Tetrahydrobenzo-quinoline sulfonamide derivatives useful as IgE modulators

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R1 and R2 independently represent:

Hydrogen; or NHC(O)NH—C1-6-alkyl; or NHSO 2 —C1-6-alkyl; or NHC(O)NH-heteroaryl optionally substituted with one or more R1 a ; or heteroaryl optionally substituted with one or more group selected from the group consisting of amino; C1-6-alkyl; C(O)O—C1-6-alkyl; nitrile; heteroaryl optionally substituted with one or more R1 a ; NH—C1-6-alkyl; NH—C1-6-heterocycloalkyl; NH—C3-9-cycloalkyl; NH-heteroaryl optionally substituted with one or more R1 a ; or NH-heteroaryl optionally substituted with one or more group selected from the group consisting of C1-6-alkyl; C1-6-hydroxyalkyl; C3-9-hydroxyheterocycloalkyl; heteroaryl optionally substituted with one or more R1 a ; or NHC(O)—C1-6-alkyl; or NHC(O)-heteroaryl optionally substituted with one or more R1 a

R1 a represents a group selected from the group consisting of:

Halogen; nitrile; C1-6-alkyl; C1-6-haloalkyl; C1-6-alkoxy; C1-6-haloalkoxy; C(O)O—C1-6-alkyl; and C(O) OH;

R3 represents a group selected from the group consisting of:

C1-6-alkyl optionally substituted with one or more R3 a groups;

C1-3-alkanediyl-C3-6-cycloalkyl optionally substituted with one or more R3 a groups;

C1-3-alkanediyl-C3-6-heterocycloalkyl optionally substituted with one or more R3 a groups;

C3-6-heterocycloalkyl optionally substituted with one or more R3 a groups; and

C3-6-cycloalkyl optionally substituted with one or more R3 a groups;

R3 a represents a group selected from the group consisting of hydrogen; Halogen; C1-2-alkyl; hydroxy; and C1-2-alkoxy; and

R4 represents:

C3-6-cycloalkyl optionally substituted with one or more R4 a group; or C1-6-alkanediyl-C3-6-cycloalkyl optionally substituted with one or more R4 a group; or C1-6-alkanediyl-C3-6-heterocycloalkyl optionally substituted with one or more R4 a group;

R4 a represents a group selected from the group consisting of hydroxy; Halogen;

and C1-2-alkyl.

2 . A compound according to claim 1 , wherein

R1 and R2 independently represent:

Hydrogen; or NH-heteroaryl optionally substituted with one or more group selected from the group consisting of C1-6-alkyl; heteroaryl optionally substituted with one or more R1 a ; or heteroaryl optionally substituted with one or more group selected from the group consisting of amino; C(O)O—C1-6-alkyl; nitrile; heteroaryl optionally substituted with one or more R1 a ; NH—C1-6-alkyl; NH—C3-9-heterocycloalkyl; NH—C3-9-cycloalkyl; or NH-heteroaryl optionally substituted with one or more R1 a .

3 . A compound according to claim 2 , wherein

When R1 is different than hydrogen, R2 is hydrogen;

When R2 is different than hydrogen, R1 is hydrogen.

4 . A compound according to claim 2 , wherein

R3 represents C1-6-alkyl optionally substituted with a fluorine atom.

5 . A compound according to claim 2 , wherein

R4 represents cyclopropyl.

6 . A compound according to claim 1 , wherein

When R1 is different than hydrogen, R2 is hydrogen; or

When R2 is different than hydrogen, R1 is hydrogen.

7 . A compound according to claim 6 , wherein

R3 represents C1-6-alkyl optionally substituted with a fluorine atom.

8 . A compound according to claim 6 , wherein

R4 represents cyclopropyl.

9 . A compound according to claim 1 , wherein

R3 represents C1-6-alkyl optionally substituted with a fluorine atom.

10 . A compound according to claim 9 , wherein

R4 represents cyclopropyl.

11 . A compound according to claim 1 , wherein

R4 represents cyclopropyl.

12 . A compound according to claim 1 which is:

3-cyclopropyl-N-(2-methylpropyl)-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8,9,10-tetrahydrobenzo[h]isoquinolin-7-yl]-3-ethylurea;

1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-7,8,9,10-tetrahydrobenzo[h]isoquinolin-10-yl]-3-ethylurea;

3-cyclopropyl-7-(methanesulfonamido)-N-(2-methylpropyl)-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

3-cyclopropyl-10-(methanesulfonamido)-N-(2-methylpropyl)-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[6-(2-methyltetrazol-5-yl) pyridin-3-yl]amino]-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

3-cyclopropyl-7-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methylpropyl)-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-10-[[6-(2-methyltetrazol-5-yl) pyridin-3-yl]amino]-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

ethyl 5-amino-1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl) sulfamoyl]-7,8,9,10-tetrahydrobenzo[h]isoquinolin-7-yl]imidazole-4-carboxylate;

3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[[5-(3-methyl-1,2,4-oxadiazol-5-yl) pyridin-3-yl]amino]-7,8,9,10-tetrahydrobenzo[h]isoquinoline-5-sulfonamide;

1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl) sulfamoyl]-7,8,9,10-tetrahydrobenzo[h]isoquinolin-7-yl]-3-(2,5-dimethylpyrazol-3-yl) urea; or

ethyl 1-[3-cyclopropyl-5-[(2-fluoro-2-methylpropyl) sulfamoyl]-7,8,9,10-tetrahydrobenzo[h]isoquinolin-7-yl]imidazole-4-carboxylate.

13 . A method for the treatment or prevention of allergy, non-allergic mast cell responses, type 1 hypersensitivity, urticaria, or familiar sinus inflammation comprising administration to a patient in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14 . A method for the treatment or prevention of airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability comprising administration to a patient in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15 . A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.