US 2013/0210809 A1 · NOVEL 2-AMINO-4-PYRAZOLYL-THIAZOLE DERIVATIVES AND THEIR USE AS ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS

Abstract

The present invention relates to novel compounds of Formula (1), wherein M, A and B are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors-subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

A compound having the Formula (I) wherein:

A radical is selected from the group of hydrogen, halogen, —CN, —CF3 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C3-C7)cycloalkyl, —(C1-C6)cyanoalkyl, —(C1-C6)alkylene-heteroaryl, —(C1-C6)alkylene-heterocycle, —(C1-C6)alkylene-aryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR1, —O—(C2-C6)alkylene-OR1, —NR1(C2-C6)allylene-OR2, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR1—(C3-C7)cycloalkyl-(C1-C6)alkyl, —(C1-C6)haloalkylene-OR1, —(C1-C6)haloalkylene-NR1R2, —(C0-C6)alkyl-S—R1, —O—(C2-C6)alkylene-S—R1, —NR1—(C2-C6)alkylene-S—R2, —(C0-C6)alkyl-S(═O)—R1, —O—(C1-C6)alkylene-S(═O)—R1, —NR1—(C1-C6)alkylene-S(═O)—R2, —(C0-C6)alkyl-S(═O)2—R1, —O—(C1-C6)alkylene-S(═O)2—R1, —NR1—(C1-C6)alkylene-S(═O)2—R2, —(C0-C6)alkyl-NR1R2, —O—(C2-C6)alkylene-NR1R2, —NR1—(C2-C6)alkylene-NR2R3, —(C0-C6)alkyl-S(═O)2NR1R2, —O—(C1-C6)alkylene-S(═O)2NR1R2, —NR1—(C1-C6)alkylene-S(═O)2NR2R3, —(C0-C6)alkyl-NR1—S(═O)2R2, —O—(C2-C6)allylene-NR1—S(═O)2R2, —NR1—(C2-C6)alkylene-NR2—S(═O)2R3, —(C0-C6)alkyl-C(═O)—NR1R2, —O—(C1-C6)alkylene-C(═O)—NR1R2, —NR1—(C1-C6)alkylene-C(═O)—NR2R3, —(C0-C6)alkyl-NR1C(═O)—R2, —O—(C2-C6)alkylene-NR1C(═O)—R2, —NR1—(C2-C6)alkylene-NR2C(═O)—R3, —(C0-C6)alkyl-C(═O)—R1, —O—(C1-C6)alkylene-C(═O)—R1 and —NR1—(C1-C6)alkylene-C(═O)—R2;
R1, R2 and R3 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)haloalkyl, —(C1-C6)alkyl, —(C1-C6)cyanoalkyl, —(C3-C7)cycloalkyl, —(C4-C10)alkylene-cycloalkyl, heteroaryl, —(C1-C6)alkylene-heteroaryl, aryl, heterocycle, —(C1-C6)alkylene-heterocycle and —(C1-C6)alkylene-aryl;
Any two radicals of R(R1, R2 or R3) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
B radical is selected from the group of hydrogen, halogen, —CN, —OH, —CF3, —SH, —NH2 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C3-C7)cycloalkyl, —(C1-C6)cyanoalkyl, —(C1-C6)alkylene-heteroaryl, —(C1-C6)allylene-heterocycle, —(C1-C6)alkylene-aryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR4, —O—(C2-C6)alkylene-OR4, —NR4(C2-C6)alkylene-OR5, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR4—(C3-C7)cycloalkyl-(C1-C6)allyl, —(C1-C6)haloalkylene-OR4, —(C1-C6)haloalkylene-NR4R5, —(C0-C6)alkyl-S—R4, —O—(C2-C6)alkylene-S—R4, —NR4—(C2-C6)alkylene-S—R5, —(C0-C6)alkyl-S(═O)—R4, —O—(C1-C6)alkylene-S(═O)—R4, —NR4—(C1-C6)alkylene-S(═O)—R5, —(C0-C6)alkyl-S(═O)2—R4, —O—(C1-C6)alkylene-S(═O)2—R4, —NR4—(C1-C6)alkylene-S(═O)2—R5, —(C0-C6)alkyl-NR4R5, —O—(C2-C6)alkylene-NR4R5, —NR4—(C2-C6)alkylene-NR5R6, —(C0-C6)alkyl-S(═O)2NR4R5, —O—(C1-C6)alkylene-S(═O)2NR4R5, —NR4—(C1-C6)alkylene-S(═O)2NR5R6, —(C0-C6)alkyl-NR4—S(═O)2R5, —O—(C2-C6)alkylene-NR4—S(═O)2R5, —NR4—(C2-C6)alkylene-NR5—S(═O)2R6, —(C0-C6)alkyl-C(═O)—NR4R5, —O—(C1-C6)alkylene-C(═O)—NR4R5, —NR4—(C1-C6)alkylene-C(═O)—NR5R6, —(C0-C6)alkyl-NR4C(O)R5, —O—(C2-C6)alkylene-NR4C(═O)—R5, —NR4—(C2-C6)alkylene-NR5C(═O)—R6, —(C0-C6)alkyl-C(═O)—R4, —O—(C1-C6)alkylene-C(═O)—R4 and —NR4—(C1-C6)alkylene-C(═O)—R5;
R4, R5 and R6 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)haloalkyl, —(C1-C6)alkyl, —(C1-C6)cyanoallyl, —(C3-C7)cycloalkyl, —(C4-C10)alkylene-cycloalkyl, heteroaryl, —(C1-C6)alkylene-heteroaryl, —(C1-C6)alkylene-heterocycle, aryl, heterocycle and —(C1-C6)alkylene-aryl;
Any two radicals of R (R4, R5 or R6) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
M is an optionally substituted heteroaryl;
provided that according to proviso (i) the compound is not:
4-(3-Methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(Pyridin-2-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-2-amine
4-(3-Isopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Methyl-4-(3-methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Methyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Methyl-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Methyl-N-(4-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(3,5-Difluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(3-Methyl-1H-pyrazol-4-yl)-N-(4-methylpyridin-2-yl)thiazol-2-amine
5-Ethyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(3-Methyl-1H-pyrazol-4-yl)-N-(6-methylpyridin-2-yl)thiazol-2-amine
N-(5-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(6-Chloropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Chloro-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(6-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Methyl-N-(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(3-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-carbonitrile
N-(6-Ethylpyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(6-Chloropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(6-Fluoropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Chloro-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(6-Methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-5-(trifluoromethyl)thiazol-2-amine
5-Phenyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Fluoro-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
(4-(1H-Pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-yl)methanol
N-(6-Methoxypyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine and
4-(3-Ethyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine;
provided that according to proviso (ii) the compound is not:
6-(5-Methyl-4-(1H-pyrazol-4-yl)thiazol-2-ylamino)picolinonitrile
5-Morpholino-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
2-(5-Methyl-4-(1H-pyrazol-4-yl)thiazol-2-ylamino)nicotinonitrile
5-(Piperidin-1-yl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(3-(Furan-2-yl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(3-Isobutyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-5-(pyrrolidin-1-yl)thiazol-2-amine
5-Fluoro-N-(6-fluoropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Fluoro-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N5,N5-Dimethyl-4-(1H-pyrazol-4-yl)-N2-(pyridin-2-yl)thiazole-2,5-diamine
N-(6-Chloropyridin-2-yl)-5-fluoro-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(6-Iodopyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(3-Iodopyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Methyl-4-(1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
4-(5-Chloro-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-(Methoxymethyl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(4-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-((Diethylamino)methyl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-(Morpholinomethyl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-(Ethoxymethyl)-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(3-Fluoro-6-methylpyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(5-Methoxypyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Fluoro-N-(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(2-(Pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-5-carbonitrile
N-(1-Methyl-1H-pyrazol-3-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Fluoro-N-(5-fluoropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(Pyridin-2-yl)-4-(3-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Methyl-N-(5-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(3-Fluoro-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(3-Phenyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Methyl-4-(1H-pyrazol-4-yl)-N-(pyrimidin-4-yl)thiazol-2-amine
4-(3-(Phenylsulfonyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
4-(3-(Methoxymethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
N-(2-Methylthiazol-4-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(thiazol-2-yl)thiazol-2-amine
N-(6-(Fluoromethyl)pyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(6-(Difluoromethyl)pyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
5-Chloro-4-(1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
N-(4-Ethylpyrimidin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(5-Fluoropyrimidin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(5-(Dimethylamino)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
5-Chloro-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(pyrimidin-2-yl)-5-(trifluoromethyl)thiazol-2-amine N-(4-Isopropylpyrimidin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(4-Methoxypyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
1-(4-(2-(4-Methylpyrimidin-2-ylamino)thiazol-4-yl)-1H-pyrazol-5-yl)ethanone
N-(5-Fluoropyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(5-(Dimethylamino)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(3-(piperidin-1-yl)-1H-pyrazol-4-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)thiazol-2-amine
4-(1H-Pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(3-morpholino-1H-pyrazol-4-yl)thiazol-2-amine
N-(4-Cyclopropylpyrimidin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(5-(Diethylamino)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine
4-(5-(Dimethylamino)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
Cyclopropyl(4-(2-(pyrimidin-2-ylamino)thiazol-4-yl)-1H-pyrazol-5-yl)methanone
1-(4-(2-(Pyrimidin-2-ylamino)thiazol-4-yl)-1H-pyrazol-5-yl)ethanone
N5-(2-Methoxyethyl)-N5-methyl-4-(1H-pyrazol-4-yl)-N2-(pyrimidin-2-yl)thiazole-2,5-diamine
N-(5-Fluoro-4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
N-(5-Fluoro-4-methylpyrimidin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
4-(3-(Ethyl(methyl)amino)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
4-(3-(Methylamino)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
4-(5-(4-Fluorophenyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
4-(5-(Methoxymethyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
5-Cyclobutyl-4-(1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
N-(Pyrimidin-2-yl)-4-(3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)thiazol-2-amine
4-(3-((2-Methoxyethyl)(methyl)amino)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)thiazol-2-amine
N-(4-Methylpyrimidin-2-yl)-4-(3-phenyl-1H-pyrazol-4-yl)thiazol-2-amine
(4-(2-(4-Methylpyrimidin-2-ylamino)thiazol-4-yl)-1H-pyrazol-3-yl)methanol
4-(3-(Methoxymethyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine
4-(3-(Ethylamino)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine and
4-(3-(2-Methoxyethyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine.

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Novel 2-amino-4-pyrazolyl-thiazole derivatives and their use as allosteric modulators of metabotropic glutamate receptors

Life of this patent

Novel 2-amino-4-pyrazolyl-thiazole derivatives and their use as allosteric modulators of metabotropic glutamate receptors

Life of this patent

Abstract

Claims35