US 7,030,145 B2Granted

Pyridinyl derivatives for the treatment of depression

AssigneeBristol-Myers Squibb Company

InventorsRichard A. Hartz, Argyrios G. Arvanitis

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Abstract

The present invention relates to novel heterocyclic antagonists of Formula (I) and pharmaceutical compositions comprising said antagonists of the corticotropin releasing factor receptor (“CRF receptor”) useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor.

Claims11

Dependent claims

A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof,
wherein
B is CH;
D is NH;
R1 is selected from the group consisting of H, —CN, C1-4 alkyl, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy and N(C1-4 alkyl)2 optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1-4 haloalkyl and C1-4 alkoxy;
R2 is selected from the group consisting of H, halo, —CN, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, —NR4R6, —C1-6alkylNR4R6, —C1-6alkylOR6, CO2R6, O2CR6, COR6, CON4R6, NR4CO2R6, NR4SO2R6, NR4COR6, OCONR4R6 and NR4CONR5R6;
optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1–4 haloalkyl, C1–4 alkoxy, CO2C1–4 alkyl or phenyl;
R3 is selected from the group consisting of H, halo, —CN, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, —NR4R6, —C1-6alkylNR4R6, —C1-6alkylOR6, CO2R6, O2CR6, COR6, CON4R6, NR4CO2R6, NR4SO2R6, and NR4COR6;
optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1-4 haloalkyl, C1-4 alkoxy, CO2C1-4 alkyl, or phenyl;
Ar is selected from the group consisting of phenyl, indanyl, and indenyl, independently and optionally substituted with 1 to 4 substituents selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy-C1-4 alkyl, —OR4, halo, C1-4 haloalkyl, —CN, —NO2, SH, —S(O)2R5, —COR4, —CO2R4, —OC(O)R5, —N(COR4)2, —NR4R7 and —CONR4R7, —NR4COR5, NR4SO2R5, NR4CONR5R7, and NR4CO2R5;
R4, R5 and R7 are independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C3-6 alkyl, C1-2 alkoxy-C1-4 alkyl and C1-4 haloalkyl;
and
R6 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, phenyl and C1-6 alkyl-phenyl.

10 more elements

{3-[4-(2-Methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(4-methoxy-2-methylphenyl)-amine;

(2-Chloro-5-fluoro-4-methoxyphenyl)-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-amine;
2-Chloro-5-fluoro-N1-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-N4,N4-dimethylbenzene-1,4-diamine;
(4,5-Dimethoxy-2-methylphenyl)-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-amine;
(2-Chloro-4-difluoromethoxyphenyl)-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-amine;
(2-Chloro-4,5-dimethoxyphenyl)-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-amine;
(2-Chloro-4-methanesulfonylphenyl)-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-amine;
5-Chloro-2-{3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-ylamino}-benzonitrile;
[3-(4-Methoxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenol;
[3-(4-Benzyloxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Ethoxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Allyloxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
4-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxy}-butyronitrile;
5-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxy}-pentanenitrile;
3-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxy}-propan-1-ol;
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxy}-acetic acid ethyl ester;
2-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxy}-butyric acid methyl ester;
{6-Methyl-3-[4-(pyridin-2-ylmethoxy)-benzenesulfonyl]-pyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2,6-Dichloropyridin-4-ylmethoxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{6-Methyl-3-[4-(2-methylthiazol-4-ylmethoxy)-benzenesulfonyl]-pyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
4-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxymethyl}-benzonitrile;
3-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxymethyl}-benzonitrile;
3-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxymethyl}-benzoic acid methyl ester;
{3-[4-(3-Methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2-Methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
2-{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxymethyl}-benzonitrile;
{6-Methyl-3-[4-(2-nitrobenzyloxy)-benzenesulfonyl]-pyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(3,5-Dimethoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2,5-Dimethoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2,3-Dimethoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2,3-Difluorobenzyloxy)-benzenesulfonyl]-6-methyl-pyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[4-(2-Fluoro-6-nitrobenzyloxy)-benzenesulfonyl]-6-methyl-pyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
1-(4-Fluoro-3-{4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenoxymethyl}-phenyl)-ethanone;
{3-[4-(2,6-Dimethylbenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
[3-(3-Chloro-4-fluorobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(3,4-Dimethylbenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(3,4-Dimethoxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(3,4-Dichlorobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[6-Methyl-3-(toluene-4-sulfonyl)-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Isopropylbenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[6-Methyl-3-(4-trifluoromethoxybenzenesulfonyl)-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Fluorobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Bromobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(4-Ethynylbenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(Biphenyl-4-sulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(2′-Methoxybiphenyl-4-sulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-methanol;
(6-Methyl-3-{4-[(2,4,6-trimethylphenylamino)-methyl]-benzenesulfonyl}-pyridin-2-yl)-(2,4,6-trimethylphenyl)-amine;
4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-benzaldehyde;
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanol;
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanone;
Acetic acid 4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-benzyl ester;
[3-(3-Methoxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
3-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenol;
[3-(3-Ethoxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(3-Allyloxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
[3-(3-Benzyloxybenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;
{3-[3-(4-Fluorobenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[3-(3-Methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[3-(3,5-Dimethoxybenzyloxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[3-(6-Chloropyridin-3-ylmethoxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
{3-[3-(2,6-Dichloropyridin-4-ylmethoxy)-benzenesulfonyl]-6-methylpyridin-2-yl}-(2,4,6-trimethylphenyl)-amine;
(2,4-Dimethylphenyl)-[3-(4-ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-amine;
[3-(4-Ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-(4-methoxy-2-methylphenyl)-amine;
(2,4-Dimethoxyphenyl)-[3-(4-ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-amine;
(2-Chloro-4-methoxyphenyl)-[3-(4-ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-amine;
or
[3-(4-Ethylbenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,5-trimethylphenyl)-amine or pharmaceutically acceptable salts or solvates thereof.

67 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof,
wherein
B is CH;
D is NH;
R1 is selected from the group consisting of H, —CN, C1-4 alkyl, C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy and N(C1-4 alkyl)2 optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1-4 haloalkyl and C1-4 alkoxy;
R2 is selected from the group consisting of H, halo, —CN, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, —NR4R6, —C1-6alkylNR4R6, —C1-6alkylOR6, CO2R6, O2CR6, COR6, CON4R6, NR4CO2R6, NR4SO2R6, NR4COR6, OCONR4R6 and NR4CONR5R6;
optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1–4 haloalkyl, C1–4 alkoxy, CO2C1–4 alkyl or phenyl;
R3 is selected from the group consisting of H, halo, —CN, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, —NR4R6, —C1-6alkylNR4R6, —C1-6alkylOR6, CO2R6, O2CR6, COR6, CON4R6, NR4CO2R6, NR4SO2R6, and NR4COR6;
optionally and independently substituted with 1 to 3 substituents selected from the group consisting of —CN, hydroxy, halo, C1-4 haloalkyl, C1-4 alkoxy, CO2C1-4 alkyl, or phenyl;
Ar is selected from the group consisting of phenyl, indanyl, and indenyl, independently and optionally substituted with 1 to 4 substituents selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy-C1-4 alkyl, —OR4, halo, C1-4 haloalkyl, —CN, —NO2, SH, —S(O)2R5, —COR4, —CO2R4, —OC(O)R5, —N(COR4)2, —NR4R7 and —CONR4R7, —NR4COR5, NR4SO2R5, NR4CONR5R7, and NR4CO2R5;
R4, R5 and R7 are independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C3-6 alkyl, C1-2 alkoxy-C1-4 alkyl and C1-4 haloalkyl;
and
R6 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, phenyl and C1-6 alkyl-phenyl.

10 more elements