Substituted pyridobenzodiazepinone-derivatives and use thereof

1. A compound of formula (I)

wherein:

R 1 is hydrogen, halogen, hydroxyl, (C 1 -C 4 )-alkyl, —NH—C(═O)—R 4 , —NH—C(═O)—O—R 5 or —NH—SO 2 —R 6 ,

wherein

R 4 is hydrogen or (C 1 -C 4 )-alkyl;

R 5 is (C 1 -C 4 )-alkyl; and

R 6 is (C 1 -C 4 )-alkyl or phenyl;

R 2 is hydrogen, fluorine, chlorine, methyl or methoxy;

R 3 is hydrogen, fluorine, chlorine or methyl;

and

G is cyano, hydroxycarbonyl, —C(═O)—NR 7A R 7B or —CH 2 —NR 8A R 8B ,

wherein

R 7A is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl, (C 1 -C 4 )-alkoxy or up to trisubstituted by fluorine;

R 7B is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;

wherein (C 1 -C 6 )-alkyl is optionally up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 9 , —O—(CH 2 CH 2 O) n —R 10 , —SR 11 , —NR 12A R 12B , —C(═O)—NR 13A R 13B , (C 3 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;

and wherein

(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and (C 1 -C 4 )-alkoxy carbonyl;

(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;

(iii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl; and

(iv) the heteroaryl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;

and wherein

R 9 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by 4- to 6-membered heterocyclyl;

R 10 is hydrogen or (C 1 -C 4 )-alkyl;

R 11 is (C 1 -C 4 )-alkyl;

R 12A , R 12B , R 13A and R 13B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;

and

n is an integer from 1 to 10;

or

R 7A and R 7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which optionally contains up to 2 further ring heteroatoms selected from the group consisting of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, oxo, —OR 14 , —NR 15A R 15B , —C(═O)—NR 16A R 16B and phenyl;

wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;

and wherein

R 14 is hydrogen, (C 1 -C 4 )-alkyl or phenyl;

wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxyl, —C(═O)—NR 17A R 17B , (C 3 -C 6 )-cycloalkyl or up to trisubstituted by fluorine;

and

R 15A , R 15B , R 16A , R 16B , R 17A and R 17B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;

R 8A is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl, (C 1 -C 4 )-alkoxy or up to trisubstituted by fluorine;

and

R 8B is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;

wherein (C 1 -C 6 )-alkyl is optionally up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 18 , —O—(CH 2 CH 2 O) p —R 19 , —SR 20 , —NR 21A R 21B , —C(═O)—NR 22A R 22B , (C 3 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;

and wherein

(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl;

(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;

(iii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl; and

(iv) the heteroaryl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;

and wherein

R 18 is hydrogen or (C 1 -C 4 )-alky optionally substituted by 4- to 6-membered heterocyclyl;

R 19 is hydrogen or (C 1 -C 4 )-alkyl;

R 20 is (C 1 -C 4 )-alkyl;

R 21A , R 21B , R 22A and R 22B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;

and

p is an integer from 1 to 10;

or

R 8A and R 8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which optionally contains up to 2 further ring heteroatoms selected from the group consisting of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, oxo, —OR 23 , —NR 24A R 24B , —C(═O)—NR 25A R 25B and phenyl;

wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;

and wherein

R 23 is hydrogen, (C 1 -C 4 )-alkyl or phenyl;

wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxyl, —C(═O)—NR 26A R 26B , (C 3 -C 6 )-cycloalkyl or up to trisubstituted by fluorine;

and

R 24A , R 24B , R 25A , R 25B , R 26A and R 26B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl,

or a salt, a solvate or a solvate of a salt thereof.

2. The compound of formula (I) according to claim 1 , wherein:

R 1 is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or —NH—SO 2 —R 6 ,

wherein

R 6 is (C 1 -C 4 )-alkyl or phenyl;

R 2 is hydrogen, fluorine, chlorine or methyl;

R 3 is hydrogen, fluorine, chlorine or methyl;

and

G is cyano, —C(═O)—NR 7A R 7B or —CH 2 —NR 8A R 8B ,

wherein

R 7A is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl or 2-ethoxyethyl;

wherein methyl and ethyl are optionally up to trisubstituted by fluorine;

R 7B is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl;

wherein (C 1 -C 4 )-alkyl is optionally up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 9 , —SR 11 , —NR 12A R 12B , (C 3 -C 6 )-cycloalkyl and phenyl;

and wherein

(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl; and

(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxy and ethoxy;

and wherein

R 9 is hydrogen, methyl or ethyl;

R 11 is methyl or ethyl;

and

R 12A and R 12B are independently hydrogen, methyl, ethyl or 2-hydroxyethyl;

or

R 7A and R 7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which optionally contains one further ring heteroatom selected from the group consisting of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, oxo, —OR 14 , NR 15A R 15B , —C(═O)—NR 16A R 16B and phenyl;

wherein (C 1 -C 3 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;

and wherein

R 14 is hydrogen, methyl or ethyl;

and

R 15A , R 15B , R 16A and R 16B are independently hydrogen, methyl or ethyl;

R 8A is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl, methoxy, ethoxy or up to trisubstituted by fluorine;

and

R 8B is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;

wherein (C 1 -C 6 )-alkyl is optionally up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 18 , —SR 20 , —NR 21A R 21B , —C(═O)—NR 22A R 22B , (C3-C6)-cycloalkyl, phenyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl;

and wherein

(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, hydroxyl, (C 1 -C 3 )-alkoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;

(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxy and ethoxy;

(iii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, hydroxyl, oxo, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl; and

(iv) the heteroaryl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy;

and wherein

R 18 is hydrogen or (C 1 -C 3 )-alkyl;

R 20 is (C 1 -C 3 )-alkyl;

and

R 21A , R 21B , R 22A and R 22B are independently hydrogen or (C 1 -C 3 )-alkyl optionally substituted by hydroxyl;

or

R 8A and R 8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which optionally contains one further ring heteroatom from the group of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, oxo, —OR 23 , —NR 24 AR 24B , —C(═O)—NR 25A R 25B and phenyl;

wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;

and wherein

R 23 is hydrogen or (C 1 -C 3 )-alkyl;

wherein (C 1 -C 3 )-alkyl is optionally substituted by hydroxyl, (C 3 -C 6 )-cycloalkyl or up to trisubstituted by fluorine;

and

R 24A , R 24B , R 25A and R 25B are independently hydrogen or (C 1 -C 3 )-alkyl optionally substituted by hydroxyl,

or a salt, a solvate or a solvate of a salt thereof.

3. The compound of formula (I) according to claim 1 , wherein:

R 1 is hydrogen, fluorine, chlorine or (C 1 -C 4 )-alkyl;

R 2 is hydrogen or fluorine;

R 3 is hydrogen, fluorine, chlorine or methyl;

and

G is —C(═O)—NR 7A R 7B or —CH 2 —NR 8A R 8B ,

wherein

R 7A is hydrogen, methyl or ethyl;

R 7B is methyl, ethyl, 2-hydroxyethyl or cyclohexyl;

wherein cyclohexyl is optionally up to disubstituted by hydroxyl;

or

R 7A and R 7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which optionally contains one further ring heteroatom selected from the group consisting of N and O, and which is optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of methyl, ethyl, oxo and hydroxyl;

wherein the methyl and ethyl are optionally substituted by hydroxyl;

R 8A is hydrogen or (C 1 -C 4 )-alkyl;

and

R 8B is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocyclyl;

wherein (C 1 -C 6 )-alkyl is optionally up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 18 , —SR 20 , —NR 21A R 21B , (C 3 -C 6 )-cycloalkyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl;

and wherein

(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, hydroxyl, (C 1 -C 3 )-alkoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;

(ii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, hydroxyl, oxo, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl; and

(iii) the heteroaryl group is optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy;

and wherein

R 18 is hydrogen, methyl or ethyl;

R 20 is methyl or ethyl;

and

R 21A and R 2lB are independently hydrogen, methyl or ethyl;

or

R 8A and R 8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which optionally contains one further ring heteroatom selected from the group consisting of N and O, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 3 )-alkyl, oxo, —OR 23 , —NR 24A R 24B and —C(═O)—NR 25A R 25B ;

wherein (C 1 -C 3 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;

and wherein

R 23 is hydrogen or (C 1 -C 3 )-alkyl;

wherein (C 1 -C 3 )-alkyl is optionally substituted by hydroxyl or up to trisubstituted by fluorine;

and

R 24A , R 24B , R 25A and R 25B are independently hydrogen, methyl or ethyl,

or a salt, a solvate or a solvate of a salt thereof.

4. The compound of formula (I) according to claim 1 , wherein:

R 1 is methyl;

R 2 is hydrogen;

R 3 is fluorine;

and

G is —CH 2 —NR 8A R 8B ,

wherein

R 8A is hydrogen, methyl or ethyl;

and

R 8B is (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl;

wherein (C 1 -C 6 )-alkyl is optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of hydroxyl, methoxy and ethoxy;

and

(C 3 -C 6 )-cycloalkyl is optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;

or

R 8A and R 8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which optionally contains one further ring heteroatom selected from the group consisting of N and O, and which is optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of methyl, ethyl, hydroxyl, methoxy, ethoxy and n-propoxy;

wherein the methyl and ethyl are optionally substituted by hydroxyl,

or a salt, a solvate or a solvate of a salt thereof.

5. A method for preparing the compound of formula (I) according to claim 1 , wherein the compound of formula (I) is a compound of the formula (I-A), a compound of formula (I-B), a compound of formula (I-C) or a compound of formula (I-D),

comprising:

[A] reacting a compound of formula (II)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

and

PG 1 is a suitable protecting group;

in the presence of a base with 2,4-dichloropyridine-3-carboxylic acid (III)

to give a compound of formula (IV)

wherein PG 1 is a suitable protecting group, and R 1 , R 2 and R 3 are as defined in claim 1 ;

coupling the compound of formula (IV) with 3,4-diaminobenzonitrile (V)

with activation of the carboxylic acid group in the compound of formula (IV) to give a compound of formula (VI)

wherein PG 1 is a suitable protecting group, and R 1 , R 2 and R 3 are as defined in claim 1 ;

cyclizing the compound of formula (VI) by heating in an inert solvent to give a compound of formula (VII)

wherein PG 1 is a suitable protecting group, and R 1 , R 2 and R 3 are as defined in claim 1 ;

and

detaching the protecting group PG 1 to obtain the compound of formula (I-A)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

or

[B] reacting a compound of formula (VIII)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ,

in the presence of an acid while heating with a compound of formula (IX)

to give the compound of formula (I-A)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

and optionally

[C] treating the compound of formula (I-A) with an aqueous acid to give the compound of formula (I-B)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

and

optionally coupling the compound of formula (I-B) with a compound of formula (X)

wherein R 7A and R 7B are as defined in claim 1 ;

with activation of the carboxylic acid function in the compound of formula (I-B) to give the compound of formula (I-C)

wherein R 1 , R 2 , R 3 , R 7A and R 7B are as defined in claim 1 ;

or

[D] reacting the compound of formula (I-A) with diisobutylaluminium hydride to give a compound of formula (XI)

wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

and

reacting the compound of formula (XI) in the presence of a suitable reducing agent with a compound of formula (XII)

wherein R 8A and R 8B are as defined in claim 1 ;

to give the compound of formula (I-D)

wherein R 1 , R 2 , R 3 , R 8A and R 8B are as defined in claim 1 ;

and the compound of formula (I-A), the compound of formula (I-B), the compound of formula (I-C) or the compound of formula (I-D) is optionally separated into its enantiomers or diastereomers, or optionally converted with the appropriate (i) solvent and/or (ii) acid or base to a solvate, a salt, or a solvate of a salt thereof.

6. A pharmaceutical composition comprising the compound of claim 1 , or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

7. A pharmaceutical composition comprising the compound of claim 1 , or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more VEGF signalling pathway inhibitors selected from the group consisting of aflibercept, ranibizumab, bevacizumab, and pegaptanib.

8. The method of claim 5 , wherein PG 1 is benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl.

9. A pharmaceutical composition comprising the compound of claim 2 , or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

10. A pharmaceutical composition comprising the compound of claim 3 , or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

11. A pharmaceutical composition comprising the compound of claim 4 , or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

12. The compound of claim 1 or a salt thereof.