2 or 3 radicals R ^{1 3} ,

(c) an optionally substituted by a group R ¹ is ^{2-substituted} C _3-6 cycloalkyl group, can be a -CH ₂ moiety replaced by a -C (O) group,

(d) a five-membered heteroaryl radical which is optionally substituted by 1, 2 or 3 radicals R ^{1 4} and contains at least one N, O or S atom and which, if appropriate, additionally contains one, two or three further N atoms,

(e) a six-membered heteroaryl radical which is optionally substituted by 1 or 2 radicals R ^{1 4} and contains one, two or three N atoms,

(f) a 5- or 6-membered heterocycle which is optionally substituted by 1 or 2 radicals R ^{1 4} and contains at least one N, O or S atom and in which additionally a -CH ₂ - unit is represented by a -C ( O) group can be replaced,

R ¹ - ¹ (a) -CN, C ₃ - ₆ -cycloalkyl, -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , or

(b) a methyl or ethyl group in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

R ¹ - ² F, Cl, Br, -CN, -OH, -OCH ₃ , or phenyl,

R ^{1 3} independently

(a) F, Cl, Br, -OH, -OCH ₃ , C _1-6 -alkyl or (b) a Ci _-3 alkyl group wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted, and

R ^{1 4 is} independently (a) F, Cl, Br, -OH, -O-Ci _-3 alkyl, -NH _2, -NHCH _3, -N (CHa) _2, -NH-C (O) -C _-4 alkyl, de-alkyl, or

(b) a Ci _-3 alkyl group wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms can be substituted,

An embodiment of the present invention consists in the compounds of the above general formula I, Ia or Ib, in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 are} as are defined above in the embodiment I, 3, 4, 5, 6, 7, 8, 9, W or 1_1_ mentioned and

R ¹ (a) an optionally substituted by a radical R ^1-1 substituted C-ι-6-alkyl group,

(C) a C ₄ _6 -cycloalkyl group which is optionally substituted by a radical R ^{1 2} and in which one -CH ₂ - unit may be replaced by a -C (O) -group,

(d) a five-membered heteroaryl radical which is optionally substituted by 1, 2 or 3 radicals R ^{1 4 and} is selected from the group consisting of

('S (' p (e) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} six-membered heteroaryl residue selected from the group consisting of

(f) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} 5- or 6-membered heterocycle which is selected from the group consisting of

R ¹ - ¹ (a) -CN, cyclopropyl, CF ₃ , -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N (CHa) ₂ , or

(b) a methyl or ethyl group in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, R ¹ - ^{2 is} -OH or -O-CH ₃ ,

R ^{1 3} independently

(a) F, Cl, Br, -OH, -OCH _3, -OCF _3, d _-4 -alkyl or (b) a Ci _-3 alkyl group wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1 , 2 or 3 fluorine atoms, and

R ^{1 4} independently

(a) F, Cl, Br, -OH, -O-Ci _-3 alkyl, -OCF _3, -NH _2, -NH-C ^ alkyl, -N (Ci _-4 alkyl) _2, -NH -C (O) -C _-4 alkyl, C _1-6 alkyl, or

An embodiment M of the present invention consists in the compounds of the above general formula I, Ia or Ib, in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as above are defined under the embodiment I, 3, 4, 5, 6, 7, 8, 9, 1_0 or 1_1_ and

R ^{1 is} selected from the group consisting of

Examples of very particularly preferred compounds of the above general formula I include the following:

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases. USED TERMS AND DEFINITIONS

Unless otherwise indicated, all substituents are independent of each other. If more than one C-ι- be ₆ alkyl groups as substituents on a group, for example, it might in the case of three substituents d- ₆ alkyl independently of one another once, once methyl n-propyl and one te / f-butyl.

In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. As used herein, an asterisk (*) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule.

Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.

_"3 alkyl Ci" The term (including those which are part of other groups) are alkyl groups having 1 to 3 carbon atoms, branched, the term _"C-M-alkyl" and unbranched alkyl groups having 1 to 4 carbon atoms, the term "C _1-6 -alkyl" is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 8 carbon atoms by the term "C _1-8 -alkyl". Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / f-butyl. Furthermore, the above-mentioned terms also include those radicals in which each methylene group may be substituted with up to two and each methyl group with up to three fluorine atoms. The term "Co- _2- alkylene" is understood to mean branched and unbranched alkylene groups having from 0 to 2 carbon atoms, a co-alkylene group being a bond. Examples include: methylene, ethylene and ethane-1, 1-diyl. Furthermore, the abovementioned terms also include those radicals in which each methylene group may be substituted by up to two fluorine atoms.

The term "C _3-7 -cycloalkyl" (including those which are part of other groups) means cyclic alkyl groups having 3 to 7 carbon atoms and the term "C _3-6 -cycloalkyl" means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "Cs-e-cycloalkylene" (even if they are part of other radicals) are understood as meaning cyclic alkylene groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "C ₂ - ₆ alkenyl" (including those which are part of other radicals) are understood to mean branched and unbranched alkenyl groups having 2 to 6 carbon atoms, provided they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals. For example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-butenyl, 2-butenyl and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.

The term "C ₂ - ₄ -alkynyl" (including those which are part of other radicals) are understood to mean branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided they have at least one triple bond. For example, this will be called: ethynyl, propynyl or butynyl. Unless otherwise stated, the definitions of propynyl and butynyl include all conceivable isomeric forms of the respective radicals. For example, propynyl includes 1-propynyl and 2-propynyl, butinyl includes 1-butynyl, 2-butynyl and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.

"Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

By the term "heterocyclic rings" or "heterocycle" is meant stable 4-, 5- or 6-membered monocyclic heterocyclic ring systems which may be both saturated and monounsaturated and which may bear, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Both nitrogen and sulfur heteroatoms can optionally be oxidized. The above heterocycles may be linked via a carbon atom or via a nitrogen atom with the remainder of the molecule. Examples include the following compounds:

"Cyclic imides" include, for example, succinimide, maleimide and phthalimide.

The term "aryl" (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example, phenyl, 1-naphthyl or 2-naphthyl be mentioned; preferred aryl radical is phenyl. Unless otherwise stated, the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, Bromine and iodine, where the radicals may be the same or different.

The term "heteroaryl" is understood as meaning five- or six-membered heterocyclic aromatics which may contain one, two, three or four heteroatoms selected from the group oxygen, sulfur and nitrogen and additionally contain so many conjugated double bonds that an aromatic system is formed becomes. These heteroaryls may additionally be benzo-fused with a phenyl ring to form nine- or ten-membered bicyclic heteroaryls. Examples of five- or six-membered heterocyclic aromatics include:

, 0th , S. N ^ NH O ^ N

N-N N ^ * H o. .O ... .s

(^ N N

NN NV * NN

Examples of nine- or ten-membered heterocyclic aromatics include:

Unless otherwise stated, the above-mentioned heteroaryls may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluoro, Chlorine, bromine and iodine, where the radicals may be the same or different. Furthermore, a nitrogen atom present in the heteroaryl radical may be oxidized to form an N-oxide.

By the term "oxo group" is meant an oxygen substituent on a carbon atom resulting in the formation of a carbonyl group -C (O) -. Introduction of an oxo group as a substituent on a non-aromatic carbon atom results in conversion of a -CH ₂ group to a -C (O) group. The introduction of an oxo group on an aromatic carbon atom leads to the conversion of a -CH group into a -C (O) group and may result in the loss of aromaticity.

If they contain suitable basic functions, for example amino groups, in particular for pharmaceutical applications into their physiologically compatible salts with inorganic or be transferred to organic acids. Suitable inorganic acids are, for example, hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, organic acids being, for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid into consideration.

Furthermore, the compounds of general formula I, provided they contain suitable carboxylic acid functions, in particular for pharmaceutical applications in their physiologically acceptable salts with inorganic or organic bases. Examples of suitable inorganic bases are alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc hydroxides or ammonium hydroxides; suitable organic amines are, for example, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.

The compounds of the invention may exist as racemates if they possess only one chiral element, but they may also be present as pure enantiomers, i. in (R) or (S) form.

However, the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.

Methods of Preparation

According to the invention, the compounds of general formula I are obtained by processes known per se, for example by the following processes:

(A) Amide coupling:

The illustrated linkage of carboxylic acids of the general formula II in which all radicals are defined as mentioned above, with amines of the general formula III in which all radicals are as defined above, with the formation of carboxylic acid amides of the general formula I in which all radicals As defined above, can be carried out by conventional methods for amide formation.

The coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example carbodiimides, e.g. Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) -carbodiimide, 0- (1H-benzotriazol-1-yl) - / V, / V, ΛΛΛMetramethyluronium hexafluorophosphate (HBTU) or tetra - Fluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used. The reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt). The couplings are normally carried out with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), Λ / -methylpyrrolidone (NMP) or mixtures thereof. If necessary, an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.

(B) Amide coupling:

(IV) (V)

An alternative method of preparing compounds of general formula I is to link carboxylic acids of general formula V wherein all of the radicals are as defined above with amines of general formula IV in which all radicals are as defined above.

It is also possible to convert the carboxylic acids of the general formula V into carbonyl chlorides and then react them with amines of the general formula IV. The synthesis of carboxylic acid chlorides is carried out by literature methods (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. E5 / 1).

(C) Reductive amination of the aldehydes or ketones; Reduction of oximes previously formed from the aldehydes or ketones:

(VI)

(D) nucleophilic substitution on halogen-substituted heteroaromatics:

(E) nucleophilic substitution on halogen-substituted heteroaromatics:

(X) (VIII)

The reaction of a phenol of general formula VIII in which all radicals are defined as mentioned above with a nitrile of general formula X in which all radicals are as defined above, is carried out by known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethyl sulfoxide and expediently in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate at a temperature of 20 ⁰ C to 160 ⁰ C. If the phenol of the general formula VIII is liquid, the reaction can also be carried out without solvent and additional base.

(F) Reduction of the nitrile group:

(IX)

The reduction of a nitrile of general formula IX to an amine of general formula III wherein all of the radicals are as defined above can be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminum hydride, diborane or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminum chloride. Compounds of the general formula III in which the radical R ^{4 is} not hydrogen but an alkyl radical can likewise be prepared from compounds of the general formula (III) Produce formula IX. Thus, ketones are obtained, for example, from the reaction of a nitrile of the general formula IX with an alkyl Grignard reagent, which can be converted by means of reductive amination into the compounds of the general formula III. The reductive amination is carried out by known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or Natriumcyanoborhydrid conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally with the addition of acetic acid. Alternatively, the ketones obtained can also be converted into oximes. The subsequent reduction of the oximes then provides compounds of the general formula

Method Description for Cynomolgus B1 Receptor Binding

CHO cells expressing the cynomolgus B1 receptor are termed "HAM ^'S S-12

From confluent cultures, the medium is removed, the cells are washed with PBS buffer, scraped or detached with versene and by

Centrifuging isolated. Subsequently, the cells are homogenized in suspension, the homogenate is centrifuged and resuspended. After determination of the protein content, 200 μl of the homogenate (50 to 250 μg protein / assay) are incubated for 60-180 minutes at room temperature with 0.5 to 5.0 nM kallidine (DesArg10, Leu9), [3,4-prolyl-3,43H (N) ] and increasing concentrations of the test substance are incubated in a total volume of 250 μl. Incubation is terminated by rapid filtration through GF / B glass fiber filters pre-treated with polyethyleneimines (0.3%). The radioactivity bound to the protein is measured with a TopCount NXT. Non-specific binding is defined as the bound radioactivity in the presence of 1.0 μM (DesArgi O) kallidine. The analysis of the concentration-binding curve can be carried out by means of a computer-aided non-linear curve fitting in order to determine the corresponding K ₁ value for the test substance.

Test results from the cynoBKI receptor binding assay:

INDICATIONS

Due to their pharmacological properties, the new compounds and their physiologically acceptable salts are suitable for the treatment of diseases and

Disease symptoms that are at least partially caused by the stimulation of bradykinin B1 receptors, or in which antagonizing the bradykinin-1 receptor may cause symptom improvement.

Another object of the present invention comprises the compounds of the invention of the above-mentioned general formula I for use as a medicament.

Due to their pharmacological activity, the substances are suitable for the treatment of (a) acute pain, such as toothache, peri- and postoperative pain, traumatic pain, muscle pain, Burn pain, pain in sunburn, trigeminal neuralgia, pain in colic, as well as in spasms of the gastrointestinal tract or the uterus;

(b) intestinal pain, such as chronic pelvic pain, gynecological pain, pain before and during menstruation, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic,

Cholecystitis, prostatitis, angina pectoris, irritable bowel pain, non-ulcer dyspepsia and gastritis, prostatitis, non-cardiac chest pain, and pain in myocardial ischemia and myocardial infarction;

(c) neuropathic pain, such as painful polyneuropathies, pain in diabetic neuropathy, AIDS-associated neuropathic pain, non-herpes associated neuralgia, post-zoster neuralgia, nerve injury, traumatic brain injury, pain due to nerve damage as a result of toxins or chemotherapy, in phantom pain, pain in multiple sclerosis, nerve root detachment and painful traumatic individual nerve damage, and central pain such as after stroke, spinal cord injury or tumors;

(d) inflammatory / pain receptor mediated pain associated with diseases such as osteoarthritis, rheumatoid arthritis, rheumatic fever, Tendo synovitis, bursitis, tendonitis, gout and gouty arthritis, traumatic arthritides, vulvodynia, lesions, and

Disorders of the muscles and fasciae of juvenile arthritis, spondylitis, psoriatic arthritis, myositis, dental diseases, influenza and other viral infections such as colds, systemic lupus erythematosus or pain in burns;

(e) tumor pain associated with cancers such as lymphocytic or myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, lymphogranulomatosis, lymphosarcoma, solid malignant tumors, and extensive metastases;

(f) headache disorders of various causes, such as cluster headache, migraine (with or without aura), and tension-type headache; (g) pain conditions of mixed cause, such as chronic low back pain, including lumbago, or fibromyalgia.

Furthermore, the compounds are suitable for treatment (h) inflammatory or inflammatory effects of sunburn and burns, gingivitis, edema after trauma from burns, cerebral edema and angioedema, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory diseases of the skin (such as psoriasis and eczema), vascular connective tissue disorders, strains and fractures, as well as musculoskeletal diseases with inflammatory phenomena such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, but also osseoarthritis, and inflammatory connective tissue diseases of other causes, and collagenoses of any genesis such as systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Still's disease or Felty syndrome;

(i) of inflammatory changes associated with respiratory diseases such as bronchial asthma, including allergic asthma (atopic and non-atopic) and bronchospasm on exertion, occupational asthma, viral or bacterial exacerbation of existing asthma and other non-allergic conditional asthmatic diseases;

(j) chronic bronchitis and chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, adult respiratory distress syndrome (ARDS), bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), vasomotor rhinitis and pneumoconiosis diseases such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tobaccoosis, byssinosis, exogenous allergic alveolitides, pulmonary fibrosis, bronchiectasis, lung diseases in alpha-anti-tritrypsin deficiency and cough;

(k) diabetes mellitus and its consequences (such as, for example, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (for example hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion); (I) sepsis and septic shock after bacterial infections or after trauma;

(m) itching (pruritus) causing syndromes and allergic skin reactions; (n) from central nervous system injuries; (o) wounds and tissue damage;

(p) benign prostatic hyperplasia and hyperactive bladder;

(q) of vascular diseases such as panarteritis nodosa, polyarthritis nodosa,

Periarteritis nodosa, temporal arteritis, Wegner's granulomatosis, giant cell arrhythmias, arteriosclerosis, erythema nodosum;

(r) disorders of motility or spasm of respiratory, genitourinary, gastrointestinal inclusive biliary or vascular structures and organs;

(s) post-operative fever;

(t) for the treatment and prevention of cardiovascular diseases such as hypertension and related disorders;

(u) for the treatment and prevention of cancer and related diseases;

(v) for the treatment and prevention of psychiatric disorders, such as depression;

(w) for the treatment and prevention of urinary incontinence and related diseases;

(x) for the treatment and prevention of diseased obesity and relatives

diseases;

(y) for the treatment and prevention of arteriosclerosis and related diseases

diseases; and (z) for the treatment and prevention of epilepsy.

The substances are suitable for causal treatment in terms of slowing down or stopping the progression of chronic progressive diseases, in particular osteoarthritis, rheumatoid arthritis and spondylarthritis.

Another object of the present invention comprises the use of the compounds of the invention of the above-mentioned general formula I for the preparation of a medicament for a therapeutic application in the indications mentioned above.

The compounds of general formula I according to the invention are preferably used for the treatment of osteoarthritis, rheumatoid arthritis or COPD. The term "treatment" or "therapy" is understood to mean a therapeutic treatment of patients with overt, acute or chronic indications, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim to terminate the pathological condition, to reduce the severity of the pathological condition or to delay the progression of the pathological condition, depending on the type or severity of the indication included.

Another object of the present invention is the use of a compound of general formula I for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumor pain, headache disorders and pain conditions of mixed cause and another of the above-mentioned diseases. The use is characterized in that it provides the administration of an effective

Amount of a compound of general formula I or a physiologically acceptable salt thereof includes a patient who requires such treatment.

The term "patient" is preferably understood to mean a human.

In addition to their suitability as human therapeutics, these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.

COMBINATIONS

For the treatment of pain, it may be advantageous to combine the compounds of the invention with invigorating substances such as caffeine or other analgesic agents. If suitable active ingredients are available for the treatment of the cause of the pain, these can be combined with the compounds according to the invention.

For a combination therapy, for example, the following compounds come into question: Non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives, which may be selected from the group consisting of alminoprofen, bucloxinic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenoic acid; Acetic acid derivatives which may be selected from the group consisting of indomethacin, acemetacin, alcofenac, isoxepac, sulindac and tolmetin; Fenamic acid derivatives which may be selected from the group consisting of meclofenamic acid, mefenamic acid and tolfenamic acid; Biphenyl-carboxylic acid derivatives; Oxicams, which may be selected from the group consisting of meloxicam, piroxicam and tenoxicam; Salicylic acid derivatives which may be selected from the group consisting of acetylsalicylic acid and sulfasalazine; Pyrazolones, which may be selected from the group consisting of apazone and feprazone); Coxibs, which may be selected from the group consisting of celecoxib and etoricoxib.

Opiate receptor agonists, which may be selected, for example, from the group consisting of such as morphine, darvon, tramadol and buprenorphine.

Cannabinoid agonists, such as GW-1000.

Sodium channel blockers, which may be selected, for example, from the group consisting of carbamazepine, mexiletine, pregabalin, tectin and ralfinamide.

N-type calcium channel blockers, such as ziconotide.

Serotonergic and noradrenergic modulators, which may be selected, for example, from the group consisting of duloxetine and amitriptyline.

Corticosteroids, which may be selected, for example, from the group consisting of betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.

Histamine H1 receptor antagonists, which may be selected, for example, from the group consisting of brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, Promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.

Leukotriene antagonists and 5-lipoxygenase inhibitors, which may for example be selected from the group consisting of zafirlukast, montelukast, pranlukast and zileuton.

Local anesthetics, which may be selected, for example, from the group consisting of ambroxol and lidocaine.

TRPV1 antagonists, which may be selected, for example, from the group consisting of AZD-1386, JTS-653 and PHE-377.

Nicotine receptor agonists such as A-366833.

P2X3 receptor antagonists such as A-317491.

anti-NGF antibodies and NGF antagonists, which may for example be selected from the group consisting of JNJ-42160443 and PPH 207.

NK1 and NK2 antagonists such as CP-728663.

NMDA antagonists, which may for example be selected from the group consisting of CNS-5161, AZ-756 and V-3381.

Potassium channel modulators such as CL-888.

GABA modulators, such as baclofen.

Anti-migraine therapeutics, which may be selected, for example, from the group consisting of sumatriptan, zolmitriptan, naratriptan and eletriptan.

For the treatment of one or more of the respiratory diseases mentioned above, it may be advantageous to use the compounds of the general formula I according to the invention with other active compounds for the treatment of To combine respiratory diseases. If suitable active substances are available for the treatment of the cause of the respiratory diseases, these can be combined with the compounds according to the invention.

Optionally, the compounds of the general formula I can also be used in combination with other pharmacologically active substances. Preference is given here to those active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 receptor (CysLTI, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as, for example, p38, ERK1 , ERK2, JNK1, JNK2, JNK3 or SAP, LTB4 receptor (BLT1, BLT2) antagonists, EGFR inhibitors, H1 receptor antagonists, antihistamines, H4 receptor antagonists, PAF antagonists and PI3-kinase inhibitors CXCR1 and / or CXCR2 Receptor antagonists and substances for cough.

The compounds of general formula I can also be used in the form of two- or three-fold combinations thereof, such as, for example, combinations of compounds of formula I with one or two compounds selected from the group consisting of

• betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists, • anticholinergics, betamimetics, 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), (6R) -L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as "BH4" ) and its derivatives, which are mentioned in WO 2006/120176, and SYK inhibitors (spike tyrosine kinase inhibitors),

Anticholinergics, betamimetics, corticosteroids, PDE4 inhibitors and MRP4 inhibitors.

The combinations of three active ingredients each one of the above-mentioned classes of compounds is part of the invention. According to the invention, compounds which are selected from the group consisting of arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterols, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol are preferably used according to the invention , Mabuterol, meluadrin, metaproterenol, milveterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, tiaramide, toluubuterol and zinterol or

6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one , 8- {2- [2- (2,4-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine- 3-one,

• 8- {2- [2- (3,5-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

• 8- {2- [2- (4-Ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one .

• 8- {2- [2- (4-Fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one .

N- (5- {2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1-dimethyl-propylamino] - 1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide, N- (5- {2- [3- (4,4-diethyl-6-fluoro-2-oxo-4H-benzo [d] [ 1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxyethyl} -2-hydroxyphenyl) -methanesulfonamide,

N- (5- {2- [3- (4,4-diethyl-6-methoxy-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1,1-dimethyl - propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide,

N- (5- {2- [1,1-dimethyl-3- (2-oxo-4,4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] - 1-hydroxy-ethyl} -2-hydroxy-phenyl) -methanesulfonamide,

• 8- {2- [1,1-Dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one,

• 8- {2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy -4H-benzo [1,4] oxazin-3-one, • 8- {2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl ) - propylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one,

• 8- {2- [1,1-Dimethyl-3- (3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy 4H-benzo [1,4] oxazin-3-one, N- [2-hydroxy-5 - ((1R) -1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl ] formamide

• 8-hydroxy-5 - ((1R) -1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1H-quinoline -2-one, • 8-hydroxy-5 - [(1R) -1-hydroxy-2- (6-phenethylaminohexylamino) ethyl] -1H-quinolin-2-one,

• 5 - [(1R) -2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenyl-amino] -phenyl} -ethyl-amino) -1-hydroxy-ethyl] -8- hydroxy-1H-quinolin-2-one,

• [3- (4- {6 - [(2R) -2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea .

• 4 - ((1R) -2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol,

• 3- (4- {6 - [(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzenesulfonamide, • 3- (3- { 7 - [(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzenesulfonamide,

• 4 - ((1R) -2- {6- [4- (3-cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol,

• Λ / -1-adamantanyl-2- {3 - [(2R) -2 - ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino} propyl ] phenyl} acetamide,

• (1R) -5- {2- [6- (2,2-difluoro-2-phenyl-ethoxy) -hexylamino] -1-hydroxy-ethyl} -8-hydroxy-1H-quinolin-2-one

• (R, S) -4- (2 - {[6- (2,2-Difluoro-4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol, • ( R, S) -4- (2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

(R, S) -4- (2 - {[4,4-difluoro-6- (4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

(R, S) -4- (2 - {[6- (4,4-difluoro-4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

(R, S) -5- (2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxy-quinoline-2 (1H) -one • (R _! S) - [2 - ({6- [2,2-Difluoro-2- (3-methylphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol,

4- (1R) -2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol, • (R, S) -2- (hydroxymethyl) -4- (1-hydroxy-2 - {[4,4,5,1,5-tetrafluoro-6- (3-phenylpropoxy) -hexyl] amino} ethyl) phenol,

• (R, S) - [5- (2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide,

(R, S) -4- [2 - ({6- [2- (3-bromophenyl) -2,2-difluoroethoxy] hexyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol,

• (R, S) -N- [3- (1,1-Difluoro-2 - {[6 - ({2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} ethyl) phenyl] urea,

3- [3- (1,1-Difluoro-2 - {[6- ({2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} -amino) hexyl] oxy} ethyl) phenyl] imidazolidine-2,4-dione, • (R, S) -4- [2 - ({6- [2,2-difluoro-2- (3-methoxyphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl ] - 2- (hydroxymethyl) phenol,

• 5 - ((1R) -2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxy-quinolin-2 (1H) -one,

• 4 - ((1R) -2 - {[4,4-Difluoro-6- (4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

(R, S) -4- (2 - {[6- (3,3-difluoro-3-phenylpropoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

• (R _! S) - (2 - {[6- (2 _: 2-Difluoro-2-phenylethoxy) -4,4-difluorohexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol, • (R , S) -4- (2 - {[6- (2,2-difluoro-3-phenylpropoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxylmethyl) phenol,

3- [2- (3-chloro-phenyl) -ethoxy] -N- (2-diethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydroxy) benzothiazol-7-yl) -ethylamino] -ethyl} -propionamide,

N- (2-diethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl) -ethylamino] -ethyl} -3- ( 2-naphthalen-1-yl-ethoxy) -propionamide,

• 7- [2- (2- {3- [2- (2-Chloro-phenyl) -ethyl-amino] -propylsulfanyl} -ethylamino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one . optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate,

Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

According to the invention, anticholinergics are preferably compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts , preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane salts. In the above-mentioned salts, the cations are the pharmacologically active ingredients. As anions X ^" , the above-mentioned salts may preferably 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 counterions, Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred Other anticholinergics may be selected from Group consisting of

2,2-diphenylpropionic acid tropol ester methobromide,

2,2-diphenylpropionic acid copoprene methobromide, 2-fluoro-2,2-diphenylacetic acid copoprene methobromide,

2-fluoro-2,2-diphenylacetic acid tropol ester methobromide,

3,3 ', 4,4'-tetrafluorobenzylic acid tropol ester methobromide,

3,3 ', 4,4'-tetrafluorobenzilatescopine ester methobromide,

4,4'-difluorobenzylic acid tropol ester methobromide, 4,4'-difluorobenzilic acid copoprene methobromide,

3,3'-Difluorobenzylic acid tropol ester methobromide,

3,3'-difluorobenzic acid copoprene methobromide,

-Hydroxy-fluorene---carboxylic acid-tropol ester-methobromide, -Fluoro-fluorene---carboxylic acid-tropol ester-methobromide,

• θ -hydroxy-fluorene-θ-carboxylic acid copoprene methobromide,

9-fluoro-fluoren-9-carboxylic acid copo-ester methobromide,

9-methyl-fluorene-9-carboxylic acid-tropol ester-methobromide, 9-methyl-fluorene-9-carboxylic acid-co-ester methobromide,

Benzylic acid cyclopropyltropine ester methobromide,

2,2-diphenylpropionic acid cyclopropyltropine ester methobromide,

-Hydroxy-xanthene-θ-carboxylic acid cyclopropyltropine ester methobromide,

-Methyl-fluorene-θ-carboxylic acid cyclopropyltropine ester methobromide,-methyl-xanthene---carboxylic acid cyclopropyltropine ester methobromide,

Θ-hydroxyfluorene-θ-carboxylic acid cyclopropyltropine ester methobromide,

4,4'-difluorobenzilate, cyclopropyltropine ester methobromide,

-Hydroxy-xanthene---carboxylic acid tropol ester methobromide,

• θ-hydroxy-xanthene---carboxylic acid copoprene methobromide, • 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide,

9-methyl-xanthene-9-carboxylic acid copo-ester methobromide,

9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide,

9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide, and

• θ-hydroxymethyl-xanthene---carboxylic acid copo-ester methobromide.

The abovementioned compounds can also be used in the context of the present invention as salts in which, instead of the methobromide, the salts Metho-X are used, where X may have the meanings given above for X ^" .

As corticosteroids, according to the invention, preferably compounds are used which are selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane or Pregna-1,4-diene-3,20-dione, 6-fluoro-11-hydroxy-16, 17 - [(1-methylethylidene) -bis (oxy)] - 21 - [[4 - [(nitrooxy) methyl ] benzoyl] oxy] -, (6-alpha, 1 1-beta, 16-alpha) - (9CI) (NCX-1024) 16,17-butylidenedioxy-6,9-difluoro-1 1-hydroxy-17- (methylthio) androst-4-en-3-one (RPR-106541),

• 6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -1,1-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester, 6,9-Difluoro-1 1 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbo- thionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl ) esters, and

6-alpha, 9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha (2,2,3,3-tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17beta carboxylic acid cyanomethyl ester,

optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.

Preferred PDE4 inhibitors according to the invention are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofylline, atizoram, oglemilast and tetomilast or

• 5 - [(N- (2,5-dichloro-3-pyridinyl) -carboxamide] -8-methoxy-quinoline (D-4418),

N- (3,5-dichloro-1-oxido-4-pyridinyl) -carboxamide] -8-methoxy-2- (trifluoromethyl) -quinoline (D-4396 (Sch-351591)), N- (3,5 Dichloropyrid-4-yl) - [1- (4-fluorobenzyl) -5-hydroxyindole-3-yl] glyoxylic acid amide (AWD-12-281 (GW-842470)), 9 - [(2-fluorophenyl) methyl ] -N-methyl-2- (trifluoromethyl) -9H-purin-6-amine (NCS-613),

4 - [(2R) -2- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-phenylethyl] pyridine (CDP-840),

• N - [(3R) -3,4,6,7-Tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo [3,2,1-jk] [1,4] benzodiazepin-3-yl ] -4-pyridinecarboxamide (PD-168787),

4- [6,7-diethoxy-2,3-bis (hydroxymethyl) -1-naphthalenyl] -1- (2-methoxyethyl) -2 (1 H) -pyridinone (T-440), 2- [4- [6,7-Diethoxy-2,3-bis (hydroxymethyl) -1-naphthalenyl] -2-pyridinyl] -4- (3-pyridinyl) -1 (2H) -phthalazinone (T-2585 )

• (3- (3-Cyclopenyloxy-4-methoxybenzyl) -6-ethylamino-8-isopropyl-3H-purine (V-11294A),

Beta- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),

Imidazo [1,5-a] pyrido [3,2-e] pyrazine-6 (5H) -one, 9-ethyl-2-methoxy-7-methyl-5-propyl- (D-22888)

• 5- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-methylphenyl) methyl] -, (3S, 5S) -2-piperdinone (HT-0712), • 4- [1 - [3,4-bis (difluoro-methoxy) -phenyl] -2- (3-methyl-1-oxo-4-pyridinyl) -ethyl] -α, alpha-bis (trifluoromethyl) -benzenemethanol (L-826141),

N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide,

• (-) p - [(4aR ^* , 10oS ^* ) -9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] - [1,6-naphthyridine -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-methylisothioureido] benzyl) -2-pyrrolidone,

Cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid],

2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoro-methoxyphenyl) -cyclohexan-1-one,

Cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol],

• (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate,

• (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate,

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine and

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (te / f-butyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a ] pyridine

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

According to the invention, compounds which are selected from the group consisting of ketuximab are preferably used as EGFR inhibitors.

Trastuzumab, panitumumab (= ABX-EGF), Mab ICR-62, gefitinib, canertinib and erlotinib or

• 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-cyclopropylmethoxyquinazoline .

• 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-fluorophenyl) amino] -6 - [[ 4 - ((R) -2-methoxymethyl-6-oxomorpholin-4-yl) - i-oxo -but-i-y-amino-cyclopropylmethoxyquinazoline,

• 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-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene-1 - yljamino ^ -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-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) amino] -1-oxo-2-butene 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-cyclopropylmethoxyquinazoline,

4-[(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxy-quinazoline, • 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene 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 - ((R ) -tetrahydrofuran-3-yloxy) quinazoline, • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 -yl] amino} - 7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene-1 - yl} amino) -7-cyclopentyloxy-quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-butene-1-ylamino] -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-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) -amino] -quinazoline,

4 - [(R) - (1-phenylethyl) 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-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2] buten-1-yl] amino} -7-methoxyquinazoline, • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-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-butene-1 yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

• 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline,

4-[(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-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- (te / f-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-methanesulfonyl-amino-cyclohexane-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-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- (piperidin-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 - [(morpholin-4-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-methanesulfonyl-amino-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-1-cyclohexane-i-yxyxy ^ methoxy-quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 - yloxy) -7-methoxy-quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino-1-cyclohexane-i-yxyxy ^ methoxy-quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline, • 4 - [(3-chloro-4 fluorophenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -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-methoxyethoxy) -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- (te / f-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-1-cyclohexan-1-yloxy ^ methoxy-quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N-methyl-amino-1-cyclohexane -i-yloxy-methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) -carbonyl-amino] -cyclohexane 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, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-Methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline,

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline,

4-[(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexane-1-ylxy ^ - methoxy-quinazoline, 4-[(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline,

4 - [(3-ethynylphenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,

• 4 - [(3-ethynylphenyl) 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 .

• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl ) - carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline,

• 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-methoxy-propyl-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,

• 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-fluorophenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-ylxy) -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 ^ 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,

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-fluorophenyl) amino] -6 - {[4- (homomorpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- [ (S) - (tetrahydrofuran-3-yl) oxy] -quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) carbonyl] -piperazin-1-yl} - ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] - 6 - [(vinylcarbonyl) amino] -quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline,

• 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4 - ((S) -6-methyl-2-oxomorpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] quinazoline, and • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N - [(ethoxycarbonyl) methyl ] amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.

According to the invention, LTD4-receptor antagonists are preferably compounds which are selected from the group consisting of montelukast, pranlukast and zafirlukast, or (E) -8- [2- [4- [4- (4-

Fluorophenyl) butoxy] phenyl] ethenyl] -2- (1H-tetrazol-5-yl) -4H-1-benzopyran-4-one (MEN-91507),

4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid (MN-001),

• 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) -thio) methyl cyclopropane-acetic acid,

• 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid and • [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl ]acetic acid,

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,

Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Examples of salts or derivatives whose formation the LTD4 receptor antagonists are capable of are: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or else furoate.

According to the invention, compounds which are selected from the group consisting of compounds are preferably used as histamine H1 receptor antagonists Epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, olopatadine, desloratidine and meclozin, optionally in the form of their Racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

According to the invention, the histamine H4 receptor antagonists used are preferably compounds such as (5-chloro-1H-indol-2-yl) - (4-methyl-1-piperazinyl) -methanone (JNJ-7777120), optionally in the form of their racemates , Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention

According to the invention, as MAP kinase inhibitors, it is preferable to use compounds which are selected from the group consisting of:

• Bentamapimod (AS-602801) • Doramapimod,

5-carbamoyl indoles (SD-169),

• 6 - [(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide (VX-702),

Alpha- [2 - [[2- (3-pyridinyl) ethyl] amino] -4-pyrimidinyl] -2-benzothiazoleacetonitrile (AS-601245),

9,12-epoxy-1H-diindolo [1,2,3-fg: 3 ', 2', 1 '-kl] pyrrolo [3,4-i] [1,6] benzodiazocine-10-carboxylic acid ( CEP-1347), and

4- [3- (4-chlorophenyl) -5- (1-methyl-4-piperidinyl) -1H-pyrazol-4-yl] -pyrimidine (SC-409), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.

According to the invention, compounds which are selected from the group consisting of: saredutant, nepadutant and figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, are used as neurokinin (NK1 or NK2) antagonists. Solvates or hydrates.

According to the invention, substances which are selected from the group consisting of hydrocodone, caramiphene, carbetipentane and dextramethorphan, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates, are preferably used as substances for coughing ,

Preferred substances of the invention are CXCR1 or CXCR2 antagonists, compounds according to the invention are preferably used, e.g. 3 - [[3 - [(dimethylamino) carbonyl] -2-hydroxyphenyl] amino] -4 - [[(R) -1- (5-methylfuran-2-yl) propyl] amino] cyclobut-3 en-1, 2-dione (SCH-527123), optionally in the form of its racemates, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.

The dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally 1 to 3 times a day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular aerosol formulations being suitable for inhalation. If appropriate, they may be combined with one or more inert customary carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol. pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragees, Capsules, powders, suspensions, solutions, metered aerosols or suppositories are incorporated.

EXPERIMENTAL PART

As a rule, mass spectra and / or ¹ H-NMR spectra are available for the compounds prepared. The ratios indicated for the flow agents relate to volume units of the respective solvents. The volume units given for ammonia refer to a concentrated solution of ammonia in water. Unless otherwise stated, the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the concentrations indicated.

For chromatographic purifications, silica gel from Millipore (MATREX ™, 35 to 70 μm) or Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63 to 200 μm, article no: 1.01097.9050) is used.

The test descriptions use the following abbreviations:

DC thin-layer chromatogram

DIPEA diisopropylethylamine

DMA Λ /, Λ / -dimethylacetamide

DMAP 4-dimethylaminopyridine DMF Λ /, Λ / -dimethylformamide

DMSO dimethyl sulfoxide

HATU O- (7-azabenzotriazol-1-yl) -Λ /, Λ /, Λ / ', Λ /' - tetramethyluronium hexafluorophosphate

R ₁ retention time

R _f Relation to the front tertiary

TBTU 2- (1 / - / - Benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

TEA triethylamine

TFA trifluoroacetic acid tert

The following analytical HPLC methods were used:

Method 1: Column: Interchim Strategy C18, 5 μM, 4.6 x 50 mm

Detection: 220 - 320 nm

Plasticizer A: water / 0.1% formic acid

Plasticizer B: acetonitrile

Gradient:

Method 2: Column: Merck Cromolith Flash RP18e, 4.6 x 25 mm

Plasticizer A: water / 0.1% formic acid

Plasticizer B: acetonitrile / 0.1% formic acid gradient:

Method 3: Column: Sunfire C18, 3.5 μM, 4.6 x 50 mm

Detection: 180-820 nm

Plasticizer A: water / 0.1% trifluoroacetic acid

Plasticizer B: acetonitrile / 0.1% trifluoroacetic acid

Temperature: 40 ^° C

Gradient:

Method 4: Column: Sunfire C18, 3.5 μM, 4.6 x 50 mm

Detection: 180-820 nm

Plasticizer A: water / 0.1% trifluoroacetic acid

Plasticizer B: acetonitrile / 0.1% trifluoroacetic acid

Temperature: 40 ^° C

Gradient:

Method 5: Column: YMC Pack ODS-AQ, 3.5 μM, 4.6 x 75 mm

Detection: 180-820 nm

Plasticizer A: water / 0.15% formic acid

Plasticizer B: acetonitrile

Temperature: RT

Gradient:

Method 6: Column: Zorbax Stable Bond C18, 3.5 μM, 4.6 x 75 mm

Detection: 180-820 nm

Plasticizer A: water / 0.15% formic acid Plasticizer B: acetonitrile Temperature: RT Gradient:

Method 7: Column: X Terra C18, 3.5 μM, 4.6 x 50 mm

Detection: 180-820 nm

Plasticizer A: water / 0.1% trifluoroacetic acid

Plasticizer B: acetonitrile / 0.1% trifluoroacetic acid

Temperature: 40 ^° C

Gradient:

Method 8: Column: X Bridge C18, 2.5 μM, 3.0 x 3.0 mm

Detection: 180-820 nm

Plasticizer A: water / 0.032% ammonia

Plasticizer B: acetonitrile

Temperature: 40 ^° C

Gradient:

Method 9: Column: X Bridge C18, 3.5 μM, 4.6 x 50 mm

Detection: 100-1000 nm Plasticizer A: water / 0.1% ammonia solvent B: acetonitrile / 0.1% ammonia gradient:

Method 10: Column: Sunfire C18, 3.5 μM, 4.6 x 50 mm

Detection: 100-1000 nm

Plasticizer A: water / 0.1% formic acid

Plasticizer B: acetonitrile / 0.1% formic acid gradient:

Method 1 1: Column: Varian XRS C18, 5 μM, 4.6 x 50 mm

Detection: 220 - 320 nm

Plasticizer A: water / 0.1% formic acid

Plasticizer B: acetonitrile

Gradient:

The following preparative methods were used for reversed-phase chromatography:

Method Preparative 1:

Column: Atlantis C18 5 μM, 100 x 30 mm

Detection: 210-500 nm

Plasticizer A: water / 0.1% trifluoroacetic acid

Plasticizer B: acetonitrile

Gradient:

The following analytical chiral HPLC methods were used:

Method Chiral 1: Flowing agent: hexane (+ 0.2% diethylamine) / ethanol) isocratic: 75: 25 flow rate: 1 ml / min column: Daicel AD-H 250 x 4.6 mm, 5 μm (column temperature: 10 ^° C.).

Method Chiral 2:

Plasticizer: hexane (+ 0.2% diethylamine) / (methanol / ethanol 1/1) isocratic: 90:10

Flow rate: 1 ml / min

Column: Daicel OJ-H 250 x 4.6 mm, 5 μm (column temperature: 10 ^° C). The following preparative chiral HPLC methods were used:

Method Preparative Chiral:

Plasticizer: hexane (+ 0.2% diethylamine) / isopropanol isocratic: 55:45 flow rate: 12 ml / min column: Daicel AD-H 250 × 20 mm, 5 μm (column temperature: 20 ^° C.).

The following microwave equipment was used: Biotage Emrys Optimizer ™, CEM Explorer ™, CEM Discover ™

Example 1: Pyrimidine-5-carboxylic acid N, N - (1 - ((5- (2-chloro-4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

1 a) 1 - [(pyrimidine-5-carbonyl) -amino1-cyclopropanecarboxylic acid ethyl ester

A solution of 15.74 g (126.9 mmol) of pyrimidine-5-carboxylic acid, 43.57 ml (312.6 mmol) of triethylamine and 44.61 g (138.9 mmol) of TBTU in 460 ml of THF was stirred for 30 minutes at room temperature. Then 9.11 g (127.3 mmol) of 1-amino-cyclopropanecarboxylic acid ethyl ester hydrochloride were added and stirring was continued overnight. The mixture was then evaporated, the residue mixed with 200 ml of water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. Column chromatography (silica gel, dichloromethane + 0-4% methanol) purified the intermediate. Yield: 95% of theory CnH ₁₃ N ₃ O ₃ (235.24)

R _t (method 1): 1.23 min.

1 b) 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropanecarboxylic acid

To a solution of 13.36 g (56.79 mmol) of ethyl 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropanecarboxylate in 240 ml of methanol were added 28.39 ml of a 2N sodium hydroxide solution and the mixture stirred for one hour at room temperature. It was then acidified with concentrated acetic acid and evaporated in vacuo to dryness. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane + 5-30% 10% acetic acid in methanol). Yield: 92% of theory

C ₉ H ₉ N ₃ O ₃ (207.19)

R _t (method 1): 1 .23 min.

1 c) (5- (2-Chloro-4-methoxyphenoxy) pyridin-2-yl) methanamine A solution of 79 mg (0.5 mmol) of 2-chloro-4-methoxyphenol and 1 12 mg (1 .0 mmol) of potassium te / f.butylate in 1 ml of DMSO was stirred for one hour at room temperature. Subsequently, 61 g (0.5 mmol) was added 5-Fluorpicolinonitril and stirred overnight at 80 ⁰ C. The mixture was then filtered through Alox B, filtered with DMF and evaporated to dryness in vacuo. The residue was hydrogenated in methanolic ammonia solution with addition of Raney nickel at 55 ° C. and a hydrogen pressure of 3 bar for 5 h. The catalyst was then filtered off and the filtrate was evaporated to dryness. The crude product thus obtained was purified by HPLC (Method Preparative 1). Yield: 47% of theory

)

1 d) Pyrimidine-5-carboxylic acid N, N- (1 - ((5- (2-chloro-4-methoxyphenoxy) pyridin-2-yl) methylcarbamovecyclopropylamide To a solution of 21 mg (0.1 mmol) of 1 - [(pyrimidine 5-carbonyl) -amino] -cyclopropanecarboxylic acid (from 1b) in 2 ml of DMF were added 28 μl (0.2 mmol) triethylamine, 35 mg (1 .1 mmol) TBTU and stirred at room temperature for 10 minutes (1 .2 mmol) of (5- (2-chloro-4-methoxyphenoxy) pyridin-2-yl) methanamine (from 1C) was added and the mixture was stirred at room temperature overnight The title compound was then isolated by chromatography from the mixture ( Method Preparative 1) Yield: 2.6% of theory

C ₂₂ H ₁₉ Cl ₂ N ₅ O ₄ (453.88)

R _t (method 7): 1 .87 min. Example 2: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

2a) (5- (2-Bromo-4-methoxyphenoxy) pyridin-2-yl) methanamine A solution of 508 mg (2.5 mmol) 2-bromo-4-methoxyphenol and 1.38 g (10.0 mmol) potassium carbonate and 305 mg (2.5 mmol) of 5-Fluorpicolinonitril in 10 ml DMSO was stirred for 4 h 130 ⁰ C. The mixture was diluted with 5 ml acetonitrile / water = 1/1 and separated by HPLC (method: preparative 1). The product fractions were freeze-dried. The residue was dissolved in 5 ml of THF, treated with 12.5 ml (12.5 mmol) of borane complex in THF (1.0 mol / l) and stirred overnight at room temperature. The thus obtained

Reaction product was purified by HPLC with 5-95% acetonitrile: water + 0.1% ammonia.

Yield: 23% of theory

2b) Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) -methylcarbamovecyclopropylamide

Analogously to Example (1 d), starting from (5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) -methanamine (from 2a) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane carboxylic acid (from 1 b) the title compound. C ₂₂ H ₂₀ BrN ₅ O ₄ (498.33)

R _t (method 8): 1.89 min.

Example 3: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-chlorophenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

3a) (5- (2-chlorophenoxy) pyridin-2-yl) methanamine

Analogously to Example (1c) was starting from 2-chlorophenol and 5-chloropicolinonitrile the

Title compound prepared.

3b) Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-chlorophenoxy) pyridin-2-yl) methylcarbamoyl) -cyclopropylamide

Analogously to Example (1 d) was starting from (5- (2-chlorophenoxy) pyridin-2-yl) methanamine (from 3a) and 1 - [(pyrimidine-5-carbonyl) amino] -cyclopropane-carboxylic acid (from 1 b ) the title compound was prepared. C ₂₁ H ₁₈ CIN ₅ O ₃ (423.85)

R _t (method 7): 1 .99 min.

Example 4: Pyrimidine-5-carboxylic acid N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridine) -y-methylcarbamoyl-cyclopropylamide

4a) (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine The title compound was prepared analogously to Example (1c) starting from 4-methoxy-2- (trifluoromethyl) phenol and 5-fluoropicolinonitrile , C ₁₄ H ₁₃ F ₃ N ₂ O ₂ (298.26)

R _t (method 2): 1 .64 min.

4b) Fe / f-butyl-1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamovecyclopropylcarbamate Analogously to Example (1d), starting from 1 - (te / f Butoxycarbonylamino) -cyclopropanecarboxylic acid and (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine, the title compound: C ₂₃ H ₂₆ F ₃ N ₃ O ₅ (481.46)

R ₁ (method 2): 2.41 min. 4c) 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) -cyclopropanecarboxamide trifluoroacetate

A solution of 570 mg (1.18 mmol) of te / f-butyl-1- ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropylcarbamate in 8 ml of methylene chloride was treated with 1.1 ml of TFA and stirred for 2 h at room temperature. The mixture was concentrated to dryness in vacuo. Yield: 88% of theory Ci ₈ H ₁₈ F ₃ N ₃ O ₃ X ₂ HF ₃ O ₂ (432.35)

4d) Pyrimidine-5-carboxylic acid N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) -cyclopropyl) amide

Analogously to Example (1d), starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and pyrimidine-5-carbon - Acid produced the title compound. C ₂₃ H ₂₀ F ₃ N ₅ O ₄ (487.43)

R _t (method 4): 1.99 min.

Example 5: Pyrimidine-5-carboxylic acid N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide

5a) 5- (4-Methoxy-2- (trifluoromethyl) phenoxy) picolinonitrile A solution of 1.09 g (8.93 mmol) of 5-fluoropicolinonitrile and 1.72 g (8.93 mmol) of 4-methoxy-2- (trifluoromethyl) phenol in 5 mL of DMSO was added 2.47 g (17.85 mmol) of potassium carbonate and stirred at 1 10 ⁰ C for 1 h. The mixture was added with saturated sodium chloride solution and extracted with te / f-butylmethyl ether. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. Yield: 100% of theory

R _t (method 1): 2.06 min. 5b) 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone To a solution of 640 mg (2.18 mmol) of 5- (4-methoxy-2- (trifluoromethyl) phenoxy) - Picolinonitrile in 5 ml of diethyl ether in a round bottom flask filled with dry nitrogen 6.21 ml (8.7 mmol) of a 1.4 molar solution of methyl magnesium bromide in THF / toluene (1/1) were added dropwise at -5 ° C and stirred for 1 h at room temperature , The reaction was decomposed with saturated ammonium chloride solution and extracted with te / f-butylmethyl ether. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. Yield: 94% of theory

R _t (method 1): 2.10 min.

5c) (E) -1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone oxime

A mixture of 640 mg (2.04 mmol) of 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone and 0.5 ml (8.48 mmol) of 50% aqueous hydroxylamine solution in 5 ml of ethanol 30 min. stirred at 100 ⁰ C. It was then diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography (silica gel, methylene chloride / methanol 95: 5). Yield: 60% of theory

R _t (method 1): 2.00 min.

5d) 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanamine 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone oxime (0.4 g, 1.23 mmol), dissolved in 20 ml of methanolic ammonia solution, were added with the addition of 100 mg

Raney nickel hydrogenated at 50 ^° C. and a hydrogen pressure of 50 psi overnight.

The catalyst was then filtered off and the filtrate was evaporated to dryness.

The crude product thus obtained was further reacted. Yield: 82% of theory

R ₁ (method 1): 1.42 min. 5e) Pyrimidine-5-carboxylic acid N- (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridine

2-yl) ethylcarbamoyl) cvclopropyl) amide

Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine (from 5d) and 1 - [(pyrimidine-5-carbonyl) - amino] -cyclopropanecarboxylic acid (from 1 b) the title compound. C ₂₄ H ₂₂ F ₃ N ₅ O ₄ (501.46)

R _t (method 1): 1.75 min.

Example 6: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-bromo-4-methoxyphenoxy) -3-fluoro-pyridin-y-methylcarbamoyl-cyclopropylamide

6a) 5- (2-bromo-4-methoxyphenoxy) -3-fluoropicolinonitrile

To a solution of 0.73 g (3.59 mmol) of 2-bromo-4-methoxyphenol in 5 ml of THF was added 130 mg (5.39 mmol) of sodium hydride and stirred for 15 minutes at room temperature. It was then cooled to -45 ° C and 0.5 g (3.59 mmol) of 3,5-difluoropicolinonitrile was added and allowed to come to room temperature overnight. Then the reaction mixture was cooled to -50 ⁰ C and 0:31 ml (5:39 mmoles) of glacial acetic acid was added. The mixture was stirred for a further 10 minutes at this temperature and then warmed to room temperature. The mixture was evaporated and the resulting crude product was purified by chromatography (Method 2).

Yield: 17% of theory

R ₁ (method 1): 2.12 min.

6b) (5- (2-bromo-4-methoxyphenoxy) -3-fluoropyridin-2-yl) methanamine

To a solution of 190 mg (0.59mmol) 5- (2-bromo-4-methoxyphenoxy) -3-fluorpicolino- nitrile in 5 ml THF 20 mg (0.65 mmol) of lithium aluminum hydride was added at 0 ⁰ C. The reaction was allowed to come to room temperature overnight. The batch was decomposed with 2N sodium hydroxide solution and filtered with suction through Celite. The filtrate was dried over sodium sulfate and concentrated to dryness in vacuo. Yield: 1 1% of theory

Ci ₃ H ₁₂ BrFN ₂ O ₂ (327.15)

R _t (method 1): 1.39 min.

6c) Pyrimidine-5-carboxylic acid N- (1- ((5- (2-bromo-4-methoxyphenoxy) -3-fluoropyridin-2-yl) -methylcarbamovDcyclopropyDamide

Analogously to Example (1d), starting from (5- (2-bromo-4-methoxyphenoxy) -3-fluoropyridine

2-yl) methanamine (from 6b) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane-carboxylic acid

(From 1 b) the title compound was prepared. C ₂₂ H ₁₉ BrFN ₅ O ₄ (516.32)

R ₁ (method 1): 1.72 min.

Example 7: Pyrimidine-5-carboxylic acid N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide [enantiomer 1]

7a) 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanamine, enantiomer 1 and enantiomer 2

540 g (1.66 mmol) of (E) -1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone oxime (from 5c), in 40 ml of methanolic ammonia solution were hydrogenated with the addition of 100 mg Raney nickel at 50 ⁰ C and a hydrogen pressure of 50 psi overnight.

The catalyst was then filtered off and the filtrate was evaporated to dryness.

The crude product thus obtained was separated and purified by preparative chiral HPLC (method Chiral 1).

Enantiomer 1: R _t preparative: (Method: Preparative Chiral 1): 1 1.2 min.

Yield: 13.5% of theory

C ₁₅ H ₁₅ F ₃ N ₂ O ₂ (312.29)

R _t (method Chiral 1): 7.70 min.

Enantiomer 2: R _t preparative: (Method: Preparative Chiral 1): 17.4 min. Yield: 13.5% of theory

R _t (method Chiral 1): 13.87 min.

7b) pyrimidine-5-carboxylic acid N- (1- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridine

2-yl) ethylcarbamoyl) cyclopropyl) amide, enantiomer 1

Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine, enantiomer 1 (from 7a) and 1 - [(pyrimidine-5) carbonyl) -amino] -cyclopropanecarboxylic acid (from 1b) the title compound. C ₂₄ H ₂₂ F ₃ N ₅ O ₄ (501 .46)

R _t (method Chiral 2): 21.19 min.

Example 8: Pyrimidine-5-carboxylic acid N- (1- (1- (5- (4- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide, enantiomer 2

Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine, enantiomer 2, (from 7a) and 1 - [(pyrimidine-5 -carbonyl) -amino] -cyclopropanecarboxylic acid (from 1b) the title compound.

C ₂₄ H ₂₂ F ₃ N ₅ O ₄ (501.46)

R _t (method Chiral 2): 15.71 min.

Example 9: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2yl) -methyl-carbamoyl) -cyclopropyl) -5- (trifluoromethyl) nicotinamide

9a) 5- (trifluoromethyl) nicotinic acid To a mixture of 9.96 ml (15.9 mmol) of a 1 .6 molar n-butyllithium solution in diethyl ether and 3.98 ml (8 mmol) of a 2 molar n-butylmagnesium chloride solution in diethyl ether in 10 ml of THF at -75 ° C 1 .5 g of 3-bromo-5- (trifluoromethyl) pyridine dissolved in 50 ml of toluene was added dropwise. After 20 minutes, 20 g (454 mmol) of dry ice were added, stirred again at -75 ° C. for 20 minutes and then at RT for 3 h. The reaction mixture was mixed with 50 ml of 1 M sodium hydroxide solution and extracted twice with diethyl ether. The aqueous phase was acidified with 4M hydrochloric acid and extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate and evaporated to dryness in vacuo. Yield: 6% of theory

C ₇ H ₄ F ₃ NO ₂ (191 .1 1)

R _t (Method 4): 1 .95 min.

9b) N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) -cyclopropyD-δ-trifluoromethv-nicotinamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5- (trifluoromethyl ) - nicotinic acid the title compound.

C ₂₅ H ₂₀ F ₆ N ₄ O ₄ (554.44) R _t (Method 4): 2.17 min.

Example 10: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) -5-oxopyrrolidine-2-carboxamide

Analogously to Example (1d), starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5-oxopyrrolidine 2-carboxylic acid produced the title compound. C ₂₃ H ₂₃ F ₃ N ₄ O ₅ (492.45)

R _t (method 3): 1 .58 min. Analogously to Example 10, the following substances were synthesized:

Example 68: 5-Chloro-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) nicotinamide

Analogously to Example (1d), starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5-chloronicotinic acid the title compound was prepared. C ₂₄ H ₂₀ CIF ₃ N ₄ O ₄ (520.89)

R ₁ (method 2): 2.22 min.

Example 69: 5-Fluoro-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) nicotinamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5-fluoro nicotinic acid the title compound. C ₂₄ H ₂₀ F ₄ N ₄ O ₄ (504.43)

R ₁ (method 2): 2.12 min

Example 70: 2-Chloro-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) thiazole-5-carboxamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 2-chloro 5-thiazolecarboxylic acid produced the title compound. C ₂₂ H ₁₈ CIF ₃ N ₄ O ₄ S (526.92) R _t (Method 2): 2.30 min

Example 71: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) -3-methylisoxazole-5-carboxamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 3-methyl isoxazole-5-carboxylic acid, the title compound. C ₂₃ H ₂₁ F ₃ N ₄ O ₅ (490.43)

R _t (method 2): 2.15 min

Example 72: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (difluoromethyl) -4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

72a) 5- (4-methoxy-2- (difluoromethyl) phenoxy) picolinonitrile

The title compound was prepared analogously to Example (5a) starting from 5-fluoropicolinonitrile and 1.72 g (8.93 mmol) of 4-methoxy-2- (difluoromethyl) phenol.

R _t (method 1): 2.02 min

72b) (5- (2- (difluoromethyl) -4-methoxyphenoxy) pyridin-2-yl) methanamine

500 mg (1.81 mmol) of 5- (4-methoxy-2- (difluoromethyl) phenoxy) picolinonitrile and 100 mg of Raney nickel in 10 ml of methanolic ammonia and 20 ml of methanol were hydrogenated overnight at room temperature and 50 psi hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The crude product thus obtained was further reacted without purification. Yield: 83% of theory

72c) pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (difluoromethyl) -4-methoxyphenoxy) pyridine

2-yl) methylcarbamoyl) cvclopropyl) amide

Analogously to Example (1 d), starting from (5- (2- (difluoromethyl) -4-methoxyphenoxy) -pyridin-2-yl) methanamine (from 72b), TBTU, TEA and 1 - [(pyrimidine-5-carbonyl) -amino] - cyclopropanecarboxylic acid (from 1 b) the title compound. C ₂₃ H _2I F ₃ N ₅ O ₄ (469.44)

R ₁ (Method 1 1): 1.63 min.

Example 73: Pyrimidine-5-carboxylic acid N N - (1 - ((3-chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

73a) 3-Chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) picolinonitrile The title compound was prepared analogously to Example (5a) starting from δ-bromo-S-chloropicolinonitrile and 4-methoxy-2- (trifluoromethyl) phenol , Yield: 72% of theory

Ci ₄ H ₈ CIF ₃ N ₂ O ₂ (328.67)

73b) (3-Chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine Trifluoroacetate 200 mg (0.61 mmol) 3-chloro-5- (4-methoxy-2- (trifluoromethyl ) Phenoxy) picolinonitrile, dissolved in 5 ml of 98% formic acid were heated under reflux for 4 hours with the addition of 500 mg of Raney nickel. The catalyst was then filtered off and the filtrate was evaporated to dryness. The crude product was purified by HPLC (Varian 300g C18 Pursuit XRS 10μ material with water / acetonitrile + 0.2% trifluoroacetic acid). Yield: 37% of theory

Ci ₄ H ₁₂ CIF ₃ N ₂ O ₂ X ₂ HF ₃ O ₂ (446.73) R ₁ (method 2): 1.72 min.

73c) Pyrimidine-5-carboxylic acid N-N- (1 - ((3-chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) -methylcarbamoyl) -cyclopropyl) -amide

Analogously to Example (1d), starting from (3-chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine (from 73b) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropanecarboxylic acid (from 1 b) the title compound.

C ₂₃ H ₁₉ CIF ₃ N ₅ O ₄ (521.88) R _t (Method 2): 2.16 min.

Example 74: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) -5-methylnicotinamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5-methyl nicotinic acid the title compound. C ₂₅ H ₂₃ F ₃ N ₄ O ₄ (500.47)

R _t (method 2): 1.95 min.

Example 75: Pyrimidine-5-carboxylic acid N- (1 - ((3-fluoro-5- (2 (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

75a) 3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridine-2-carbonitrile

Analogously to Example (6a), starting from 2-hydroxybenzotrifluoride, sodium hydride and

2-cyano-3,5-difluoropyridine, the title compound.

75b) (3-fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine

Analogously to Example (5d), starting from 3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridine

2-carbonitrile and Raney nickel produced the title compound.

R _t (method 2): 1 .61 min.

75c) Pyrimidine-5-carboxylic acid N- (1 - ((3-fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) -methylcarbamovecyclopropylamide

Analogously to Example (1 d), starting from (3-fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine (from 75b) and 1 - [(pyrimidine-5-carbonyl) amino] - cyclopropanecarboxylic acid (from 1 b) the title compound.

R ₁ (method 2): 2.01 min.

Example 76: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) -4-methylthiazole-5-carboxamide

45 mg (0.31 mmol) of 4-methylthiazole-5-carboxylic acid in 2 ml of dichloromethane were admixed with 49 mg (0.37 mmol) of 1-chloro-N, N, 2-trimethylpropylamine and stirred at room temperature for 3 h. This solution was added to 100 mg (0.26 mmol) of 1-amino-N- ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 70 μl (0.52 mmol) TEA in 2 ml of DMF and stirred overnight at room temperature. Subsequently, the reaction was decomposed with methanol, and then the mixture was evaporated. The crude product thus obtained was isolated by chromatography and purified. (HPLC; Microsorb C18; 8 μm 41.4 × 250 mm with acetonitrile / water / trifluoroacetic acid 10/90/01 => 100/0 / 0.1 with 180 ml flow rate). Yield: 17% of theory C ₂₃ H _2I F ₃ N ₄ O ₄ S (506.5)

R _t (method 2): 2.08 min.

Example 77: Pyrimidine-5-carboxylic acid (1- {1- [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

77a) 3-fluoro-5- (2- (trifluoromethyl) phenoxy) picolinonitrile

The title compound was prepared analogously to Example (5a) starting from 2-cyano-3,5-difluoropyridine, 2-hydroxybenzotrifluoride and potassium carbonate.

Yield: 36% of theory

77b) 1- (3-Fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone Analogously to Example (5b), starting from 3-fluoro-5- (2- (trifluoromethyl) phenoxy) -picolino- nitrile and 3 mol / l methylmagnesium bromide in diethyl ether the title compound. Yield: 95% of theory

R _t (method 2): 2.55 min.

77c) (E) -1- (3-Fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone oxime

100 mg (0.33 mmol) of 1- (3-fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone and 90 μl of TEA in 10 ml of acetonitrile were admixed with 200 mg (2.82 mmol) of hydroxylamine hydrochloride and stirred for 2 h Reflux cooked. After addition of 5 equivalents of hydroxylamine hydrochloride was stirred at 85 ° C for 1 h. The precipitate was filtered off with suction and further reacted crude.

Yield (crude): 100% of theory

R _t (method 2): 2.44 min.

77d) 1- (3-Fluoro-5- (2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanamine

The title compound was prepared analogously to Example (5d) starting from (E) -1- (3-fluoro-5- (2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanone oxime and Raney nickel.

R ₁ (method 2): 1.71 min.

77e) Pyrimidine-5-carboxylic acid- (1- {1- [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl-1-ethylcarbamovD-cyclopropyl-amide

Analogously to Example (1 d), starting from 1- (3-fluoro-5- (2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine (from 77d) and 1 - [(pyrimidine-5-carbonyl) - amino] -cyclopropanecarboxylic acid (from 1 b) the title compound.

R _t (method 2): 1.98 min. Example 78: (R) -5-Fluoro-N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) nicotinamide

78a) (R) -1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) - N - ((R) -1-phenylethyl) ethanamine trifluoroacetate

840 mg (2.70 mmol) of 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanone (from 5b) in 8 ml of dichloromethane were mixed with 237 μl (4.1 mmol) of acetic acid and 343 μl (2.7 mmol) of R - (+) - 1-phenylethylamine and stirred for 1 h at room temperature. Subsequently, 874 mg (4.1 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred at room temperature for 2 h. The reaction was treated with saturated potassium carbonate solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by HPLC (Microsorb C18, 8 μm 41.4 × 250 mm with acetonitrile / water / trifluoroacetic acid 10/90/01 => 100/0 / 0.1 with 180 ml flow rate). Yield: 34% of theory

C ₂₃ H ₂₃ F ₃ N ₂ O ₂ X ₂ HF ₃ O ₂ (530.46)

78b) (R) -1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanamine

430 mg (0.81 mmol) of (R) -1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) - N - ((R) -1-phenylethyl) ethanamine trifluoroacetate, in 10 ml of methanol were added with the addition of 45 mg

Palladium carbon hydrogenated at room temperature and a hydrogen pressure of 50 psi.

The catalyst was then filtered off and the filtrate was evaporated to dryness.

Yield: 99% of theory

R _t (method 2): 1.75 min.

78c) (R) -te / f-butyl-1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamovecyclopropylcarbamate trifluoroacetate Analogously to Example (1 d) was starting from (R) -1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanamine and 1- (NT-Boc-amino) -cyclopropanecarboxylic acid the title compound was prepared. C ₂₄ H ₂₈ F ₃ N ₃ O ₅ X ₂ HF ₃ O ₂ (609.51) R _t (Method 2): 2.63 min.

78d) (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamide

Analogously to Example (4c), starting from (R) -te / f-butyl, 1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropylcarbamate trifluoroacetate and Trifluoroacetic acid produced the title compound.

R _t (method 2): 1.79 min.

78e) (R) -5-fluoro-N- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) -cyclopropyl) nicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 5-fluoronicotinic acid produced the title compound. C ₂₅ H ₂₂ F ₄ N ₄ O ₄ (518.46)

R _t (method 2): 2.29 min.

Example 79: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) isothiazole-5-carboxamide

Analogously to Example (1d), starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and isothiazole-5 carboxylic acid produced the title compound. C ₂₂ H ₁₉ F ₃ N ₄ O ₄ S (492.47) R _t (Method 2): 22.2 min. Example 80: 3-Ethoxy-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) isothiazole-5-carboxamide

To a solution of 43 mg (0.25 mmol) of 3-ethoxyisothiazole-5-carboxylic acid in 2 ml of THF was added 0.1 ml (0.56 mmol) of DIPEA and a solution of 90 mg (0.28 mmol) of O - [(ethoxycarbonyl) -cyanomethyleneamino] -N, N, N ', N'-tetramethyluronium tetrafluoroborate in 0.5 ml of DMF and stirred for 15 min. At room temperature. Then, a solution of 114 mg (0.3 mmol) of 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) -methylcyclopropanecarboxamide (from 4c) in O, 5 ml of DMF were added and the mixture was stirred at room temperature overnight, then evaporated and the crude product obtained was purified by HPLC (Microsorb C18; 8 μm 41.4 × 250 mm with acetonitrile / water / trifluoroacetic acid 10/90/01 → 100/0 / 0.1 with a flow rate of 180 ml) Yield: 30% of theory C ₂₄ H ₂₃ F ₃ N ₄ O ₅ S (536.52)

R _t (method 2): 2.46 min.

Example 81: (R) -2-Hydroxy-N- (1- (1- (5- (4- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) isonicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 2-hydroxyisonicotinic acid produced the title compound. C ₂₅ H ₂₃ F ₃ N ₄ O ₅ (516.47) R _t (Method 9): 1 .46 min. Example 82: (R) -5-Hydroxy-N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) nicotinamide

82a) (R) -5-Hydroxy-N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) -ethylcarbamovDcyclopropyDnicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 5-hydroxyisonicotinic acid, the title compound. C ₂₅ H ₂₃ F ₃ N ₄ O ₅ (516.47)

R _t (Method 9): 1 .20 min.

Example 83: Pyrimidine-5-carboxylic acid N- (1- ((5- (2-cyano-4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide

60 mg (0.12 mmol) of pyrimidine-5-carboxylic acid N- (1- ((5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) -methylcarbamoyl) -cyclopropyl) amide (from 2b) were dissolved in 300 μl of DMF dissolved, mixed with 29 mg (0.32 mmol) of copper (l) cyanide and stirred at 160 ⁰ C for 7 h. The reaction was filtered and the product was chromatographically isolated and purified. Yield: 30% of theory C ₂₃ H ₂₀ F ₃ N ₆ O ₄ (444.44)

R ₁ (method 10): 2.16 min.

Example 84: (R) -5-Chloro- N - (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) nicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 5-chloronicotinic acid produced the title compound. C ₂₅ H ₂₂ CIF ₃ N ₄ O ₄ (534.91)

R _t (method 2): 2.38 min.

Example 85: (R) -5-Methoxy-N- (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) nicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 5-methoxynotinic acid produced the title compound. C ₂₆ H ₂₅ F ₃ N ₄ O ₅ (530.50)

R ₁ (method 2): 2.22 min.

Example 86: (R) -N- (1- (1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) -5-methylnicotinamide

Analogously to Example (1 d) starting from (R) -1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethyl) cyclopropanecarboxamid (from 78d) and 5-methyl nicotinic acid produced the title compound. C ₂₆ H ₂₅ F ₃ N ₄ O ₄ (514.50)

R _t (method 2): 2.09 min.

Example 87: Pyrimidine-5-carboxylic acid- (R) -N- (1- (1- (1- (5- (2-cyano-4-methoxyphenoxy) -pyridin-2-yl) -ethylcarbamoyl) -cyclopropyl) -amide

87a) (R) -N- (1- (1- (5-Hydroxypyridin-2-yl) ethylcarbamoyl) cyclopropyl) pyrimidine

5-carboxamide

Starting from 6 - ((1R) -1-aminoethyl) -pyridin-3-ol, hydrochloride, TBTU, TEA and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane-carboxylic acid were prepared analogously to Example (1d) (From 1 b) the title compound was prepared.

R _t (method 2): 0.30 min.

87b) pyrimidine-5-carboxylic acid- (R) -N- (1- (1- (5- (2- (covano-4-methoxyphenoxy) pyridin-2-yl) -ethylcarbamovecyclopropylamide

Analogously to Example (5a), starting from 2-fluoro-5-methoxybenzonitrile, (R) -N- (I - (1- (5-

Hydroxypyridin-2-yl) ethylcarbamoyl) cyclopropyl) pyrimidine-5-carboxamide (from 87a) and

Potassium carbonate in DMF produced the title compound. C ₂₄ H ₂₂ N ₆ O ₄ (485.47)

R _t (method 10): 2.05 min.

Example 88: (R) -Pyrimidine-5-carboxylic acid N- (1- (1- (1- (5- (2- (bromo-4-methoxyphenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide

88a) 5- (2-bromo-4-methoxyphenoxy) picolinonitrile The title compound was prepared analogously to Example (5a) starting from 5-fluoropicolinonitrile, 2-bromo-4-methoxyphenol and potassium carbonate in DMSO.

88b) 5- (2-bromo-4-methoxyphenoxy) picolinaldehyde

To a solution of 2 g (6.55 mmol) of 5- (2-bromo-4-methoxyphenoxy) picolinonitrile in 8 ml of THF at -2 ° C to + 2 ° C a 1 -molare Lithiumtriethylborhydrid solution (6.55 mmol) in THF dropwise. The reaction was 15 min. stirred under ice-cooling and then poured onto saturated ammonium chloride solution. The mixture was extracted with te / f-butylmethyl ether, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on silica gel with petroleum ether / ethyl acetate 10-20%.

Yield: 66% of theory

R _t (method 11): 2.07 min.

88c) (S, E) -N - ((5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) methylene) -2-methylpropane

2-Sulfinamide 1.3 g (4.22 mmol) of 5- (2-bromo-4-methoxyphenoxy) -picolinaldehyde in 15 ml of dichloromethane were mixed with 0.49 g (4.02 mmol) of (S) -2-methylpropane-2-sulfinamide, 50 mg (0.21 mmol ) Pyridine tosylate and 5.08 g (42.19 mmol) of magnesium sulfate and stirred for 1 week at room temperature. The reaction mixture was diluted with methylene chloride and washed with water. The organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by chromatography on silica gel with petroleum ether / ethyl acetate 40-50%. Yield: 43% of theory

Ci ₇ H ₁₉ BrN ₂ O ₃ S (411.31)

R ₁ (method 11): 2.24 min.

88d) (S) -N - ((R) -1- (5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) ethyl) -2-methylpropane

2-sulfinamide

To a solution of 0.75 g (1.82 mmol) of (S, E) -N - ((5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide in 4 ml Dichloromethane was added dropwise at -50 ⁰ C, a 1 mol / l Methylmagesiumbromidlösung in toluene / THF (1/1). The reaction became 30 min. stirred at -50 ⁰ C and then hydrolyzed with half-saturated ammonium chloride solution. The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated to dryness in vacuo. Yield: 66% of theory Ci ₈ H ₂₃ BrN ₂ O ₃ S (427.36)

R ₁ (method 11): 2.06 min.

88e) (R) -1- (5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) ethanamine hydrochloride 0.78 g (1.83 mmol) of (S) -N - ((R) -1- (5- (2-Bromo-4-methoxyphenoxy) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide in 2.5 ml of methanol was treated with 1.37 ml (5.48 mmol) of 4M hydrochloric acid in dioxane and stirred for 15 min. stirred at room temperature. The reaction mixture was concentrated to dryness in vacuo. The residue was triturated in diethyl ether, filtered off with suction and dried. Yield: 87% of theory Ci ₄ H ₁₅ BrN ₂ O ₂ ^* HCl (395.65) R ₁ (Method 11): 1.34 min.

88f) (R) -pyrimidine-5-carboxylic acid N- (1- (1- (5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) -ethylcarbamovecyclopropyl-damide. Analogously to Example (1d), starting from ( R) -1- (5- (2-bromo-4-methoxyphenoxy) pyridin-2-yl) ethanamine hydrochloride (from 88e) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropanecarboxylic acid (from 1 b) the title compound was prepared C ₂₃ H ₂₂ BrN ₅ O ₄ (512.36)

R ₁ (method 11): 1.73 min.

Example 89: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-chloro-4-methoxyphenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) amide

89a) 5- (2-chloro-4-methoxyphenoxy) pyrimidine-2-carbonitrile The title compound was prepared analogously to Example (5a) starting from 5-bromopyrimidine-2-carbonitrile, 2-chloro-5-methoxyphenol and potassium carbonate in DMSO.

89b) (5- (2-chloro-4-methoxyphenoxy) pyrimidin-2-yl) methanamine

480 mg (1.83 mmol) of 5- (2-chloro-4-methoxyphenoxy) pyrimidine-2-carbonitrile, in 5 ml of ethyl acetate and 5 ml of acetic acid, are added with 25 mg of Pd / carbon (10%) at room temperature and a hydrogen Hydrogenated pressure of 3 bar. The catalyst was then filtered off and the filtrate was evaporated to dryness. Yield: 98% of theory

89c) Pyrimidine-5-carboxylic acid N- (1 - ((5- (2-chloro-4-methoxyphenoxy) pyrimidin-2-yl) methylcarbamovecyclopropylamide Following Example (1d), starting from (5- (2-chloro 4-methoxy-phenoxy) -pyrimidin-2-yl) -methanamine (from 89b) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane-carboxylic acid (from 1 b), the title compound was prepared.

R _t (method 2): 1.79 min.

Example 90: Pyrimidine-5-carboxylic acid N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) amide

90a) 5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidine-2-carbonitrile Analogously to Example (5a), starting from 5-bromopyrimidine-2-carbonitrile, 4-methoxy-2- (trifluoromethyl) phenol and potassium carbonate in DMSO made the title compound. C ₁₃ H ₈ F ₃ N ₃ O ₂ (295.22)

R _t (method 2): 2.53 min.

90b) (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methanamine The title compound was prepared analogously to Example (5d) starting from 5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyrimidine-2-carbonitrone N and Raney nickel.

R _t (method 2): 1.10 min.

90c) pyrimidine-5-carboxylic acid N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidine

2-yl) methylcarbamoyl) cvclopropyl) amide

Analogously to Example (1 d) starting from (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methanamine (from 90b), TBTU, TEA and 1 - [(pyrimidine-5-carbonyl ) -amino] - cyclopropanecarboxylic acid (from 1 b) the title compound. C ₂₂ H ₁₉ F ₃ N ₆ O ₄ (488.42)

R _t (method 2): 1.91 min.

Example 91: 3-Methoxy-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) isoxazole-5-carboxamide

91a) Fe / f-butyl-1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamovecyclopropylcarbamate

Analogously to Example (1 d) starting from (5- (4-methoxy-2- (trifluoromethyl) phenoxy) - pyrimidin-2-yl) methanamine (from 89b) and 1- (NT-Boc-amino) -cyclopropancarbonsäure the title compound produced. C ₂₂ H ₂₅ F ₃ N ₄ O ₅ (482.45)

91 b) 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -cyclopropanecarboxamide

Analogously to Example (4c) was starting from te / f-butyl-1 - ((5- (4-methoxy-2- (trifluoromethyl) - phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropylcarbamate and trifluoroacetic the

Title compound prepared.

C ₁₇ H ₁₇ F ₃ N ₄ O ₃ (382.34) R _t (Method 2): 1:59 min. 91 c) 3-Methoxy-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) -methylcarbamoyl) -cyclopropyl) isoxazole-5-carboxamide

Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) cyclopropanecarboxamide (from 91 b) and 3-methoxy -isoxazole-5-carboxylic acid produced the title compound. C ₂₂ H ₂₀ F ₃ N ₅ O ₆ (507.42)

R _t (method 2): 2.13 min.

Example 92: N - ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -1- (3,3,3-trifluoropropanamido) cyclopropanecarboxamide

Analogously to Example (1 d) was starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) cyclopropanecarboxamide (from 91 b) and 3.3 , 3-trifluoropropionic acid, the title compound. C ₂₀ H ₁₈ F ₆ N ₄ O ₄ (492.37)

R _t (method 2): 2.16 min.

Example 93: N- (1- ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) isoxazole-5-carboxamide

Analogously to Example (1 d) was starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) cyclopropanecarboxamide (from 91 b) and isoxazole-5 Carbonic acid produced the title compound. C ₂ H ₁₈ F ₃ N ₅ O ₅ (477.39)

R _t (method 2): 2.02 min. Example 94: 1- (2-Cyanoacetamido) -N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) cyclopropanecarboxamide

Analogously to Example (76a), starting from cyanoacetic acid, 1-chloro-N, N, 2-trimethyl-propylamine, TEA and 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidine) 2-yl) - methyl) cyclopropanecarboxamide (from 91 b) the title compound was prepared.

R _t (method 2): 1.95 min.

Example 95: Pyrimidine-5-carboxylic acid N- (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropyl) amide

95a) 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethanone Analogously to Example (5b), starting from 5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidine 2-carbonitrile (from 90a) and a 3 molar methylmagnesium bromide solution in diethyl ether, the title compound was prepared.

95b) (E) -1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethanone oxime Analogously to Example (5c), starting from 1- (5- (4-methoxy-2 - (trifluoromethyl) phenoxy) - pyrimidin-2-yl) ethanone and a 50% hydroxylamine solution in water the title compound. C ₁₄ H ₁₂ F ₃ N ₃ O ₃ (327.26)

95c) 1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethanamine Analogously to Example (5d), the title compound was prepared starting from (E) -1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethanone oxime and Raney nickel in methanolic ammonia solution.

95d) pyrimidine-5-carboxylic acid N- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -

PVrimidin-2-yl) ethylcarbamoyl) cvclopropyl) amide

Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyrimidin-2-yl) ethanamine (from 99d) and 1 - [(pyrimidine-5-carbonyl) - amino] -cyclopropanecarboxylic acid (from 1 b) the title compound. C ₂₃ H ₂₁ F ₃ N ₆ O ₄ (502.45) R _t (Method 2): 2.04 min.

Example 96: N- (1- (1- (5- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropyl) isoxazole-5-carboxamide

96a) te / f-butyl-1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl-carbamovecyclopropylcarbamate trifluoroacetate

Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyrimidin-2-yl) ethanamine (from 99d) and 3- (te / f-butoxycarbonylamino) tetrahydrofuran 3-carboxylic acid produced the title compound. C ₂₃ H ₂₇ F ₃ N ₄ O ₅ X ₂ HF ₃ O ₂ (610.50)

96b) 1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) -cyclopropanecarboxamide

Analogously to Example (4c) was starting from te / f-butyl-1- (1- (5- (4-methoxy-2- (trifluoromethyl) - phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropylcarbamate trifluoroacetate and trifluoroacetic the Title compound prepared.

C ₁₈ H ₁₉ F ₃ N ₄ O ₃ (396.36) R _t (Method 2): 1.70 min. 96c) N- (1- (1- (1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) -cyclopropyl) isoxazole-5-carboxamide

Analogously to Example (1 d) starting from 1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) cyclopropanecarboxamide (from 101 b) and isoxazole 5-carboxylic acid, the title compound. C ₂₂ H ₂₀ F ₃ N ₅ O ₅ (491.42) R ₁ (Method 2): 2.17 min.

Example 97: 3-Methoxy-N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropyl) isoxazole-5-carboxamide trifluoroacetate

Analogously to Example (1d), starting from 1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) cyclopropanecarboxamide (from 101 b) and 3- Methoxy-isoxazole-5-carboxylic acid, the title compound. C ₂₃ H ₂₂ F ₃ N ₅ O ₅ C ₂ HF ₃ O ₂ (635.47)

R _t (method 2): 2.28 min.

Example 98: N- (1- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) -1- (3,3,3-trifluoropropanamido) -propanecarboxamide

Analogously to Example (1d), starting from 1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) cyclopropanecarboxamide (from 101 b) and 3, 3,3-trifluoropropionic acid produced the title compound.

R _t (method 2): 2.34 min. Example 99: Pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) amide

99a) 5- (2- (trifluoromethyl) phenoxy) pyrimidine-2-carbonitrile The title compound was prepared analogously to Example (5a) starting from 5-bromopyrimidine-2-carbonitrile, 2-hydroxybenzotrifluoride and potassium carbonate in DMSO.

99b) (5- (2- (Trifluoromethyl) phenoxy) pyrimidin-2-yl) methanamine The title compound was prepared analogously to Example (5d) starting from 5- (2- (trifluoromethyl) phenoxy) pyrimidine-2-carbonitrile and Raney nickel ,

99c) Pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamovecyclopropylamide

Analogously to Example (1d), starting from (5- (2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methanamine (from 105b), TBTU, TEA and 1 - [(pyrimidine-5-carbonyl) amino] - cyclopropane-carboxylic acid (from 1 b) the title compound.

C _2I H ₁₇ F ₃ N ₆ O ₃ C ₂ HF ₃ O ₂ (572.42) R _t (Method 2): 1.78 min.

Example 100: Pyrimidine-5-carboxylic acid N- (1 - ((6- (2-chloro-4-methoxyphenoxy) pyridazin-3-yl) methylcarbamoyl) cyclopropyl) amide

100a) pyridazin-3 (2H) -one 10 g (60.9 mmol) of 4,5-dichloro-o-pyridazine-3 (2H) -one and 22 ml (152.4 mmol) of TEA in 75 ml of methanol were added with 2 g of Pd / carbon (10%) at room temperature and a hydrogen pressure hydrogenated at 60 psi. The mixture was then filtered and the filtrate evaporated to dryness. The residue was triturated with ethyl acetate, filtered and the filtrate evaporated to dryness. Yield: 45% of theory C ₄ H ₄ N ₂ O (96.09) R _f = 0.3. Ethyl acetate / hexane (10/90)

100b) 6-chloro-1,6-dihydropyrazine

To 5 g (52.08 mmol) of pyridazine-3 (2H) -one in 15 ml of acetonitrile was added 7.2 ml (78.12 mmol) of phosphorus oxychloride and stirred at 100 ⁰ C for 1 h. The reaction was evaporated to dryness. The residue was purified on silica gel with ethyl acetate / hexane (40/60). Yield: 76% of theory C ₄ H ₅ CIN ₂ (1 16.55) R _f = 0.6 ethyl acetate / hexane (10/90)

100c) 3- (2-Chloro-4-methoxyphenoxy) pyridazine 10.26 g (57 mmol) of 2-chloro-4-methoxyphenol in THF were mixed with 1.64 g (68.4 mmol).

Sodium hydride and stirred for 30 min. At room temperature. This solution was added to 5 g (43.85 mmol) of 6-chloro-1, 6-dihydropyridazin in 75 ml of toluene and stirred at 100 ⁰ C for 3 h. Thereafter, another 1.3 equivalents of the sodium phenolate were added and stirred overnight at 100 ° C. The reaction mixture was diluted with ethyl acetate, washed with water, the organic phase dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with ethyl acetate / hexane (40/60). Yield: 40% of theory

CnH ₉ CIN ₂ O ₂ (236.66) R _f = 0.4 ethyl acetate / petroleum ether (30/70)

100d) 3- (2-Chloro-4-methoxyphenoxy) pyridazine-1-oxide

4.5 g (19.06 mmol) of 3- (2-chloro-4-methoxyphenoxy) pyridazine in 150 ml of dichloromethane were mixed with 5.28 g (30.69 mmol) of meta-chloroperbenzoic acid and 2 h at Room temperature stirred. The reaction was washed with sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was taken up in diethyl ether and the precipitate was filtered off with suction. Yield: 41% of theory

CnH ₉ CIN ₂ O ₃ (252.66)

R _f = 0.3 acetic acid ethyl ester / hexane (80/20)

100e) 6- (2-Chloro-4-methoxyphenoxy) pyridazine-3-carbonitrile 6 g (23.8 mmol) of 3- (2-chloro-4-methoxyphenoxy) pyridazine 1-oxide and 7.52 ml (52.12 mmol) of TEA in 120 ml Acetonitrile were treated with 1 1.1 g (11 1.9 mmol) of trimethylsilyl cyanide and stirred at 65 ° C for 24 h. Subsequently, trimethylsilyl cyanide and TEA were added again and stirred at 65 ° C for 24 h. The reaction was poured into potassium carbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate / hexane (20/80). Yield: 48% of theory

R _f = 0.8 ethyl acetate / hexane (40/60)

100f) (6- (2-Chloro-4-methoxyphenoxy) pyridazin-3-yl) methanamine Hydrochloride 2 g (7.66 mmol) of 6- (2-chloro-4-methoxyphenoxy) pyridazine-3-carbonitrile in 25 ml of ethanol were added Added 0.5 g of Pd / charcoal (10%) at room temperature and a hydrogen pressure of 60 psi. It was then filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel

Chloroform / methanol (95/5). From the product thus obtained, the hydrochloride was precipitated with 2N hydrochloric acid in dioxane. Yield: 85% of theory

C _H H ₁₀ CIN ₃ O ₂ ΗCl (288.13) R _f = 0.8 methanol / dichloromethane (20/80)

100g) Pyrimidine-5-carboxylic acid N- (1 - ((6- (2-chloro-4-methoxyphenoxy) pyridazin-3-yl) methylcarbamovecyclopropylamide Starting from (6- (2-chloro-4-methoxyphenoxy) pyridazin-3-yl) -methanamine, hydrochloride (from 104f), TBTU, TEA and 1 - [(pyrimidine-5-carbonyl) - were prepared analogously to Example (1d). amino] - cyclopropanecarboxylic acid (from 1 b) the title compound. C ₂ H ₁₉ CIN ₆ O ₄ C ₂ HF ₃ O ₂ (568.89) R _t (Method 2): 1 .77 min.

Example 101: Pyrimidine-5-carboxylic acid (1 - {[5- (4-methoxy-2-trifluoromethyl-phenoxy) -pyrazino-2-ylmethyl] -carbamoyl} -cyclopropyl) -amide

101 a) 5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrazine-2-carbonitrile

To a solution of 370 mg (2.65 mmol) of 4-methoxy-2-trifluoromethyl-phenol in 15 ml of DMF was added 125 mg (3.13 mmol) of sodium hydride and stirred for 1 h at room temperature. Then, 0.5 g (2.60 mmol) of 5-cyano-2-chloropyrazine was added for 2 hours at room temperature. The mixture was evaporated and the residue was purified by HPLC. Yield: 98% of theory

101 b) (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrazin-2-yl) methanamine Trifluoroacetate Analogously to Example (5d), starting from 5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrazine 2-carbonitrile and Raney nickel, the title compound. Ci ₃ H ₁₂ F ₃ N ₃ O ₂ C ₂ HF ₃ O ₂ (413.27)

101 c) Pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) -methylcarbamovDcyclopropyDamide Analogously to Example (1d), starting from (5- (4-methoxy -2- (trifluoromethyl) phenoxy) pyrazine-2-yl) methanamine trifluoroacetate (from 105b), TBTU, TEA and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane-carboxylic acid (from 1b) the title compound C ₂₂ H ₁₉ F ₃ N ₆ O ₄ (488.42)

R _t (method 2): 1 .97 min. Example 102: Pyrimidine-5-carboxylic acid [1- ({5- [2- (1, 1-difluoroethyl) -4-fluoro-phenoxy] -pyridin-2-ylmethyl} -carbamoyl) -cyclopropyl] -amide

Analogously to Example (1 d), starting from C- {5- [2- (1,1-di-fluoroethyl) -4-fluorophenoxy] -pyridin-2-yl} -methylamine, TBTU, TEA and 1 - [(pyrimidine -5-carbonyl) -amino] -cyclopropanecarboxylic acid (from 1 b), the title compound. C ₂₃ H ₂₀ F ₃ N ₅ O ₃ (471 .44)

R _t (Method 5): 3.71 min.

Example 103: Pyrimidine-5-carboxylic acid- (1 - {1- [5- (4-fluoro-2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.

C ₂₃ H ₁₉ F ₄ N ₅ O ₃ (489.43)

R _t (method 6): 2.46 min.

Example 104: Pyrimidine-5-carboxylic acid- (1 - {1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide.

R _t (method 2): 2.15 min.

Example 105: Pyrimidine-5-carboxylic acid- (1 - {[5- (2-ethyl-4-methoxy-phenoxy) -pyridin-2-yl-methyl] -carbamoyl} -cyclopropyl) -amide.

C ₂₄ H ₂₅ N ₅ O ₄ (447.49)

R _t (method 8): 1 .52 min.

Example 106: Pyrimidine-5-carboxylic acid- (1 - {1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide.

C ₂₃ H ₁₉ BrF ₃ N ₅ O ₃ (550.33) R _t (Method 2): 2.29 min.

Example 107: Pyrimidine-5-carboxylic acid- (1 - {1- [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide.

Analogously to Example (1d), the title compound was prepared by amide linkage using TBTU.

R _t (method 2): 2.13 min.

Example 108: Pyrimidine-5-carboxylic acid 1- (1- {1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -3-fluoro-pyridin-1-yl] -ethylcarbamoyl-1-cyclopropoxy-amide

C ₂₃ H ₁₈ BrF ₄ N ₅ O ₃ (568.32)

R _t (method 2): 2.35 min.

Example 109: Pyrimidine-5-carboxylic acid (1- {1- [5- (4-chloro-2-trifluoromethyl-phenoxy) -pyridine] -yl-1-ethylcarbamoyl-1-cyclopropyl-amide

C ₂₃ H ₁₉ CIF ₃ N ₅ O ₃ (505.88)

R _t (method 2): 2.26 min. Example 1 10: Pyrimidine-5-carboxylic acid- (1 - {1- [5- (2-chloro-phenoxy) -3-fluoro-pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.

C ₂₂ H ₁₉ CIFN ₅ O ₃ (455.88)

R _t (method 2): 2.03 min.

Example 11 1: 2-Methoxy-pyrimidine-5-carboxylic acid- (1 - {1- [5- (2-chloro-phenoxy) -3-fluoro-pyridine] -yl-1-ethylcarbamoyl-1-cyclopropyl-amide

C ₂₃ H ₂₁ CIFN ₅ O ₄ (485.90)

R ₁ (method 2): 2.17 min.

Example 1 12: 2-Methylamino-pyrimidine-5-carboxylic acid- (1 - {1- [5- (2-chloro-phenoxy) -3-fluoro-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide

Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU. C ₂₃ H ₂₂ CIFN ₆ O ₃ (484.92)

R _t (method 2): 2.04 min.

Example 113: 2-Methyl-pyrimidine-5-carboxylic acid- (1 - {1- [5- (2-chloro-phenoxy) -3-fluoro-pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

C ₂₃ H ₂₁ CIFN ₅ O ₃ (469.90)

R _t (method 2): 2.05 min.

Example 114: Pyrimidine-5-carboxylic acid- (1 - {1- [5- (2-bromo-4-methoxy-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

C ₂₃ H ₂₂ BrN ₅ O ₄ (512.36)

R ₁ (Method 1 1): 1.72 min.

Example 115: 2-Methyl-pyrimidine-5-carboxylic acid- (1 - {1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide

R _t (method 2): 2.25 min.

Example 1 16: 2-Methoxy-pyrimidine-5-carboxylic acid- (1 - {1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide

C ₂₄ H ₂₁ F ₄ N ₅ O ₄ (519.45)

R _t (method 2): 2.15 min.

Example 1 17: Pyrimidine-5-carboxylic acid- (1 - {1- [3-chloro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl} -cyclopropyl) -amide

C ₂₃ H ₁₉ CIF ₃ N ₅ O ₃ (505.88)

R _t (method 8): 1 .67 min.

Example 1 18: Pyrimidine-5-carboxylic acid 1- (1- {1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -3-chloro-pyridin-1-yl-ethylcarbamoyl-1-cyclopropyl-amide

C ₂₃ H ₁₈ BrCIF ₃ N ₅ O ₃ (584.78) R _t (Method 2): 2.65 min.

Example 1 19: 2-Methylamino-pyrimidine-5-carboxylic acid- (1 - {1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide

C ₂₄ H ₂₂ F ₄ N ₆ O ₃ (518.47)

R _t (method 2): 2.08 min.

Example 120: Pyrimidine-5-carboxylic acid (1 - {[3-chloro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl} -cyclopropyl) -amide

C ₂₂ H ₁₇ CIF ₃ N ₅ O ₃ (491.86)

R _t (method 2): 2.02 min. Example 121: 2-Methylamino-pyrimidine-5-carboxylic acid (1 - {[3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl-1-carbamoyl) -c) cyclopropyl) -amide

C ₂₃ H ₂₀ F ₄ N ₆ O ₃ (504.44)

R _t (method 8): 1 .55 min.

Example 122: 2-Methoxy-pyrimidine-5-carboxylic acid (1 - {[3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl} -cyclopropyl) -amide

C ₂₃ H ₁₉ F ₄ N ₅ O ₄ (505.43)

R _t (method 8): 1.61 min.

Example 123: N- (1 - {[3-Fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl} -cyclopropyl) -5-methyl-nicotinamide

C ₂₄ H ₂₀ F ₄ N ₄ O ₃ (488.44)

R _t (method 8): 1 .63 min.

Example 124: 2-Methyl-pyrimidine-5-carboxylic acid- (1 - {[3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridine] -ylmethyl-1-carbamoyl-1-cyclopropyl-amide

R _t (method 8): 1 .53 min.

Example 125: 5-Amino-N- (1 - {[3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl} -cyclopropyl) -nicotinamide

C ₂₃ H ₁₉ F 4 N ₅ O ₃ (484.92) R _t (Method 8): 1 .51 min.

Example 126: N - ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -3- (3,3,3-trifluoropropanamido) tetrahydrofuran-3-carboxamide

128a) 3- (te / f-butoxycarbonylamino) tetrahydrofuran-3-carboxylic acid

To 1 g (7.63 mmol) of 3-amino-tetrahydrofuran-3-carboxylic acid and 1:07 ml (7.63 mmol) of TEA in 10 ml of dioxane / water (1/1) at 0 ⁰ C a solution of 1.83 g (8:39 mmol) of di -te / f-butyl dicarbonate in 3 ml of dioxane. This was followed by 72 hours

Room temperature stirred. The mixture was concentrated to dryness in vacuo. The residue was purified by HPLC (Microsorb C18, 8 μm 41 .4 x 250 mm with acetonitrile / water / trifluoroacetic acid 10/90/01 => 100/0 / 0.1 with 180 ml flow rate). Yield: 28% of theory

R _t (method 2): 1 .25 min.

126b) tert-Butyl-3 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) tetrahydrofuran-3-ylcarbamate. Analogously to Example (1 d), starting from (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methanamine (from 89b) and 3- (te / f-butoxycarbonylamino) tetrahydrofuran-3-carboxylic acid, the title compound. C ₂₃ H ₂₇ F ₃ N ₄ O ₆ (512.48)

126c) 3-Amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -tetrahydrofuran-3-carboxamide

Analogously to Example (4c) starting from te / f-butyl-3 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) tetrahydrofuran-3-ylcarbamat and trifluoroacetic acid, the title compound produced.

R _t (method 2): 1 .61 min.

126d) N - ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -3- (3,3,3-trifluoropropanamido) tetrahydrofuran-3-carboxamide Analogously to Example (1 d) starting from 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c) and 3,3,3-trifluoropropionic acid produced the title compound. C ₂₂ H ₂₀ F ₃ N ₅ O ₆ (522.40) R _t (Method 2): 14.2 min.

Example 127: 3-Methoxy-N- (3 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) tetrahydrofuran-3-yl) isoxazole-5-carboxamide

Analogously to Example (1 d) starting from 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c) and 3-methoxy-isoxazole-5-carboxylic acid produced the title compound. C ₂₃ H ₂₂ F ₃ N ₅ O ₇ (537.45)

R ₁ (method 2): 2.14 min.

Example 128: Pyrimidine-5-carboxylic acid N- (3 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) tetrahydrofuran-3-yl) amide

Analogously to Example (1 d) starting from 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropane-carboxylic acid (from 1 b) the title compound was prepared. C ₂₃ H ₂₁ F ₃ N ₆ O ₅ (518.45)

R _t (method 2): 1.90 min.

Example 129: N- (3 - ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) tetrahydrofuran-3-yl) isoxazole-5-carboxamide

Analogously to Example (1 d) starting from 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c) and Isoxazole-5-carboxylic acid produced the title compound. C ₂₂ H ₂₀ F ₃ N ₅ O ₆ (507.42)

R _t (method 2): 1 .92 min.

Example 130: 3- (2-Cyanoacetamido) -N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide

Starting from cyanoacetic acid, 1-chloro-N, N, 2-trimethyl-propylamine, TEA and 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) -phenoxy) -pyrimidine were prepared analogously to Example (76a). 2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c), the title compound. C ₂ H ₂₀ F ₃ N ₅ O ₅ (479.41) R _t (Method 2): 2.01 min.

Example 131: N - ((5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) -3- (2,2,2-trifluoroacetamido) tetrahydrofuran-3-carboxamide

Analogously to Example (1 d) starting from 3-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methyl) tetrahydrofuran-3-carboxamide (from 126c) and Trifluoressig- the title compound. C ₂₀ H ₁₈ F ₆ N ₄ O ₅ (508.37) R _t (method 2): 2.29 min

The following examples describe pharmaceutical dosage forms containing as active ingredient any compound of the general formula I, but without limiting the scope of the present invention to this:

Example I

Dry ampoule containing 75 mg of active ingredient per 10 ml

Composition:

Active substance 75.0 mg

Mannitol 500 mg water for injections ad 10.0 ml

production:

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example Il

Tablet with 50 mg active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) lactose 98.0 mg

(3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215. 0 mg

production: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.

Example III

Tablet with 350 mg active ingredient

Composition:

(1) Active ingredient 350 .0 mg

(2) lactose 136 .0 mg

(3) corn starch 80 .0 mg

(4) polyvinylpyrrolidone 30 .0 mg

(5) Magnesium stearate 4 .0 mg

600 .0 mg

Preparation: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 12 mm.

Example IV

Capsules with 50 mg active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) corn starch dried 58.0 mg

(3) lactose powdered 50.0 mg

(4) Magnesium stearate 2.0 mg 160.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) under intensive mixing.

This powder mixture is filled on a capsule filling machine into size 3 hard gelatine capsules.

Example V

Capsules with 350 mg active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) corn starch dried 46.0 mg

(3) lactose powdered 30.0 mg

(4) magnesium stearate 4.0 mg

430.0 mg

production:

This powder mixture is filled on a capsule filling machine in hard gelatin capsules Gr6Be 0.

Example VI

Suppositories containing 100 mg of active ingredient

1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (MG 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Claims

1. Compounds of the general formula I

in the

(c) optionally substituted with one radical R ¹ is substituted C ² can be a -CH ₂ moiety replaced by a -C (O) group substituted _3- 6 cycloalkyl group,

(f) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} six-membered _{heteroaryl-Co-2} alkylene group containing one, two or three N atoms and which may be benzo-fused, in addition,

(h) a 5- or 6-membered heterocycle which is optionally substituted by 1 or 2 radicals R ^{1 4} and contains at least one N, O or S atom and in which additionally a -CH ₂ - unit is represented by a -C ( O) group can be replaced,

(i) -OR ¹ - ¹ - ¹ ,

C) -NR ^{1 1 3} R ¹ - ^{1 4} or

(k) -C (= NR ¹ - ⁵ ) -CN, R ¹ - ¹ halogen, -CN, C ₃ - ₆ -cycloalkyl, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -C (O) R ^{1 1 1} , -S (O) ₂ -R ^{1 1 2} ,

-CO ₂ R ¹ - ¹ - ^1, -0-C (O) -R ¹ - ¹ - ^1, -NR ¹ R ^{3 1} ¹ - ^{1 4,} -NR ^{1 / l} - ³ -C (O) -R ¹ - ¹ - ¹ , -NR ¹ - ¹ - ³ -C (O) -R ¹ - ¹ \ -NR ^{1 / l} - ³ -CO ₂ -R ¹ - ¹ - ¹ or -C (O) -NR ^{1 1 3} R ¹ - ^{1 4} ,

R ¹ - ¹ - ¹ (a) H,

(b) C _1-4 alkyl,

(c) d- _3- alkyl, in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

(d) a phenyl group optionally substituted by 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ¹ , (e) C _3-6 cycloalkyl or

(f) a pyridyl group which is optionally substituted by 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ² ,

p ⁱ . ¹ . ¹ . ¹ independently

(a) halogen, -CN, -OH, -O-Ci _-4 alkyl, C ₃ - ₆ cycloalkyl, C _1-4 alkyl or (b) _d-C3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each

Methyl group may be substituted by 1, 2 or 3 fluorine atoms,

R ¹ - ¹ - ¹ - ² are independently halogen or Ci _-4 alkyl,

R ¹ - ¹ - ² (a) Ci _-4 alkyl,

(b) C-ι- ₃ alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted, or

R ¹ - ¹ - ³ , R ¹ - ¹ - ⁴ independently

(a) H,

(b) optionally substituted with 1, 2 or 3 radicals R ¹ - ¹ - ⁴ - ¹ substituted

Ci kylgruppe _-4-Al, (c) an optionally substituted with 1, 2 or 3 radicals R ¹ - ¹ - ¹ - ¹ substituted phenyl group,

(d) C _3-6 cycloalkyl, or R ^{1 "1" 3} and R ^{1 "1" 4} together with the N-atom to which they are attached form a 5- or 6-membered heterocyclic ring which additionally contains one further heteroatom selected from N, O and S. can, or

p ⁱ . ¹ . ⁴ . ¹ _una epending another are halogen, -NH _2, -NH (Ci _-4 alkyl), -N (Ci _-4 alkyl) ₂ or -SO ₂ -R ¹ - ^{1 2,}

»1.2 halogen, -CN, OH, -O-CH ₃ or phenyl,

R ¹ - ³ (a) halogen, -CN, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -CO ₂ R ¹ - ^{1 1} , d _-6 alkyl or

R ¹ - ⁴ independently of one another (a) halogen, -CN, -OR ¹ - ¹ - ¹ , -SR ¹ - ¹ - ¹ , -S (O) -R ^{1 1 2} , -S (O) ₂ -R ^{1 1 2} , -NR ^{1 1 3} R ^{1 1 4} ,

-N ^(R1 - ⁴ - ¹⁾ -C (O) -C _-4 alkyl, d _-6 alkyl,

(c) an oxo group,

R ¹ - ⁴ - ¹ H or d _-4 -alkyl,

R ¹ - ⁵ -OH or -Ods-alkyl,

R ² and R ³ together with the carbon atom to which they are attached, a substituted by a radical R ^{2 1} Cs-β-cycloalkylene group in which a -CH ₂ unit by a heteroatom O, N, S or by a Group CO, SO or SO ₂ can be replaced,

R ² - ¹ H, -OH,

R ⁴ (a) H,

(b) C _1-4 alkyl, (c) C _1-3 -alkyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

R ⁵ (a) H, halogen, -CN, -OH, (b) C _1-6 -alkyl,

(d) C _3-7 cycloalkyl, (e) -Ode-alkyl,

(f) -O-Cs- _T- cycloalkyl,

(i) -S-Ci-4-alkyl, -SO ₂ -R ^52, (j) optionally substituted with one or two Ci _-3 alkyl five-membered heteroaryl group which is selected from the group consisting of pyrrolyl, oxazolyl, isoxazolyl , oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or (k) an optionally substituted with one or two Ci _-3 alkyl six-membered heteroaryl group which is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl and triazinyl,

R ⁵ - ² -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / Λ piperidinyl or / and -morpholinyl

R ⁶ is (a) H, halogen, -CN, -OH, (b) Ci _-6 alkyl,

(c) Ci _-3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted,

(d) C _3-7 cycloalkyl, (e) C _2-4 alkynyl,

(f) -O-Ci-6-alkyl,

(g) -O-Cs- _T- cycloalkyl,

(h) -NH _2, -NH (CI.3 alkyl), -N (Ci _-3 alkyl) _2, (i) -C (O) -R ^{6 1,}

C) -S-Ci _-4 alkyl, -SO-Ci ₄ alkyl, -SO ₂ -C _-4 alkyl,

R ⁶ - ¹ -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / -piperidinyl, Λ / -morpholinyl, - OH, -O-Ci _-8- alkyl or -O-Cs-r-cycloalkyl,

R ⁷ (a) H, halogen, -CN, -OH,

(b) C _1-6 alkyl,

(d) C _3-7 cycloalkyl,

(e) -OC _1-6 -alkyl,

(f) -O-Cs- _T- cycloalkyl,

(i) -Sds-alkyl, -SO ₂ -R ⁷² ,

R ⁷ - ¹ -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / -piperidinyl, Λ / -morpholinyl, - OH, -O-Ci _-8- alkyl or -OC ^ -cycloalkyl,

R ⁷ - ² -NH _2, -NH (Ci _-6 alkyl), - N (Ci _-6 alkyl) _2, Λ / -Acetidinyl, Λ / -pyrrolidinyl, Λ / Λ piperidinyl or / -morpholinyl, X ¹ N or CR ⁸

H, F, Cl, CH _3,

N or CH and

X ^{3 is} N or CH,

their enantiomers, their diastereomers, their mixtures and their salts.

2. Compounds of general formula I according to claim 1, in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 are} as defined above in claim 1 and

(C) a optionally substituted by a radical R ^{1 2} substituted C _3-6 cycloalkyl group in which a -CH ₂ unit may be replaced by a -C (O) group, (d) an optionally with 1, 2 or 3 radicals R ^{1 3} substituted phenyl group,

(e) a five-membered heteroaryl radical which is optionally substituted by 1, 2 or 3 radicals R ^{1 4} and contains at least one N, O or S atom and which, if appropriate, additionally contains one, two or three further N atoms,

(h) a 5- or 6-membered optionally substituted by 1 or 2 R ^{1 4} radicals

(i) -OR ¹ - ¹ - ¹ or C) -NR ^{1 1 3} R ¹ - ^{1 4} ,

R ¹ - ¹ (a) -CN, C ₃ -6-cycloalkyl, -OR ¹ - ¹ - ¹ , -NR ^{1 1 3} R ¹ - ^{1 4} , or (b) C-ι- ₃ alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted,

R ¹ - ¹ - ¹ (a) H, (b) Ci- ₄ alkyl,

R ^1-1'3 , R ^{1-1'4 are} independently (a) H,

(b) C _1-4 alkyl,

(c) C _3-6 cycloalkyl, or

R ¹ - ² halogen, -CN, -OH, -O-CH ₃ or phenyl,

R ^1-3 independently

(a) halogen, -CN, -OR ¹ - ¹ - ¹ , d _-6- alkyl or

R ^{1 4} independently

(a) halogen, -CN, -OR ¹ - ¹ - ¹ , -NR ¹ - ¹ - ³ R ¹ - ¹ - ⁴ , -N (R ¹ - ^{4 / l} ) -C (O) -Ci ₄ - Alkyl, C _1-6 alkyl, or

(b) C-ι- ₃ alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted, and

R ^1A1 is H or _d-4 alkyl, mean

their enantiomers, their diastereomers, their mixtures and their salts.

3. Compounds of general formula I according to claim 1, in which R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 are} as defined in claim 1 or 2 and

R ² and R ^3, together with the carbon atom to which they are attached, denote a C 8 -e-cycloalkylene group in which a -CH ₂ moiety may be replaced by an oxygen atom,

their enantiomers, their diastereomers, their mixtures and their salts.

4. Compounds of general formula I according to claim 1, in which R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ^{3 are} as defined above in claim 1, 2 or 3 and

R ⁴ (a) H,

(b) methyl or ethyl in which each methylene group may be substituted by 1 or 2 fluorine atoms and the methyl group by 1, 2 or 3 fluorine atoms,

their enantiomers, their diastereomers, their mixtures and their salts.

5. Compounds of general formula I according to claim 1, in which R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as defined in claim 1, 2, 3 or 4 are defined and

R ⁵ (a) is H, halogen, -CN or (b) d- _3- alkyl,

their enantiomers, their diastereomers, their mixtures and their salts.

6. Compounds of general formula I according to claim 1, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , X ¹ , X ² and X ³ as defined in claim 1, 2, 3, 4 or 5 are defined and

R ⁶ (a) H, halogen, -CN, -OH, (b) C _1-3 -alkyl, (c) _d-C3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms can be substituted,

(d) C _{_2-4} alkynyl, (e) -O-Cs-e-cycloalkyl,

(f) -NH ₂ , -NH (CH ₃ ), -N (CHs) ₂ ,

(g) -S-CH ₃ , -SO-CH ₃ , -SO ₂ -CH ₃ ,

their enantiomers, their diastereomers, their mixtures and their salts.

7. Compounds of general formula I according to claim 1, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ , X ² and X ³ as defined in claim 1, 2, 3, 4 , 5 or 6 are defined and

R ⁷ (a) H, halogen, -CN,

(b) Ci _-3 alkyl, or -O-Ci _-3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms can be substituted,

(c) C _3-5 cycloalkyl, (d) -NH _2, -NH (Ci _-3 alkyl), -N (Ci _-3 alkyl) ₂ means

their enantiomers, their diastereomers, their mixtures and their salts.

8. Compounds of general formula I according to claim 1, in which R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as defined in claim 1, 2, 3, 5 , 6 or 7 are defined and

R ⁴ H means

their enantiomers, their diastereomers, their mixtures and their salts.

9. Compounds of general formula Ia

in which R ¹ , R ² , R ³ , R ⁶ , R ⁷ and X ^{1 are} as defined above in claim 1, 2, 3, 6 or 7,

their enantiomers, their diastereomers, their mixtures and their salts.

10. Compounds of the general formula Ib

in which R, R, R and X are as defined above in claim 1, 2, 6, 7 or 8,

their enantiomers, their diastereomers, their mixtures and their salts.

1 1. Compounds of general formula I, Ia or Ib according to claim 1, 9 or 10, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and X ³ as defined in claim 1 above , 2, 3, 4, 5, or 8 are defined and

R ^{6 is} -O-Ci-3-alkyl and

R ^{7 is} -CN, -CF ₃ , Cl or Br,

their enantiomers, their diastereomers, their mixtures and their salts.

12. Compounds of the general formula I, Ia or Ib according to claim 1, 9 or 10, in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² and X ³ as defined above Claim 1, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 are defined and

(c) a C 3-6 -cycloalkyl group optionally substituted by a radical R ^1-2 in which a -CH ₂ - moiety may be replaced by a -C (O) -group,

(d) a five-membered heteroaryl radical which is optionally substituted by 1, 2 or 3 radicals R ^1-4 and contains at least one N, O or S atom and which, if appropriate, additionally contains one, two or three further N atoms,

R ¹ - ¹ (a) -CN, C _3- 6 cycloalkyl, -OH, -OCH _3, -NH _2, -NHCH _3, -N (CHa) _2, or

R ¹ - ² F, Cl, Br, -CN, -OH, -OCH ₃ , or phenyl,

R ^{1 3} independently

(a) F, Cl, Br, -OH, -OCH ₃ , d _-6- alkyl or

(b) a Ci _-3 alkyl group wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms may be substituted, and

R ^{1 4} independently

(a) F, Cl, Br, -OH, -O-Ci _-3 alkyl, -NH _2, -NHCH _3, -N (CH ₃₎ _2, -NH-C (O) -d _-4 alkyl , d- ₆ alkyl, or (b) a Ci _-3 alkyl group wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms can be substituted,

their enantiomers, their diastereomers, their mixtures and their salts.

13. Compounds of the general formula I, Ia or Ib according to claim 1, 9 or 10, wherein the RR ²² , RR ³³ , RR ⁴⁴ , RR ⁵⁵ , RR ⁶⁶ , RR ⁷⁷ , XX ¹¹ , XX ²² 1 and X ³ as defined in claim 1, 3, 4, 5,

6, 7, 8, 9, 10 or 1 1 are defined and

(c) an optionally substituted by a group R ^{1 2} substituted C ₄ _6 cycloalkyl group, in which one -CH ₂ moiety replaced by a -C (O) group can be replaced, (d) optionally substituted with 1, 2 or 3 R ⁴ radicals R ⁴ substituted five-membered

Heteroaryl radical selected from the group consisting of

N'N

W / A ^ * M N - MN

.0.

N "S

&, N N - NN

.N. .N

N ': P N

~ * Ni '* NN

(e) optionally substituted with 1 or 2 radicals R ¹ is ^{4-substituted} six-membered heteroaryl residue selected from the group consisting of

(f) a 5- or 6-membered optionally substituted by 1 or 2 R ^{1 4} radicals

Heterocycle selected from the group consisting of

R ¹ - ¹ (a) -CN, cyclopropyl, CF ₃ , -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , or (b) a methyl or ethyl group in which each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,

R ¹ - ^{2 is} -OH or -O-CH ₃ ,

R ^{1 3} independently

(a) F, Cl, Br, -OH, -OCH ₃ , -OCF ₃ , d _-4 -alkyl or

R ^{1 4} independently (a) F, Cl, Br, -OH, -Od _-3 alkyl, -OCF _3, -NH _2, -NH-C ^ alkyl, -N (Ci _-4 alkyl) _2, -NH-C (O) -Ci _-4 alkyl, C _1-6 alkyl, or

their enantiomers, their diastereomers, their mixtures and their salts.

14. Compounds of the general formula I, Ia or Ib according to claim 1, 9 or 10, wherein the RR ²² , RR ³³ , RR ⁴⁴ , RR ⁵⁵ , RR ⁶⁶ , RR ⁷⁷ , XX ¹¹ , XX ²² and X ³ as defined in claim 1, 3, 4, 5,

6, 7, 8, 9, 10 or 1 1 are defined and

R ^{1 is} selected from the group consisting of

their enantiomers, their diastereomers, their mixtures and their salts.

15. The following compounds of general formula I according to claim 1:

their enantiomers, their diastereomers, their mixtures and their salts.

16. Physiologically acceptable salts of the compounds according to any one of claims 1 to 15 with inorganic or organic acids or bases.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a physiologically acceptable salt according to claim 16 in addition to optionally one or more inert carriers and / or diluents.

18. A compound of general formula I according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16 or 17 for use as a medicament.

19. A compound of general formula I according to at least one of claims 1 to 16 for the manufacture of a medicament for the acute and prophylactic treatment of pain, intestinal pain, neuropathic pain, inflammatory / Pain receptor-mediated pain, tumor pain and headache disorders.

20. A compound of general formula I according to at least one of claims 1 to 16 for the manufacture of a medicament for the acute and prophylactic treatment of

Osteoarthritis.

21. A process for the preparation of a medicament according to claim 17, characterized in that a compound according to at least one of claims 1 to 16 is incorporated into one or more inert carriers and / or diluents by a non-chemical route.