2-substituted thiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals
View Patent ↗The present invention relates to 2-substituted thiazole-4-carboxamide derivatives of the formula (I), the use thereof as medicament for the treatment of various disorders, and processes for the preparation thereof
1. A compound of the formula (I) with building blocks A, B, C and D
in which
the building blocks B and D are in ortho position relative to one another, and
Q 1 is a heteroaryl ring having 5 ring atoms,
R 1 and R 2 are independently of one another
(i) hydrogen, hydroxy, nitro, halogen, cyano, —CF 3 , —NR 5 R 6 or
(ii) —C(O)—R 10 , —C(O)—R 7 , —C(O)—C 1 -C 3 -fluoroalkyl, —C(O)—NR 5 R 6 , —NH—C(O)—R 7 or
(iii) a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -fluoroalkyl or a C 1 -C 6 -fluoroalkoxy radical,
in each case optionally substituted one or more times, identically or differently, by C 1 -C 3 -alkoxy, hydroxy, —C(O)—R 10 or —NR 8 R 9 , or
(iv) —O—SO 2 , —NR 5 R 6 , —SO 2 —R 7 , —SO 2 —NR 5 R 6
Q 2 is an aryl, heteroaryl or a hydrogenated bicyclic heteroaryl ring;
R 3 and R 4 are independently of one another
(i) hydrogen, halogen or —NR 11 R 12 , or
(ii) a C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy radical which are in each case optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 3 -alkoxy, —NR 8 R 9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C 1 -C 3 -alkyl or —C(O)—R 7 ,
where
R 5 and R 6 are independently of one another hydrogen or a C 1 -C 6 -alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C 1 -C 3 -alkoxy, —NR 8 R 9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C 1 -C 3 -alkyl or —C(O)—R 7 , or
R 5 and R 6 form alternatively together with the nitrogen atom a 5- to 7-membered ring which optionally comprises a further heteroatom in addition to the nitrogen atom, and which is optionally substituted one or more times, identically or differently, by C 1 -C 6 -alkyl and/or by —C(O)—R 7 , and
R 7 is a C 1 -C 6 -alkyl radical, and
R 8 , R 9 , R 10 are independently of one another hydrogen or a C 1 -C 6 -alkyl radical, and
R 11 and R 12 are independently of one another hydrogen or a C 1 -C 6 -alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C 1 -C 3 -alkoxy, —NR 8 R 9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C 1 -C 3 -alkyl or —C(O)—R 7 ,
or a salt, enantiomer or diastereomer thereof.
2. The compound Compounds of formula (I) according to claim 1 with building blocks A, B, C and D,
in which
the building blocks B and D are in ortho position relative to one another, and
Q 1 is a pyrazolyl, thienyl, imidazolyl or 1,2,4-oxadiazolyl ring,
R 1 and R 2 are independently of one another
(i) hydrogen, hydroxy, halogen, cyano, —CF 3 , —NR 5 R 6 or
(ii) a C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -fluoroalkyl or a C 1 -C 6 -fluoroalkoxy radical or
(iii) —SO 2 R 7 ,
Q 2 is a phenyl, thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 1,2,3,4-tetrahydroquinoxalinyl or a 3,4-dihydro-2H-benzo[1,4]oxazinyl ring,
R 3 and R 4 are independently of one another
(i) hydrogen, halogen, —NR 11 R 12 or
(ii) a C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy radical, in each case optionally substituted by morpholine or —NR 8 R 9 ,
where
R 5 and R 6 are independently of one another hydrogen or a C 1 -C 6 alkyl radical which may optionally be substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 or C 1 -C 3 -alkoxy, and
R 7 is a C 1 -C 4 alkyl radical, and
R 8 and R 9 are independently of one another hydrogen or a C 1 -C 4 alkyl radical,
R 11 and R 12 are independently of one another hydrogen or a C 1 -C 6 alkyl radical which may optionally be substituted one or more times, identically or differently, by morpholine or by —N(CH 3 ) 2 , —NH—CH 3 or —NH—C 2 H 5 ,
or a salt, enantiomer or and diastereomer thereof.
3. The compound of formula (I) with building blocks A, B, C and D according to claim 1 ,
in which
Q 1 is a pyrazolyl or thienyl ring,
or a salt, enantiomer or diastereomer thereof.
4. The compound of the general formula (I) with building blocks A, B, C and D according to claim 1 , in which
R 1 and R 2 are independently of one another
(i) hydrogen, or
(ii) a C 1 -C 6 -alkyl radical,
or a salt, enantiomer or diastereomer thereof.
5. The compound of formula (I) with building blocks A, B, C and D according to claim 1 ,
in which
Q 2 is a phenyl or pyrazolyl ring,
or a salt, enantiomer and diastereomer thereof.
6. The compound of formula (I) with building blocks A, B, C and D according to claim 1 ,
in which
R 3 and R 4 are independently of one another hydrogen or C 1 -C 6 -alkyl, or a salt, enantiomer or diastereomer thereof.
7. The compound of formula (I) according to claim 1 with building blocks A, B, C and D
in which
the building blocks B and D are in ortho position relative to one another, and
Q 1 is a pyrazolyl or thienyl ring,
R 1 and R 2 are independently of one another
(i) hydrogen
(ii) a C 1 -C 6 -alkyl radical
Q 2 is a phenyl or pyrazolyl ring,
R 3 and R 4 are independently of one another hydrogen or C 1 -C 6 -alkyl,
or a salt, enantiomer or diastereomer thereof.
8. The compound according to claim 1 , which is
2-(1H-pyrazol-4-yl)thiazole-4-(3-carbamoyl-1-methyl)-1H-pyrazol-4-yl)carboxamide),
N-[2-(aminocarbonyl)phenyl]-2-(5-methyl-3-thienyl)-4-thiazolecarboxamide, or
N-[2-(aminocarbonyl)-5-methylphenyl]-2-(1H-pyrazol-4-yl)-thiazole-4-carboxamide.
9. A process for preparing a compound according to claim 1 , comprising
a) reacting 2-bromothiazole-4-carboxylic acid with an intermediate of formula (II) with an amide coupling reagent
and
b) reaction of the intermediates of the formula (III) with boronic acids or boronic acid pinacol esters in a Suzuki-Miyaura reaction to give compounds of the formula (I)
where
Q 1 , Q 2 , R 1 , R 2 , R 3 and R 4 have the meanings indicated in formula (I) according to claim 1 .
10. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.