US 2007/0185095 A1 · Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists

Abstract

The present invention is directed to compounds of formula: (I); wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, R1, R2, R3, R4, and n are as defined for formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds for treating gastrointestinal disorders.

A compound of formula I:

wherein
X1, X2, X3, X4, and X5 are independently selected from the group consisting of C, CR5, N, O, and S, wherein at least one of X1, X2, X3, X4, and X5 is not N;
X6 is selected from the group consisting of a bond and CR5R6;
X7 is CR5 or N;
X8 is selected from the group consisting of a bond, CR1R6, NR5, O, S, SO, and SO2;
X9 is CR5 or N;
X10 is selected from the group consisting of a bond, CR5R6, (CR5R6)2, O, S, and NR5;
R1 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR1R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S, wherein said ring may be substituted by one or more A;
R2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR1(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR1R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR1R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S, wherein said ring may be substituted by one or more A;
R3 is a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S, wherein said ring may be substituted by one or more A;
R4 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, CO0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S, wherein said ring may be substituted by one or more A;
R5 and R6 are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl and aryl;
A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R5, OC2-6alkylNR5R8, C1-6alkyl(CO)NR5R8, OC1-6alkyl(CO)NR5R8, C0-6alkylNR5(CO)R8, OC2-6alkylNR5 (CO)R8, C0-6alkylNR5(CO)NR5R8, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R8, OC2-6alkyl(SO2)NR5R8, C0-6alkylNR5(SO2)R8, OC2-6alkylNR5(SO2)R8, C0-6alkylNR5(SO2)NR5R8, OC2-6alkylNR5(SO2)NR5R8, (CO)NR5R8, O(CO)NR5R8, NR5OR8, C0-6alkylNR5(CO)OR8, OC2-6alkylNR5(CO)OR8, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
n is 0, 1, 2, 3, or 4;
or
a pharmaceutically acceptable salt or hydrate thereof;
provided that:
a) when X2=X4=X5=N, and either of X8 or X10 is a bond, then X9 is not N,
b) when X7 is N at least two of X1, X2, X3, X4, and X5 are not N,
c) X1 and X3 are not O;
and provided that the compound is not:
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridine-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine,
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-thiophen-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridine-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine,
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridine-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3ylmethyl]-3-pyridine-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3-pyridine-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
3-Pyridin-4-yl-8-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
(−)-8-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl-methyl)[1,3,4]oxadiazol-2-yl]benzonitrile,
3-{5-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl][1,3,4]oxadiazol-2-yl}benzonitrile,
3-(5-{[3-(2-Methoxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile,
3-{3-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-5-yl}benzonitrile,
3-(3-{[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile,
3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-3yl}benzonitrile, and
3-{5-[3-(2-Hydroxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl][1,2,4]oxadiazol-3-yl}-benzonitrile.

37 more elements

Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists

Life of this patent

Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists

Life of this patent

Abstract

Claims38