US 2017/0253602 A1 · SUBSTITUTED PYRIDOBENZODIAZEPINONE-DERIVATIVES AND USE THEREOF

1:

A compound of the formula (I)
in which
R1 is hydrogen, halogen, hydroxyl, (C1-C4)-alkyl, —NH—C(═O)—R4, —NH—C(═O)—O—R5 or —NH—SO2—R6 in which
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C4)-alkyl;
and
R6 is (C1-C4)-alkyl or phenyl;
R2 is hydrogen, fluorine, chlorine, methyl or methoxy;
R3 is hydrogen, fluorine, chlorine or methyl;
and
G is cyano, hydroxycarbonyl, —C(═O)—NR7AR7B or —CH2—NR8AR8B in which
R7A is hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl, (C1-C4)-alkoxy or up to trisubstituted by fluorine;
R7B is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;
where (C1-C6)-alkyl may be up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR9, —O—(CH2CH2O)n—R10, —SR11, —NR12AR12B, —C(═O)—NR13AR13B, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;
and where
(i) the cycloalkyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl;
(ii) the phenyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C4)-alkyl and (C1-C4)-alkoxy;
(iii) the heterocyclyl groups mentioned may be up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl;
and
(iv) the heteroaryl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C4)-alkyl and (C1-C4)-alkoxy;
and in which
R9 is hydrogen or (C1-C4)-alkyl which may be substituted by 4- to 6-membered heterocyclyl;
R10 is hydrogen or (C1-C4)-alkyl;
R11 is (C1-C4)-alkyl;
R12A, R12B, R13A and R13B are each independently hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl;
and
n is an integer in the range from 1 to 10 inclusive;
or
R7A and R7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which may contain up to 2 further ring heteroatoms from the group of N, O and S, and which may be up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, oxo, —OR14, —NR15AR15B, —C(═O)—NR16AR16B and phenyl;
where (C1-C4)-alkyl for its part may be substituted by hydroxy or up to three times by fluorine;
and in which
R14 is hydrogen, (C1-C4)-alkyl or phenyl;
where (C1-C4)-alkyl may be substituted by hydroxyl, —C(═O)—NR17AR17B, (C3-C6)-cycloalkyl or up to trisubstituted by fluorine;
and
R15A, R15B, R16A, R16B, R17A and R17B are each independently hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl;
R8A is hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl, (C1-C4)-alkoxy or up to trisubstituted by fluorine;
and
R8B is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;
where (C1-C6)-alkyl may be up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR18, —O—(CH2CH2O)p—R19, —SR20, —NR21AR21B, —C(═O)—NR22AR22B, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;
and where
(i) the cycloalkyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl;
(ii) the phenyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C4)-alkyl and (C1-C4)-alkoxy;
(iii) the heterocyclyl groups mentioned may be up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl;
and
(iv) the heteroaryl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C4)-alkyl and (C1-C4)-alkoxy;
and in which
R18 is hydrogen or (C1-C4)-alkyl which may be substituted by 4- to 6-membered heterocyclyl;
R19 is hydrogen or (C1-C4)-alkyl;
R20 is (C1-C4)-alkyl;
R21A, R21B, R22A and R22B are each independently hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl;
and
p is an integer in the range from 1 to 10 inclusive;
or
R8A and R8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which may contain up to 2 further ring heteroatoms selected from the group consisting of N, O and S, and which may be up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, oxo, —OR23, —NR24AR24B, —C(═O)—NR25AR25B and phenyl;
where (C1-C4)-alkyl for its part may be substituted by hydroxy or up to three times by fluorine;
and in which
R23 is hydrogen, (C1-C4)-alkyl or phenyl;
where (C1-C4)-alkyl may be substituted by hydroxyl, —C(═O)—NR26AR26B (C3-C6)-cycloalkyl or up to trisubstituted by fluorine;
and
R24A, R24B, R25A, R25B, R26A and R26B are each independently hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl;
or a salt, a solvate or a solvate of a salt thereof.

58 more elements

2:

The compound of the formula (I) according to claim 1 in which
R1 is hydrogen, fluorine, chlorine, (C1-C4)-alkyl or —NH—SO2—R6 in which
R6 is (C1-C4)-alkyl or phenyl;
R2 is hydrogen, fluorine, chlorine or methyl;
R3 is hydrogen, fluorine, chlorine or methyl;
and
G is cyano, —C(═O)—NR7AR7B or —CH2—NR8AR8B in which
R7A is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl or 2-ethoxyethyl;
where methyl and ethyl may be up to trisubstituted by fluorine;
R7B is hydrogen, (C1-C4)-alkyl or (C3-C6)-cycloalkyl;
where (C1-C4)-alkyl may be up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR9, —SR11, —NR12AR12B, (C3-C6)-cycloalkyl and phenyl;
and where
(i) the cycloalkyl groups mentioned may be 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 mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxy and ethoxy;
and in which
R9 is hydrogen, methyl or ethyl;
R11 is methyl or ethyl;
and
R12A and R12B are each independently hydrogen, methyl, ethyl or 2-hydroxyethyl;
or
R7A and R7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which may contain one further ring heteroatom selected from the group consisting of N, O and S, and which may be up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, oxo, —OR14, —NR15AR15B, —C(═O)—NR16AR16B and phenyl;
where (C1-C3)-alkyl for its part may be substituted by hydroxy or up to three times by fluorine;
and in which
R14 is hydrogen, methyl or ethyl;
and
R15A, R15B, R16A and R16B are each independently hydrogen, methyl or ethyl;
R8A is hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl, methoxy, ethoxy or up to trisubstituted by fluorine;
and
R8B is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
where (C1-C6)-alkyl may be up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR18, —SR20, —NR21AR21B, —C(═O)—NR22AR22B, (C3-C6)-cycloalkyl, phenyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl;
and where
(i) the cycloalkyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, hydroxyl, (C1-C3)-alkoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
(ii) the phenyl groups mentioned may be 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 mentioned may be up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, hydroxyl, oxo, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
and
(iv) the heteroaryl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C3)-alkyl and (C1-C3)-alkoxy;
and in which
R18 is hydrogen or (C1-C3)-alkyl;
R20 is (C1-C3)-alkyl;
and
R21A, R21B, R22A and R22B are each independently hydrogen or (C1-C3)-alkyl which may be substituted by hydroxyl;
or
R8A and R8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which may contain one further ring heteroatom from the group of N, O and S, and which may be up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C4)-alkyl, oxo, —OR23, —NR24AR24B, —C(═O)—NR25AR25B and phenyl;
where (C1-C4)-alkyl for its part may be substituted by hydroxy or up to three times by fluorine;
and in which
R23 is hydrogen or (C1-C3)-alkyl;
where (C1-C3)-alkyl may be substituted by hydroxyl, (C3-C6)-cycloalkyl or up to trisubstituted by fluorine;
and
R24A, R24B, R25A and R25B are each independently hydrogen or (C1-C3)-alkyl which may be substituted by hydroxyl;
or a salt, a solvate or a solvate of a salt thereof.

48 more elements

3:

The compound of the formula (I) according to claim 1 in which
R1 is hydrogen, fluorine, chlorine or (C1-C4)-alkyl;
R2 is hydrogen or fluorine;
R3 is hydrogen, fluorine, chlorine or methyl;
and
G is —C(═O)—NR7AR7B or —CH2—NR8AR8B in which
R7A is hydrogen, methyl or ethyl;
R7B is methyl, ethyl, 2-hydroxyethyl or cyclohexyl;
where cyclohexyl may be up to disubstituted by hydroxyl;
or
R7A and R7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which may contain one further ring heteroatom selected from the group consisting of N and O, and which may be up to disubstituted, identically or differently, by a radical selected from the group consisting of methyl, ethyl, oxo and hydroxyl;
where methyl and ethyl may in turn be substituted by hydroxyl;
R8A is hydrogen or (C1-C4)-alkyl;
and
R8B is (C1-C6)-alkyl, (C3-C6)-cycloalkyl or 5- or 6-membered heterocyclyl;
where (C1-C6)-alkyl may be up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR18, —SR20, —NR21AR21B, (C3-C6)-cycloalkyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl;
and where
(i) the cycloalkyl groups mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, hydroxyl, (C1-C3)-alkoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
(ii) the heterocyclyl groups mentioned may be up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, hydroxyl, oxo, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
and
(iii) the heteroaryl group mentioned may be up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C1-C3)-alkyl and (C1-C3)-alkoxy;
and in which
R18 is hydrogen, methyl or ethyl;
R20 is methyl or ethyl;
and
R21A and R21B are each independently hydrogen, methyl or ethyl;
or
R8A and R8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 5- to 7-membered heterocycle which may contain one further ring heteroatom selected from the group consisting of N and O, and which may be up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C1-C3)-alkyl, oxo, —OR23, —NR24AR24B and —C(═O)—NR25AR25B;
where (C1-C3)-alkyl for its part may be substituted by hydroxy or up to three times by fluorine;
and in which
R23 is hydrogen or (C1-C3)-alkyl;
where (C1-C3)-alkyl may be substituted by hydroxyl or up to trisubstituted by fluorine;
and
R24A, R24B, R25A and R25B are each independently hydrogen, methyl or ethyl;
or a salt, a solvate or a solvate of a salt thereof.

32 more elements

5:

A method for preparing a compound of the formula (I) according to claim 1, wherein the compound of the formula (I) is a compound of the formula (I-A), a compound of the formula (I-B), a compound of the formula (I-C) or a compound of the formula (I-D),
comprising:
[A] reacting a compound of the formula (II)
in which R1, R2 and R3 are as defined in claim 1;
and
PG1 is a suitable protecting group;
in the presence of a base with 2,4-dichloropyridine-3-carboxylic acid (III)
to give a compound of the formula (IV)
in which PG1, R1, R2 and R3 are as defined above;
then
coupling the compound of the formula (IV) with 3,4-diaminobenzonitrile (V)
with activation of the carboxylic acid function in the compound of the formula (IV) to give a compound of the formula (VI)
in which PG1, R1, R2 and R3 are as defined above;
then
cyclizing the compound of the formula (VI) by heating in an inert solvent to give a compound of the formula (VII)
in which PG1, R1, R2 and R3 are as defined above;
and then
detaching the protecting group PG1 to obtain the compound of the formula (I-A)
in which R1, R2 and R3 are as defined above;
or
[B] reacting a compound of the formula (VIII)
in which R1, R2 and R3 are as defined in claim 1
in the presence of an acid while heating with a compound of the formula (IX)
to give the compound of the formula (I-A)
in which R1, R2 and R3 are as defined above;
and optionally
[C] treating the compound of the formula (I-A) with an aqueous acid to give the compound of the formula (I-B)
in which R1, R2 and R3 are as defined above;
and
optionally coupling the compound of the formula (I-B) with a compound of the formula (X)
in which R7A and R7B are as defined in claim 1;
with activation of the carboxylic acid function in the compound of the formula (I-B) to give the compound of the formula (I-C)
in which R1, R2, R3, R7A and R7B are as defined above;
or optionally
[D] reacting the compound of the formula (I-A) with diisobutylaluminium hydride to give a compound of the formula (XI)
in which R1, R2 and R3 are as defined above;
and then
reacting the compound of the formula (XI) in the presence of a suitable reducing agent with a compound of the formula (XII)
in which R8A and R8B are as defined in claim 1;
to give the compound of the formula (I-D)
in which R1, R2, R3, R8A and R8B are as defined above;
and the compound of the formula (I-A), the compound of the formula (I-B), the compound of the formula (I-C) or the compound of the 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.

39 more elements

Substituted pyridobenzodiazepinone-derivatives and use thereof

Life of this patent

Substituted pyridobenzodiazepinone-derivatives and use thereof

Life of this patent

Abstract

Claims22