Substituted piperidines as CCR3 antagonists

1. A compound of formula 1,

wherein

A is CH 2 , O or N—C 1-6 -alkyl;

R 1 is selected from

NHR 1.1 , NMeR 1.1 ;

NHR 1.2 , NMeR 1.2 ;

NHCH 2 —R 1.3 ;

NH—C 3-6 -cycloalkyl, whereas optionally one carbon atom is replaced by a nitrogen atom, whereas the ring is optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, O—C 1-6 -alkyl, NHSO 2 -phenyl, NHCONH-phenyl, halogen, CN, SO 2 —C 1-6 -alkyl, COO—C 1-6 -alkyl;

a C 9 or 10 -bicyclic-ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound via a nitrogen atom to the basic structure of formula 1 and whereas the ring system is optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, COO—C 1-6 -alkyl, C 1-6 -haloalkyl, O—C 1-6 -alkyl, NO 2 , halogen, CN, NHSO 2 —C 1-6 -alkyl, methoxy-phenyl;

a group selected from NHCH(pyridinyl)CH 2 COO—C 1-6 -alkyl, NHCH(CH 2 O—C 1-6 -alkyl)-benzoimidazolyl, optionally substituted with halogen or CN;

or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazole;

R 1.1 is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -haloalkyl, C 1-6 -alkylene-OH, C 2-6 -alkenylene-OH, C 2-6 -alkynylene-OH, CH 2 CON(C 1-6 -alkyl) 2 , CH 2 NHCONH—C 3-6 -cycloalkyl, CN, CO-pyridinyl, CONR 1.1.1 R 1.1.2 , COO—C 1-6 -alkyl, N(SO 2 —C 1-6 -alkyl)(CH 2 CON(C 1-4 -alkyl) 2 ) O—C 1-6 -alkyl, O-pyridinyl, SO 2 —C 1-6 -alkyl, SO 2 —C 1-6 -alkylen-OH, SO 2 —C 3-6 -cycloalkyl, SO 2 -piperidinyl, SO 2 NH—C 1-6 -alkyl, SO 2 N(C 1-6 -alkyl) 2 , halogen, CN, CO-morpholinyl, CH 2 -pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, NHC 1-6 -alkyl and ═O;

R 1.1.1 H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -haloalkyl, CH 2 CON(C 1-6 -alkyl) 2 , CH 2 CO-azetindinyl, C 1-6 -alkylen-C 3-6 -cycloalkyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, C 1-6 -alkylen-OH or thiadiazolyl, optionally substituted with C 1-6 -alkyl;

R 1.1.2 H, C 1-6 -alkyl, SO 2 C 1-6 -alkyl;

or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one N or O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 1-4 -alkylene-OH, OH, ═O;

or

R 1.1 is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently from each other one or two N, S, or SO 2 , replacing a carbon atom of the ring, wherein the ring is optionally substituted with C 1-4 -alkyl or ═O;

R 1.2 is selected from

heteroaryl, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, CH 2 COO—C 1-6 -alkyl, CONR 1.2.1 R 1.2.2 , COR 1.2.3 , COO—C 1-6 -alkyl, CONH 2 , O—C 1-6 -alkyl, halogen, CN, SO 2 N(C 1-6 -alkyl) 2 or heteroaryl optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl;

heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or SO 2 , replacing a carbon atom of the ring;

an aromatic or non-aromatic C 9 or 10 -bicyclic-ring, whereas one or two carbon atoms are replaced by N, O or S each optionally substituted with one or two residues selected from the group consisting of N(C 1-6 -alkyl) 2 , CONH—C 1-6 -alkyl, ═O;

a heterocyclic non-aromatic ring, optionally substituted with pyridinyl;

4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO—C 1-6 -alkyl,

R 1.2.1 H, C 1-6 -alkyl, C 1-6 -alkylene-C 3-6 -cycloalkyl, C 1-4 -alkylene-phenyl, C 1-4 -alkylene-furanyl, C 3-6 -cycloalkyl, C 1-4 -alkylene-O—C 1-4 -alkyl, C 1-6 -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO 2 , replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl

R 1.2.2 H, C 1-6 -alkyl;

R 1.2.3 a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO 2 , replacing a carbon atom of the ring;

R 1.3 is selected from phenyl, heteroaryl or indolyl, each optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, O—C 1-6 -alkyl, O—C 1-6 -haloalkyl, phenyl, heteroaryl;

R 2 is selected from the group consisting of C 1-6 -alkylene-phenyl, C 1-6 -alkylene-naphthyl, and C 1-6 -alkylene-heteroaryl; each optionally substituted with one, two or three residues selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, O—C 1-6 -alkyl, O—C 1-6 -haloalkyl, halogen;

R 3 is H, C 1-6 -alkyl;

R 4 is H, C 1-6 -alkyl;

or R 3 and R 4 together are forming a CH 2 —CH 2 group.

2. The compound of formula 1 according to claim 1 , wherein

A is CH 2 , O or N—C 1-4 -alkyl;

R 1 is selected from

NHR 1.1 , NMeR 1.1 ;

NHR 1.2 , NMeR 1.2 ;

NHCH 2 —R 1.3 ;

NH—C 3-6 -cycloalkyl, whereas optionally one carbon atom is replaced by a nitrogen atom, whereas the ring is optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, O—C 1-6 -alkyl, NHSO 2 -phenyl, NHCONH-phenyl, halogen, CN, SO 2 —C 1-6 -alkyl, COO—C 1-6 -alkyl;

a C 9 or 10 -bicyclic-ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound via a nitrogen atom to the basic structure of formula 1 and whereas the ring system is optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, COO—C 1-6 -alkyl, C 1-6 -haloalkyl, O—C 1-6 -alkyl, NO 2 , halogen, CN, NHSO 2 —C 1-6 -alkyl, m-methoxyphenyl;

a group selected from NHCH(pyridinyl)CH 2 COO—C 1-6 -alkyl, NHCH(CH 2 O—C 1-6 -alkyl)-benzoimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;

R1.1 is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, CH 2 CON(C 1-6 -alkyl) 2 , CH 2 NHCONH—C 3-6 -cycloalkyl, CN, CONR 1.1.1 R 1.1.2 , COO—C 1-6 -alkyl, O—C 1-6 -alkyl, SO 2 —C 1-6 -alkyl, SO 2 —C 1-6 -alkylen-OH, SO 2 —C 3-6 -cycloalkyl, SO 2 -piperidinyl, SO 2 NH—C 1-6 -alkyl, SO 2 N(C 1-6 -alkyl) 2 , halogen, CN, CO-morpholinyl, CH 2 -pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, NHC 1-6 -alkyl, ═O;

R 1.1.1 H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -haloalkyl, CH 2 CON(C 1-6 -alkyl) 2 , CH 2 CO-azetindinyl, C 1-6 -alkylen-C 3-6 -cycloalkyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, C 1-6 -alkylen-OH or thiadiazolyl, optionally substituted with C 1-6 -alkyl;

R 1.1.2 H, C 1-6 -alkyl, SO 2 C 1-6 -alkyl;

or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH

R 1.2 is selected from

heteroaryl, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, CH 2 COO—C 1-6 -alkyl, CONR 1.2.1 R 1.2.2 , COO—C 1-6 -alkyl, CONH 2 , O—C 1-6 -alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N(C 1-6 -alkyl) 2 , CONH—C 1-6 -alkyl, ═O;

piperidinyl, optionally substituted with pyridinyl;

4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO—C 1-6 -alkyl,

R 1.2.1 H, C 1-6 -alkyl;

R 1.2.2 H, C 1-6 -alkyl;

R 1.3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, O—C 1-6 -alkyl, O—C 1-6 -haloalkyl;

R 2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, O—C 1-6 -alkyl, O—C 1-6 -haloalkyl, halogen; or CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R 3 is H, C 1-4 -alkyl;

R 4 is H, C 1-4 -alkyl;

or R 3 and R 4 together are forming a CH 2 —CH 2 group.

3. The compound of formula 1 according to claim 1 , wherein

A is CH 2 , O or NMe;

R 1 is selected from

NHR 1.1 , NMeR 1.1 ;

NHR 1.2 , NMeR 1.2 ;

NHCH 2 —R 1.3 ;

NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, NHSO 2 -phenyl, NHCONH-phenyl, halogen;

NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO 2 —C 1-4 -alkyl, COO—C 1-4 -alkyl;

piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO 2 —C 1-4 -alkyl, m-methoxyphenyl;

dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, COO—C 1-4 -alkyl, C 1-4 -haloalkyl, O—C 1-4 -alkyl, NO 2 , halogen;

a group selected from NHCH(pyridinyl)CH 2 COO—C 1-4 -alkyl, NHCH(CH 2 O—C 1-4 -alkyl)-benzoimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;

R 1.1 is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, C 1-4 -haloalkyl, CH 2 CON(C 1-4 -alkyl) 2 , CH 2 NHCONH—C 3-6 -cycloalkyl, CN, CONR 1.1.1 R 1.1.2 , COO—C 1-4 -alkyl, O—C 1-4 -alkyl, SO 2 —C 1-4 -alkyl, SO 2 —C 1-4 -alkylen-OH, SO 2 —C 3-6 -cycloalkyl, SO 2 -piperidinyl, SO 2 NH—C 1-4 -alkyl, SO 2 N(C 1-4 -alkyl) 2 , halogen, CO-morpholinyl, CH 2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, NHC 1-4 -alkyl, ═O;

R 1.1.1 H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-4 -haloalkyl, CH 2 CON(C 1-4 -alkyl) 2 , CH 2 CO-azetindinyl, C 1-4 -alkylen-C 3-6 -cycloalkyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, C 1-4 -alkylen-OH or thiadiazolyl, optionally substituted with C 1-4 -alkyl;

R 1.1.2 H, C 1-4 -alkyl, SO 2 C 1-4 -alkyl;

or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH

R 1.2 is selected from

pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, CH 2 COO—C 1-4 -alkyl, CONR 1.2.1 R 1.2.2 , COO—C 1-4 -alkyl, CONH 2 , O—C 1-4 -alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N(C 1-4 -alkyl) 2 , CONH—C 1-4 -alkyl, ═O;

piperidinyl, optionally substituted with pyridinyl;

4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO—C 1-4 -alkyl,

R 1.2.1 H, C 1-4 -alkyl;

R 1.2.2 H, C 1-4 -alkyl;

R 1.3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, O—C 1-4 -alkyl, O—C 1-4 -haloalkyl;

R 2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, C 1-4 -haloalkyl, O—C 1-4 -haloalkyl, halogen; or CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R 3 is H;

R 4 is H;

or R 3 and R 4 together are forming a CH 2 —CH 2 group.

4. The compound of formula 1 according to claim 1 , wherein

A is CH 2 , O or NMe;

R 1 is selected from

NHR 1.1 , NMeR 1.1 ;

NHR 1.2 , NMeR 1.2 ;

NHCH 2 —R 1.3 ;

NH-piperidinyl, optionally substituted with pyridinyl;

NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO 2 -phenyl, NHCONH-phenyl, F;

NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO 2 Me, COO-t-Bu;

piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO 2 -n-Bu, m-methoxyphenyl;

dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF 3 , OMe, NO 2 , F, Br;

a group selected from NHCH(pyridinyl)CH 2 COOMe, NHCH(CH 2 OMe)-benzoimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;

R 1.1 is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF 3 , CH 2 CONMe 2 , CH 2 NHCONH-cyclohexyl, CN, CONR 1.1.1 R 1.1.2 , COOMe, COOEt, OMe, SO 2 Me, SO 2 CH 2 CH 2 OH, SO 2 Et, SO 2 -cyclopropyl, SO 2 -piperidinyl, SO 2 NHEt, SO 2 NMeEt, F, Cl, CO-morpholinyl, CH 2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═O;

R 1.1.1 H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH 2 -i-Pr, CH 2 -t-Bu, CH(CH 3 )CH 2 CH 3 , CH 2 CHF 2 , CH 2 CONMe 2 , CH 2 CO-azetindinyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, CH 2 -tetrahydro-furanyl, CH 2 -furanyl, CH 2 CH 2 OH or thiadiazolyl, optionally substituted with Me;

R 1.1.2 H, Me, Et, SO 2 Me, SO 2 Et

or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH

R 1.2 is selected from

pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH 2 COOEt, CONR 1.2.1 R 1.2.2 , COOMe, COOEt, CONH 2 , OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe 2 , CONHMe, ═O;

4,5-dihydro-naphtho [2,1-d]thiazole, optionally substituted with NHCOMe,

R 1.2.1 H, Me;

R 1.2.2 H, Me;

R 1.3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF 2 ;

R 2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH 3 , CF 3 , OCF 3 , F, Cl, Br, Et; or CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R 3 is H;

R 4 is H;

or R 3 and R 4 together are forming a CH 2 —CH 2 group.

5. The compound of formula 1 according to claim 1 , wherein

A is CH 2 , O or NMe;

R 1 is selected from

NHR 1.1

NHR 1.2 ,

R 1.1 is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Bu, CF 3 , CH 2 CONMe 2 , CH 2 NHCONH-cyclohexyl, CN, CONR 1.1.1 R 1.1.2 , COOMe, COOEt, OMe, SO 2 Me, SO 2 CH 2 CH 2 OH, SO 2 Et, SO 2 -cyclopropyl, SO 2 -piperidinyl, SO 2 NHEt, SO 2 NMeEt, F, Cl, CO-morpholinyl, CH 2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═O;

R 1.1.1 H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH 2 -i-Pr, CH 2 -t-Bu, CH(CH 3 )CH 2 CH 3 , CH 2 CHF 2 , CH 2 CONMe 2 , CH 2 CO-azetindinyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, CH 2 -tetrahydro-furanyl, CH 2 -furanyl, CH 2 CH 2 OH or thiadiazolyl, optionally substituted with Me;

R 1.1.2 H, Me, Et, SO 2 Me, SO 2 Et

or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH

R 1.2 is selected from

pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH 2 COOEt, CONR 1.2.1 R 1.2.2 , COOMe, COOEt, CONH 2 , OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe 2 , CONHMe, ═O;

4,5-dihydro-naphtho [2,1-d]thiazole, optionally substituted with NHCOMe,

R 1.2.1 H, Me;

R 1.2.2 H, Me;

R 2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH 3 , CF 3 , OCF 3 , F, Cl, Br, Et

R 3 is H;

R 4 is H.

6. The compound of formula 1 according to claim 1 , wherein

A is CH 2 , O or NMe;

R 1 is selected from the group consisting of

R 2 is selected from the group consisting of

R 3 is H;

R 4 is H;

or R 3 and R 4 together are forming a CH 2 —CH 2 group.

7. The compound of formula 1 according to claim 1 , wherein the compound is present in the form of the individual optical isomers, a mixture of the individual enantiomers, a racemate or in the form of the enantiomerically pure compounds.

8. The compound of formula 1 according to claim 1 , wherein the compound is present in the form of the R-enantiomer R-1

9. A pharmaceutical composition of matter comprising one or more compounds of formula 1 according to claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition of matter according to claim 9 further comprising a substance selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists, SYK-inhibitors and combinations of any of such substances.

11. The compound of formula 1 according to claim 1 , wherein the compound is

12. The compound of formula 1 according to claim 1 , wherein the compound is

13. The compound of formula 1 according to claim 1 , wherein the compound is

14. The compound of formula 1 according to claim 1 , wherein the compound is

15. The compound of formula 1 according to claim 1 , wherein the compound is

16. The compound of formula 1 according to claim 1 , wherein the compound is

17. The compound of formula 1 according to claim 1 , wherein the compound is

18. The compound of formula 1 according to claim 1 , wherein the compound is

19. The compound of formula 1 according to claim 1 , wherein the compound is

20. The compound of formula 1 according to claim 1 , wherein

21. The compound of formula 1 according to claim 1 , wherein the compound is

22. The compound of formula 1 according to claim 1 , wherein the compound is

23. The compound of formula 1 according to claim 1 , wherein the compound is

24. The compound of formula 1 according to claim 1 , wherein the compound is

25. The compound of formula 1 according to claim 1 , wherein the compound is

26. The compound of formula 1 according to claim 1 , wherein the compound is

27. The compound of formula 1 according to claim 1 , wherein the compound is

28. The compound of formula 1 according to claim 1 , wherein the compound is

29. The compound of formula 1 according to claim 1 , wherein the compound is

30. The compound of formula 1 according to claim 1 , wherein the compound is

31. The compound of formula 1 according to claim 1 , wherein the compound is

32. The compound of formula 1 according to claim 1 , wherein the compound is

33. The compound of formula 1 according to claim 1 , wherein the compound is

34. The compound of formula 1 according to claim 1 , wherein the compound is

35. The compound of formula 1 according to claim 1 , wherein the compound is

36. The compound of formula 1 according to claim 1 , wherein the compound is

37. The compound of formula 1 according to claim 1 , wherein the compound is

38. The compound of formula 1 according to claim 1 , wherein the compound is

39. The compound of formula 1 according to claim 1 , wherein the compound is

40. The compound of formula 1 according to claim 1 , wherein the compound is

41. The compound of formula 1 according to claim 1 , wherein the compound is

42. The compound of formula 1 according to claim 1 , wherein the compound is

43. The compound of formula 1 according to claim 1 , wherein the compound is

44. The compound of formula 1 according to claim 1 , wherein the compound is

45. The compound of formula 1 according to claim 1 , wherein the compound is