Glutamate receptor antagonists Number:7,151,098 from the United States Patent and Trademark Office (PTO) owispatent The present invention is a compound of formula ##STR00001## wherein X is an ethynediyl group, R.sup.1, R.sup.2 and R.sup.3 are as defined in the specification.<H antagonists, Glutamate, Glutamate, recep, 7151098.html, Patent, pto, 7151098

Title: Glutamate receptor antagonists

Abstract: The present invention is a compound of formula ##STR00001## wherein X is an ethynediyl group, R.sup.1, R.sup.2 and R.sup.3 are as defined in the specification.

Patent Number: 7,151,098 Issued on 12/19/2006 to Adam, et al.

Inventors: Adam; Geo (Schopfheim, DE), Alanine; Alexander (Schlierbach, FR), Goetschi; Erwin (Reinach, CH), Mutel; Vincent (Pringy, FR), Woltering; Thomas Johannes (Grenzach-Wyhlen, DE)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)

Appl. No.: 11/363,351

Filed: February 27, 2006

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
11146693	Jun., 2005	7018998
10300449	Nov., 2005	6960578
09687241	Jan., 2003	6509328

Foreign Application Priority Data


Oct 15, 1999 [EP]			99120519

Current U.S. Class: 514/221 ; 540/517

Current International Class: C07D 243/12 (20060101); A61K 31/55 (20060101); C07D 413/10 (20060101); C07D 417/04 (20060101)

Field of Search: 540/517 514/221

References Cited [Referenced By]

U.S. Patent Documents


5716953	February 1998	Donati et al.
6051712	April 2000	Binggeli et al.
6407094	June 2002	Adam et al.
6544985	April 2003	Adam et al.
6548495	April 2003	Adam et al.
6949542	September 2005	Adam et al.

Foreign Patent Documents


0487155	May., 1992	EP
60-32775	Feb., 1985	JP
62174062	Jul., 1987	JP
4-283572	Oct., 1992	JP
WO 92/03438	Mar., 1992	WO
WO 94/03437	Feb., 1994	WO
WO 96/05818	Feb., 1996	WO
WO 97/05109	Feb., 1997	WO
WO 99/26927	Jun., 1999	WO
WO 01/29011	Apr., 2001	WO
WO 01/29012	Apr., 2001	WO

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Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Johnston; George W. Rocha-Tramaloni; Patricia S. Prior; Kimberly J.

Parent Case Text

PRIORITY TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 11/146,693, filed Jun. 7, 2005, now U.S. Pat. No. 7,018,998, which is a division of U.S. application Ser. No. 10/300,449, filed Nov. 20, 2002, which is now U.S. Pat. No. 6,960,578, issued: Nov. 1, 2005, which is a division of U.S. application Ser. No. 09/687,241, filed Oct. 13, 2000, which is now U.S. Pat. No. 6,509,328, issued: Jan. 21, 2003, which claims the benefit of European Application No. 99120519.6 filed Oct. 15, 1999.

Claims

The invention claimed is:

1. A compound of formula I ##STR00012## wherein X is a single bond; R.sup.1 is phenyl substituted by halogen; and R.sup.3 is selected from the group consisting of unsubstituted phenyl, unsubstituted pyridine, unsubstituted thiophenyl and unsubstituted thiazolyl, or substituted phenyl, substituted pyridine, substituted thiophenyl and substituted thiazolyl, said substituted phenyl, said substituted pyridine, said substituted thiophenyl or said substituted thiazoyl being substituted by a substitutent selected from the group consisting of halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1, wherein R.sup.1 is phenyl substituted by chlorine.

3. A compound of claim 1, wherein R.sup.1 is phenyl substituted by fluorine.

4. The compound of claim 3, wherein R.sup.1 is 2-fluorophenyl.

5. The compound of claim 3, wherein R.sup.1 is 4-fluorophenyl.

6. The compound of claim 3, wherein R.sup.1 is selected from the group consisting of 2,3-difluorophenyl, 2,4-difluorophenyl, and 2,5-difluorophenyl.

7. The compound of claim 1, wherein R.sup.3 is phenyl substituted by halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl.

8. The compound of claim 7, wherein R.sup.3 is phenyl substituted by halogen, cyano, nitro, hydroxy, carboxy, carbamoyl, thiocarbamoyl, or N-hydroxycarbamoyl.

9. The compound of claim 7, wherein R.sup.3 is phenyl substituted by an unsubstituted or substituted 5-membered aromatic heterocycle wherein the 5-membered aromatic heterocycle is selected from the group consisting of imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, and isoxazolyl.

10. A compound of claim 1, wherein R.sup.3 is pyridine substituted by halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl.

11. A compound of claim 10, wherein R.sup.3 is pyridine substituted by cyano or carboxy.

12. A compound of claim 10, wherein R.sup.3 is pyridine substituted by an unsubstituted or substituted 5-membered aromatic heterocycle wherein the 5-membered aromatic heterocycle is thiazolyl or imidazolyl.

13. A compound of claim 1, wherein R.sup.3 is thiophenyl substituted by halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alklylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl.

14. A compound of claim 13, wherein R.sup.3 is thiophenyl substituted by halogen and cyano.

15. A compound of claim 1, wherein R.sup.3 is thiazolyl substituted by halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl.

16. A compound of claim 15, wherein R.sup.3 is thiazole substituted by an unsubstituted or substituted 5-membered aromatic heterocycle wherein the 5-membered aromatic heterocycle is imidazolyl.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I ##STR00013## wherein X is a single bond; R.sup.1 is phenyl substituted by halogen; and R.sup.3 is selected from the group consisting of unsubstituted phenyl, unsubstituted pyridine, unsubstituted thiophenyl and unsubstituted thiazolyl, or substituted phenyl, substituted pyridine, substituted thiophenyl and substituted thiazolyl, said substituted phenyl, said substituted pyridine, said substituted thiophenyl or said substituted thiazoyl being substituted by a substitutent selected from the group consisting of halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl substituted by a substitutent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidated carboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-membered aromatic heterocycle substituted by a substituent selected from the group consisting of amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy, carboxy esterified with lower alkyl, carboxy amidated with lower alkylamino which is eventually substituted by hydroxy, lower alkyl, lower alkyl substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, acylamino, amidino and amidino substituted by a substituent selected from the group consisting of lower alkyl, --C(NRR').dbd.NR'' wherein R, R' and R'' are hydrogen or lower alkyl, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino, lower alkoximino which is esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl; and with the proviso that when X is a single bond and R.sup.3 is pyridinyl, R.sup.1 is not hydrogen or methyl, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

18. A compound selected from the group consisting of 3-[7-(4-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(3,4-Dichloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(2-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2,3-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(4-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-be- nzo[b][1,4]diazepin-2-one; 4-(3-Amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 8-(2-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-acetamide; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-methanesulfonamide; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo- [b][1,4]diazepin-2-one; 8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 2-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 8-(4-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(2-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 4-(3-Chloro-thiophen-2-yl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 3-[7-(2-Fluoro-6-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazep- in-2-yl]-benzonitrile; 8-(2-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2- -yl]-pyridine-2-carbonitrile; 4-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbonitrile; 3-[7-(3-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(3-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,4]triazol-4-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 5-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-2-carbonitrile; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(2-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-- 1,3-dihydro-benzo[b][1,4]diazepin-2-one; 4-Fluoro-3-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepi- n-2-yl]-benzonitrile; 4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-pyridine-2-carbonitrile; 8-(2-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydrobenzo[b][- 1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 3-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 8-(4-Fluoro-phenyl)-4-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 3-[7-(2,5-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 8-(2,5-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbothioic acid amide; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 2-{4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-pyridin-2-yl}-thiazole-4-carboxylic acid ethyl ester; 8-(4-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[2-(4-hydroxymethyl-thiazol-2-yl)-pyridin-4-yl]-1,3- -dihydro-benzo[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid (2-hydroxy-ethyl)-amide; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzoic acid; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carboxylic acid; 8-(4-Fluoro-phenyl)-4-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,- 3-dihydro-benzo[b][1,4]diazepin-2-one; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N- -hydroxy-benzamidine; 8-(4-Fluoro-phenyl)-4-{3-[5-(3-hydroxy-propyl)-[1,2,4]oxadiazol-3-yl]-phe- nyl}-1,3-dihydro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepi- n-2-one; and 4-(3-Chloro-2,4-dihydroxy-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b- ][1,4]diazepin-2-one.

19. A compound of claim 18 selected from the group consisting of 3-[7-(4-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(3,4-Dichloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(2-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2,3-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2-Fluoro-6-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazep- in-2-yl]-benzonitrile; 3-[7-(3-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; and 3-[7-(2,5-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile.

20. A compound of claim 18 selected from the group consisting of 8-(4-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo- [b][1,4]diazepin-2-one; 8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(3-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(2-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-- 1,3-dihydro-benzo[b][1,4]diazepin-2-one; and 8-(2,4-Difluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro- -benzo[b][1,4]diazepin-2-one.

21. A compound of claim 18 selected from the group consisting of 8-(4-Fluoro-phenyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,4]triazol-4-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydrobenzo[b][- 1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2,5-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; AND 4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,- 3-dihydro-benzo[b][1,4]diazepin-2-one.

22. A compound of claim 18 selected from the group consisting of 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbonitrile; 4-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbonitrile; 4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-pyridine-2-carbonitrile; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbothioic acid amide; 2-{4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-pyridin-2-yl}-thiazole-4-carboxylic acid ethyl ester; 8-(4-Fluoro-phenyl)-4-[2-(4-hydroxymethyl-thiazol-2-yl)-pyridin-4-yl]-1,3- -dihydro-benzo[b][1,4]diazepin-2-one; and 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carboxylic acid.

23. A compound of claim 18 selected from the group consisting of 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 8-(4-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid (2-hydroxy-ethyl)-amide; and 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide.

24. A compound of claim 18 selected from the group consisting of 8-(2-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-{3-[5-(3-hydroxy-propyl)-[1,2,4]oxadiazol-3-yl]-phe- nyl}-1,3-dihydro-benzo[b][1,4]diazepin-2-one; and 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one.

25. A compound of claim 18 selected from the group consisting of 8-(4-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 4-(3-Amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]dia- zepin-2-one; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-acetamide; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-methanesulfonamide; 8-(2-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 4-Fluoro-3-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]d- iazepin-2-yl]-benzonitrile; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzoic acid; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N- -hydroxy-benzamidine; 8-(4-Fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepi- n-2-one; and 4-(3-Chloro-2,4-dihydroxy-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydrobenzo[b]- [1,4]diazepin-2-one.

26. A compound of claim 18 selected from the group consisting of 2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 2-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 8-(4-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 4-(3-Chloro-thiophen-2-yl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; and 5-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-2-carbonitrile.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisisting of 3-[7-(4-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(3,4-Dichloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(2-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 3-[7-(2,3-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(4-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-be- nzo[b][1,4]diazepin-2-one; 4-(3-Amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 8-(2-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-acetamide; N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-methanesulfonamide; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo- [b][1,4]diazepin-2-one; 8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 2-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 8-(4-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(2-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 4-(3-Chloro-thiophen-2-yl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 3-[7-(2-Fluoro-6-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazep- in-2-yl]-benzonitrile; 8-(2-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-- 2-one; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2- -yl]-pyridine-2-carbonitrile; 4-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbonitrile; 3-[7-(3-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzonitrile; 8-(3-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]d- iazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,4]triazol-4-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 5-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-2-carbonitrile; 4-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(2-fluoro-phenyl)-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-- 1,3-dihydro-benzo[b][1,4]diazepin-2-one; 4-Fluoro-3-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepi- n-2-yl]-benzonitrile; 4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-pyridine-2-carbonitrile; 8-(2-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydrobenzo[b][- 1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 3-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 8-(4-Fluoro-phenyl)-4-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro- -benzo[b][1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 3-[7-(2,5-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-benzonitrile; 8-(2,5-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-t- hiobenzamide; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carbothioic acid amide; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid ethyl ester; 2-{4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-pyridin-2-yl}-thiazole-4-carboxylic acid ethyl ester; 8-(4-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[2-(4-hydroxymethyl-thiazol-2-yl)-pyridin-4-yl]-1,3- -dihydro-benzo[b][1,4]diazepin-2-one; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid (2-hydroxy-ethyl)-amide; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-b- enzoic acid; 4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-p- yridine-2-carboxylic acid; 8-(4-Fluoro-phenyl)-4-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,- 3-dihydro-benzo[b][1,4]diazepin-2-one; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N- -hydroxy-benzamidine; 8-(4-Fluoro-phenyl)-4-{3-[5-(3-hydroxy-propyl)-[1,2,4]oxadiazol-3-yl]-phe- nyl}-1,3-dihydro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1,3-dih- ydro-benzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepi- n-2-one; and 4-(3-Chloro-2,4-dihydroxy-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b- ][1,4]diazepin-2-one; and a pharmaceutically acceptable carrier.

Description

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.

L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.

At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be subdivided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the general formula I:

##STR00002##

These compounds have been discovered to act as metabotropic glutamate receptor antagonists and accordingly are useful for the treatment of a range of neurological disorders, including psychosis, schizophrenia, Alzheimer's and other cognitive and memory disorders.

Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on one or more compounds in accordance with the invention and their production, as well as the use of the compounds in accordance with the invention in the control or prevention of neurological disorders, and, respectively, for the production of corresponding medicaments.

DETAILED DESCRIPTION

The present invention relates to compounds of formula I

##STR00003## wherein X is a single bond or an ethynediyl group, wherein, in case X is a single bond, in case X is an ethynediyl group,

R.sup.1 is hydrogen; lower alkyl, optionally substituted with hydroxy; halo-lower alkyl; lower cycloalkyl, optionally substituted with hydroxy, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or halogen; lower cycloalkenyl, optionally substituted with lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, halogen, or oxo; lower alkenyl; phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy, halo; 5 or 6 membered heterocyclic ring, optionally substituted with lower alkyl, halogen, oxo, benzyloxy, benzoyl, methanesulfonyl, benzenesulfonyl, acetyl, pivaloyl, tert. butoxycarbonyl, or tert. butylcarbonyl; or benzofuranyl;

R.sup.3 is phenyl; pyridine; thiophenyl or thiazolyl, which are optionally substituted with halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilyl-ethynyl, or from lower alkyl, lower alkynyl, lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, lower alkylaminocarbonyl, which are optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated; or a 5-membered aromatic heterocycle which is optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, carboxy which is optionally esterified with lower alkyl or amidated with lower alkylamino which is eventually substituted by hydroxy, or lower alkyl which is optionally substituted by halogen, hydroxy, amino, lower alkylamino, acylamino, or amidino, which is optionally substituted by lower alkyl, --C(NRR').dbd.NR'' (where R, R' and R'' are hydrogen or lower alkyl), hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, or lower alkoxyimino, which is optionally esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, or sulfamoyl which is optionally substituted by lower alkyl,

with the proviso that, if X is a single bond and R.sup.3 is pyridinyl, R.sup.1 is not hydrogen, or methyl;

and their pharmaceutically acceptable acid addition salts.

It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.

The compounds of the present invention can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.

Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on one or more compounds in accordance with the invention and their production, as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.

Preferred compounds of formula I are those in which R.sup.3 is phenyl substituted in meta position by cyano; halogen; or imidazolyl, which is optionally substituted by lower alkyl; or 1,3-thiazolyl which is optionally substituted by hydroxy-lower alkyl, carboxy, or --CO--NH--(CH.sub.2).sub.2OH; 1,3-oxazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl which is optionally substituted with lower alkyl; tetrazolyl; or isoxazolyl, which is optionally substituted by lower alkyl;

The following are examples of such compounds: 3-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzo- nitrile; 4-(3-Chloro-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diaz- epin-2-one; 4-(3-Imidazol-1-yl-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diaze- pin-2-one; 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazep- in-2-yl]-benzonitrile; 8-(4-Fluoro-phenylethynyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b- ][1,4]diazepin-2-one; 8-(4-Fluoro-phenylethynyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-b- enzo[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo- [b][1,4]diazepin-2-one; 8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(4-Fluoro-phenylethynyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b- ][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b]- [1,4]diazepin-2-one; 8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-ben- zo[b][1,4]diazepin-2-one; 8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benz- o[b][1,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihyd- ro-benzo[b][1,4]diazepin-2-one; 2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-thiazole-4-carboxylic acid; 2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl- ]-phenyl}-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; and 4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,- 3-dihydro-benzo[b][1,4]diazepin-2-one;

Compounds of formula I, in which R.sup.3 is thiophenyl, preferably tiophen-2-yl, optionally substituted with halogen, cyano; or pyridinyl, preferably pyridin-4-yl, optionally substituted, preferably in the 2-position, with halogen, or cyano; are also preferred.

The following are examples of such compounds: 8-(4-Fluoro-phenylethynyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-b- enzo[b][1,4]diazepin-2-one; 2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-t- hiophene-3-carbonitrile; 4-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyrid- ine-2-carbonitrile; and 4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-y- l]-pyridine-2-carbonitrile.

All tautomeric forms of the compounds of invention are also embraced herewith.

The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 7 carbon atoms, preferably with 1 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.

The term "lower alkynyl" used in the present description denotes straight-chain or branched unsaturated hydrocarbon residues with 2 7 carbon atoms, preferably with 2 4 carbon atoms, such as ethynyl, n-propynyl, and the like.

The term "lower cycloalkyl" used in the present description denotes cyclic saturated hydrocarbon residues with 3 5 carbon atoms, preferably with 3 carbon atoms, such as cyclopropyl.

The term "lower alkoxy" denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.

The term "halogen" embraces fluorine, chlorine, bromine and iodine.

The expression "5 or 6 membered heterocyclic ring" embraces thiophene, furane, thiazole, pyridine, partially hydrated pyridine, for example 2-pyridone, partially hydrogenated prydine, for example tetrahydropyridine, five-membered aromatic heterocycle containing up to 4 heteroatoms, selected from O, S, N, embracing imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl; 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl; 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl; 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-2-yl; 1,2,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl; 1,2,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl; tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl;

The compounds of formula I and their pharmaceutically acceptable salts can be manufactured according to the following methods:

##STR00004##

Compounds of formula I, in which R.sup.1, R.sup.3 and X are as described above can be prepared according to scheme A, by, for example, cleaving the BOC protecting group in compounds of formula II, and concomitant cyclization of the deprotected compound. The deprotection-cyclization step can be carried out by treating the compounds of formula II with a bronsted acid, like for example trifluoroacetic acid (TFA), in an inert solvent, like for example dichloromethane (DCM). The reaction is preferably carried out at temperatures between 0.degree. C. and 50.degree. C. It may be advantageous to use also anisole or 1,3-dimethoxybenzene as a carbocation scavenger in the reaction mixture. Any other suitable amino protecting group, such as e.g. Fmoc or benzyloxycarbonyl (Z), can be alternatively used instead of the BOC group.

##STR00005##

Compounds of formula II, in which R.sup.1, R.sup.3 and X are as described above, can be prepared according to scheme B by for example reacting a compound of formula III with a dioxinone (formula IV) in an inert solvent like for example toluene or xylene at elevated temperatures, preferably between 80.degree. C. and 160.degree. C.

Alternatively, compounds of formula II can also be prepared by for example reaction of a compound of formula III with a .beta.-ketoester (formula IVa), in which R.sup.3 is as described above using the same conditions as described for the reaction with the dioxinones.

##STR00006##

According to scheme C, compounds of formula III in which R.sup.1 is as described above for compounds where X is a single bond can be prepared by different routes from the iodo-compound IX, depending on the nature of R.sup.1. As shown in scheme C, the key steps are coupling reactions of Suzuki- and Stille-type in presence or absence of carbonmonoxide. The exact conditions for the respective compounds can be found in the experimental part.

##STR00007##

According to scheme D, the key intermediate iodide IX can be prepared from commercially available 2-nitroaniline by a standard iodination-protection sequence.

##STR00008##

According to scheme E, compounds of formula IIIa in which R.sup.1 is as described above for compounds where X is an ethynediyl group can be prepared by different routes from the iodo-compound IX, depending on the nature of R.sup.1. As shown in Scheme E, the transformation can for example be carried out by directly attaching the R.sup.1-alkynediyl-substituent via a Sonogashira-type coupling followed by the reduction of the nitro group or

b) by two stepwise Sonogashira-type couplings, in which first trimethylsilyl-acetylene is coupled to iodide IX to yield, after deprotection with sodium hydroxide in methanol, the intermediate XII which then can be transformed via a second Sonogashira-type coupling with the appropriate reactant R.sup.1--I, R.sup.1--Br or R.sup.1--OSO.sub.2CF.sub.3 and reduction of the nitro group to the desired compounds.

The exact conditions for the respective compounds can be found in the experimental part.

##STR00009##

According to Scheme F, the dioxinones and .beta.-keto esters building blocks with the formula IV and IVa can be prepared by methods known to someone skilled in the art from the corresponding carboxylic acid derivatives R.sup.3--COR, i.e. free acids, methyl or ethyl esters and acid chlorides. The exact conditions for the corresponding compounds can be found in the experimental part.

Another synthetic route to prepare compounds of formula Ic, in which R.sup.1 and X have the meaning as described above and R.sup.3 is a phenyl-carboxamide of formula C(O)NR.sup.4R.sup.5, in which R.sup.4 and R.sup.5 are hydrogen, lower alkyl or R.sup.4 and R.sup.5 together form a morpholino-residue or a N-methyl-piperazine is outlined in scheme G:

##STR00010##

The exact conditions for the respective compounds can be found in the experimental part.

Still another way to prepare compounds of formula I is the reaction of 4-aryl-8-iodo-1,3-dihydro-benzo[b][1,4]diazepin-2-ones (Formula Id, Synthetic Scheme H) with alkynes of formula R.sup.1--C.ident.C--, in which R.sup.1 has the meaning as described above, in a Sonogashira-coupling.

##STR00011##

The exact conditions for the respective compounds can be found in the experimental part.

The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.

The compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are acute and chronic pain, Huntington's chorea, ALS,