MXPA06010711A

MXPA06010711A - Pharmaceutical composition comprising a benzodiazepine derivative and an inhibit or of the rsv fusion protein

Info

Publication number: MXPA06010711A
Application number: MXPA/A/2006/010711A
Authority: MX
Inventors: Powell Kenneth; Kelsey Richard; Carter Malcolm; Dowdell Verity; Henderson Elisa; Wilson Lara; Alber Dagmar; Chambers Phil; Taylor Debra; Tyms Stan
Original assignee: Arrow Therapeutics Limited
Priority date: 2004-03-19
Filing date: 2006-09-19
Publication date: 2007-04-20

Abstract

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and:(a) an inhibitor of the RSV fusion protein;and (b) a benzodiazepine derivative capable of inhibiting RSV replication is found to be highly active against RSV.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A DERIVATIVE OF BENZODIAZEPINE AND AN INHIBITOR OF THE PROTEIN OF RSV FUSION Description of the Invention The present invention relates to a series of anti-viral benzodiazepine derivatives. In particular, it relates to a series of benzodiazepine derivatives that interact with an inhibitor of the RSV fusion protein to provide an additive or synergistic therapeutic effect to treat or prevent an RSV infection. The Respiratory Syncytial Virus (RSV) is the main cause of respiratory disease in patients of all ages. In adults, it tends to cause moderate cold symptoms. In children of school age, it can cause a cold and bronchial cough. Babies and children who barely walk can cause bronchiolitis (inflammation of the smaller airways of the lungs) or pneumonia. It has also been found to be a frequent cause of middle ear infections (otitis media) in pre-school children. RSV infection in the first year of life has been implicated in the development of asthma during childhood. Current anti-RSV therapy involves the use of a monoclonal antibody for RSV, called paiivizumab. Said use of palivizumab is a prophylactic, rather than therapeutic, treatment of RSV. However, although this antibody is usually effective, it is expensive. Actually, its cost means that it is inaccessible to many people with the need for anti-RSV therapy. Therefore, there is an urgent need for effective alternatives to existing anti-RSV therapy. Small compounds that inhibit RSV replication by inhibiting the fusion (F) protein of RSV block the entry of the virus into the host cell and the exit of the host cell through exit without syncytial formation. Although these compounds have been shown to have high potency, RSV rapidly develops resistance to these compounds through mutations in the F protein (Morton, C. J. et al, 2003. Virology 311, 275-288). PCT / GB03 / 04050 filed September 20, 2003 describes a series of benzodiazepine derivatives that inhibit RSV replication. Serial passage experiments have indicated that resistance to these inhibitors is slow to develop and sequence resistant mutants that do not reveal any major changes in the F protein. Therefore, it can be assumed that these benzodiazepines have a common and novel mode of action , which does not involve the inhibition of protein F. It has now surprisingly been shown that a combination of (a) an RSV fusion protein inhibitor and (b) an anti-RSV benzodiazepine is highly active against RSV. Components (a) and (b) are found to have at least one additive effect. In addition, it is also a finding of the invention that the two components interact synergistically, to provide a combined effect that is greater than the sum of the effects of the individual components. The present invention, therefore, provides, in a first embodiment, a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluents and: (a) an inhibitor of the RSV fusion protein; and: (b) a benzodiazepine derivative capable of inhibiting RSV replication. It is a finding of the present invention that components (a) and (b) have at least one additive effect. The concepts of synergism and additive, of course, are well known in this pharmacology. In this way it is well established that a therapeutically useful additive combination is one in which the effect of the combination is greater than the greater effects produced by each of the components at the same concentrations as in the mixture. Thus, in the case of the present, a given formulation containing x% / weight of) component (a) e and% / weight of component (b) has an activity that is at least as large as the activity of a formulation containing, as the only active ingredient, either x% / weight of component (a) or and% / weight of component (b). In such additive combinations, the active ingredients typically operate through different physiological trajectories. In the case of the present, for example, it is believed that component (a) and component (b) are for inhibiting separate RSV proteins. An additive combination is therapeutically useful since it can achieve a therapeutically useful effect using lower concentrations of each active component. This allows the side effects of the medication to be minimized. In this manner, the additive combination can be formulated so that each active ingredient is present at a concentration that is sub-clinical in cells other than the diseased target cells. The additive combination however is therapeutically effective in target cells corresponding to both ingredients. As for component (a), an inhibitor of the RSV fusion protein can be identified through an assay comprising: (a) labeling RSV with octadecyl-rhodamine dye (R18); (b) pre-incubate the labeled virus with Hep-2 cells seeded in a 6-well plate at 1 hour at 4 ° C; (c) remove the unbound virus; (d) adding the candidate fusion protein inhibitor; (e) incubating the 6-well plates at 37 ° C for 1 hour; Y (f) determining any increase in fluorescence, typically using fluorescence microscopy. In the above test, any increase in fluorescence means a fusion event. In this way, if no increase in fluorescence is detected, 100% inhibition is achieved. If the increase in fluorescence is equal to that observed with a corresponding assay wherein a control of the growth medium and the solvent (for example, growth medium with 10% fetal bovine serum and DIVISO) is used in the step ( d) In place of the candidate fusion protein inhibitor, 0% inhibition is achieved. Accordingly, the percentage of inhibition obtained with the candidate fusion protein inhibitor can be determined by quantitative determination of the fluorescence in step (f). As used herein, component (a) is typically a compound that achieves at least 10%, typically -at least 30%, preferably at least 50%, and most preferably at least 75%, inhibition of pro 'RSV fusion theorem as determined by the previous assay. Typically, component (a) is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: - X is a direct bond or alkyl of 1 to 6 carbon atoms; the alkyl of 1 to 6 carbon atoms being optionally substituted by halogen, oxo, cyano, hydroxyl, OCOR4 or S (O) n-alkyl of 1 to 6 carbon atoms; - Y is R4, NR4R5, NCOR4, = N-OR4, -CONHR4, COOR4, -OR4, aryl, heteroaryl, cyclyl or heterocyclyl, wherein R4 and R5 are H or alkyl of 1 to 6 carbon atoms; - Z is CR6R \ wherein R6 and R7 are independently H, or straight chain, branched or cyclic alkyl of 1 to 6 carbon atoms; - n is 1-2; - R1 is CONR4R5, CO2R4 or alkyl of 1 to 6 carbon atoms, the alkyl of 1 to 6 carbon atoms may be optionally substituted with OR4 or NR8Rg; - R8 and R9 are each independently H, alkyl of 1 to 6 carbon atoms, SO2R5, CO2R or COR4; - R2 is selected from the group consisting of NH2, CONR6R \ heteroaryl, alkenyl of 2 to 6 carbon atoms, CO2R4, N = CPh2, C (= NH) NH2 and alkyl of 1 to 6 carbon atoms; said alkyl optionally may be substituted with a member selected from the group consisting of halogen, CN, NR10Rn, OSO2R4 and OR4; - R-io and R ?? are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, CO2R4, COR and SO2R4; - R3 is selected from the group consisting of (1) CO2Rg; (2) alkyl of 1 to 6 carbon atoms optionally substituted with CN, OR4 or NR6R7; and (3) alkenyl of 2 to 6 carbon atoms substituted with CN; - Q is a member selected from the group consisting of A is C or N, optionally substituted with H, halogen, alkyl of 1 to 6 carbon atoms, ayanyl of 2 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, CO2R4, aryl, benzoaminocarbonyl, hydroxybenzyl, SO2NR4R5 or cycloalkyl of 3 to 6 carbon atoms. Where A is a carbon, then it can also be optionally substituted by O or S through a double bond; B is C or N; wherein B is C then optionally substituted by H, alkyl of 1 to 6 carbon atoms, NO2, CN, halogen, COR4, COOR4, CONHR4C (= NH) NH2 or C (= NOH) NH2. Typically, at least two of R1, R2 and R3 are hydrogen, and the other is hydrogen or -C (NH) -NH2. Preferably, all R1, R2 and R3 are hydrogen. Typically, either -XY is H, or X is an alkylene group of 1 to 6 carbon atoms which is unsubstituted or substituted by a hydroxy group and Y is H, OH, CN, -NR'R ", -COR ', -SO2R' or phenyl, wherein R 'and R "are identical or different and represent an alkyl group of 1 to 4 carbon atoms. Typically, Z is -CH2-. Typically, Q is a portion wherein B is -CH- or -N-, Ai is -C (O) - or -NH- and A2 is -CH2-, -CHR'- or -NR "-, where R 'is a halogen atom and R "represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, -SO2- (alkyl of 1 to 6 carbon atoms), -SO2-N (alkyl of 1 to 6 carbon atoms) 2 or - (CO-NH) a- (alkyl of 1 to 4 carbon atoms) -phenyl, wherein a is 0 or 1, said group is unsubstituted or is substituted with a hydroxy or cyano substituent. Particularly preferred compounds of the invention are compounds of the formula (la) and their pharmaceutically acceptable salts: wherein - B, X and Y are as described in formula (I) above; D is cyclopropyl, ethyl, 4-cyanobutyl, isopropenyl, methylsulfonyl, dimethylsulphamoyl, benzyloaminocarbamoyl or para-hydroxybenzyl. Component (a) can also be a compound of the formula (II), or a pharmaceutically acceptable salt thereof, wherein: - L-, is -CH2- or -CHR2-CO- - each X is the same or different and is CH or N; - each R1 is the same or different and is alkyl of 1 to 6 carbon atoms, halogen, hydroxy, phenyl or (CH2) m = NH2; - n is 1 or 2; - R2 is alkoxy of 1 to 6 carbon atoms or alkoxy-phenyl of 1 to 6 carbon atoms; - R3 is alkyl of 1 to 6 carbon atoms; - L2 is -CH2- or -NH-; - Y is alkyl of 1 to 6 carbon atoms or alkenyl of 1 to 6 carbon atoms; - Z is H, N (R4) 2-, -C (= O) -R5 > -C (= CH2) -R5, -CH (OH) -R5, -CH (CH3) -R5, -CH (OCH3) -R5; - each R4 is the same or different and is H, alkyl of 1 to 6 carbon atoms. - R5 is alkylcarbonyl of 1 to 6 carbon atoms, amino, hydroxyl, aryl, heteroaryl, carbocyclyl, heterocyclyl; and - m = 1-6 To avoid any doubt, when L-i is -CHR2-CO-, the carbonium portion is attached to the phenyl or pyridine ring. Typically, L1 is -CH2-. Typically, L2 is -NH-. Typically, R 1 is methyl or hydroxy. Typically, n is 2. Typically, each R1 is different. Typically, Y is alkyl of 1 to 4 carbon atoms. Typically, Z is -NH2. Other preferred compounds of the formula (II) are the compounds of the formula where: X is C or N; R1 is alkyl of 1 to 6 carbon atoms, halogen, phenyl or (CH2) m = NH2; R 2 is alkoxy of 1 to 6 carbon atoms or alkoxy-phenyl of 1 to 6 carbon atoms; - R3 is alkyl of 1 to 6 carbon atoms; - Y is alkyl of 1 to 6 carbon atoms or alkenyl of 1 to 6 carbon atoms; - Z is H, NR 4, -C (= O) -R 5, -C (= CH 2) -R 5, -CH (OH) -R 5, -CH (CH 3) -R 5, -CH (OCH 3) -R 5; - R 4 is H, alkyl of 1 to 6 carbon atoms; R5 is alkylcarbonyl of 1 to 6 carbon atoms, amino, hydroxyl, aryl, heteroaryl, carbocyclyl, heterocyclyl; - m = 1-6 Component (a) can also be a compound of formula (III), or a pharmaceutically salt thereof, wherein - X is -N = C- or -CH = CH-; - R1 is H, hydroxyl, alkyl, halogen, nitro or alkoxy; said alkoxy being optionally monosubstituted with carboxy, amino, monoalkylamino, dialkylamino or acetoamino; - R2 is pyrazolyl, triazolyl or tetrazolyl and is optionally substituted by amino or alkyl.

Component (a) can also be a compound of the formula (IV), or a pharmaceutically acceptable salt thereof.

The compound of the formula (IV) is 4,4'-Bis- (4,6-bis-. {3- [bis- (2-carbamoyl-etiI) -sulfamoyl] -phenylamino} - [1] , 3,5] triazin-2-ylamino) -biphenyl-2,2'-disulfonic acid. Preferably, component (a) is: 1-Cyclopropii-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydroimidazo [4,5-c] pyridin-2 -one { 2- [2- (1,2-Dihydro-benzotriazol-1-ylmethyl) -benzoimidazol-1-yl]] ethyl} -diethylamine. { 2- [2- (3-lodo-2,3-dihydro-indazol-1-ylmethyl) -benzimidazol-1-yl] -ethyl} -dimethylamine 1-Isopropenil-3- [1- (3-methyl-bu ti l) -1H-benzo imidazo l-2-ylmet i I] -1,3-dihydro-benzoimidazol-2-one 1 - (4-H) id roxi-benzyl) -3- [1 - (3-methyl-butyl) -1H-benzoim idazo I-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1-lsopropenyl-3- [1- (3-oxo-butyl) -1 H -benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1-Ethyl-3- [1 - (2-h id roxy-2-f-enyl-ethyl ) - H- benzo imidazo l-2-ylmethyl] - 1,3-dihydro-benzoimidazol-2-one 1-Ethyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] 1,3-Dihydrobenzoimidazol-2-one 7- [2- (3-Isopropenyl-2-oxo-2,3-dihydrobenzoimidazol-1-ylmethyl) -benzoimidazol-1-yl] -heptan-nitrile 5-. { 3- [1- (3-Methanesulfonyl-propyl) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazol-1-yl} -pentan-nitrile benzyl amide of 3- [1- (3-Methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydrobenzoimidazole-1-carboxylic acid 1-methanesulfonyl-3- [1- (3-methyl-butyl) -1H-benzoimidazole-2-iimethyl] -1, 3- [1- (3-Methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dlhydro-benzoimidazole-1-sulfonic acid, 3-dihydro-benzoimidazol-2-one dimethylamide 1 -lsopropenyl-3- (1-propyl-1H-benzoimidazol-2-methylmethyl) -1,3-dihydro-imidazo [4,5-c] pyridin-2-one Bis (5-amidino-2-benzimidazolyl) - m etano 2-. { 2- [1- [1- (2-Amino-ethyl) -piperidin-4-ylamino] -4-methyl-benzoimidazol-1-ylmethyl} -6-methyl-pyridin-3-ol, or a pharmaceutically acceptable salt thereof. In a further embodiment, the composition contains a RSV fusion inhibitor, as described above, and a benzodiazepine that can be identified as having anti-RSV activity through the method of Example 8. Typically, component (b) is a compound of formula (V), or a pharmaceutically acceptable salt thereof, wherein: - R1 represents alkyl of 1 to 6 carbon atoms, aryl or heteroaryl; R 2 represents hydrogen or alkyl of 1 to 6 carbon atoms; each R3 is the same or different and represents halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, amino, mono- (alkyl of 1 to 6 carbon atoms) amino, d - (alkoxy of 1 to 6 carbon atoms) amino, nitro, cyano, -CO2R ', -CONR' R ", -NH-CO-R ', -S (O) R \ -S (O) 2R', -NH-S (O) 2R \ -S (O) NR'R" or -S (O) 2NR'R ", wherein each of R 'and R" is identical or different and represents hydrogen or alkyl of 1 to 6 carbon atoms; n is from 0 to 3; - R4 represents hydrogen or alkyl of 1 to 6 carbon atoms; - R 5 represents alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 atoms of carbon, heterocyclyl-alkyl of 1 to 6 carbon atoms aryl-C (O) -C (O) -, heteroaryl-C (O) -C (O) -, carbocyclyl-C (O) -C (O) -, heterocyclyl-C (O) -C (O) - or -XR6; X represents -CO-, -S (O) - or -S (O) 2-; and R6 represents alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 6 carbon atoms , heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl-alkyl of 1 to 6 carbon atoms, aryl-hydroxyalkyl of 1 to 6 carbon atoms, heteroaryl-hydroxyalkyl of 1 to 6 carbon atoms, carbocyclyl-hydroxyalkyl of 1 to 6 carbon atoms, heterocyclyl-hydroxyalkyl of 1 to 6 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms-O-, heteroaryl-alkyl of 1 to 6 atoms of carbon-O-, carbocyclyl-alkyl of 1 to 6 carbon atoms-O-, heterocyclyl-alkyl of 1 to 6 carbon atoms-O- or -NR'R "wherein each of R 'and R" is same or different and represents hydrogen, alkyl of 1 to 6 carbon atoms, carbocyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl of 1 to 6 carbon atoms no, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms or heterocyclyl-alkyl of 1 to 6 carbon atoms.

Typically, R 'and R "both are not hydrogen.As used herein, an alkyl group of 1 to 6 carbon atoms or portion is a group or linear or branched alkyl portion containing from 1 to 6 carbon atoms, such as a group or alkyl portion of 1 to 4 carbon atoms Examples of groups and alkyl portions of 1 to 4 carbon atoms include methyl, ethyl, n-propyl, / '-propyl, n-butyl, / -butyl and f- For the avoidance of doubt, when two alkyl portions are present in a group, the alkyl portions may be the same or different.As used herein, a hydroxyalkyl group is typically the alkyl group which is substituted by one or more hydroxy groups. is substituted by one, two or three hydroxy groups Preferably, it is substituted by a single hydroxy group The preferred alkyl hydroxy groups are (monohydroxy) ethyl groups As used herein, an acyl group is an acyl group of 2 to 7 carbon atoms, for example, a group -CO-R, wherein R is an alkyl group of 1 to 6 carbon atoms. As used herein, an aryl group is typically an aryl group of 6 to 10 carbon atoms such as phenyl or naphthyl. Phenyl is preferred. An aryl group can be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents. Suitable substituents on an aryl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono- (alkyl of 1 to 6 carbon atoms) carbamoyl, di (alkyl of 1 to 6 carbon atoms) carbamoyl, amino, mono (alkyl of 1 to 6 atoms) carbon) amino, di (to Iq of 1 to 6 carbon atoms) amino, -CO2R ', -CONR'R ", -S (O) R \ -S (O) 2R', -S (O ) NRV, -S (O) 2NR'R "-NH-S (O) 2R 'or -NH-CO-R', wherein each of R 'and R" is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms. Examples of suitable substituents on an aryl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl from 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 carbon atoms), carbamoyl, d (alkyl of 1 to 6 carbon atoms) carbamoyl, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (of 1 to 6 carbon atoms) amino, -C02R ', -CONR'R ", -S (O) R', -S (O) 2R \ -S (O) NR'R ", -NH-S (O) 2R 'or -NH-CO-R', wherein each of R 'and R" is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms Preferred substituents on an aryl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms , alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, nitro, cyano, -CO2R ', -S (O) R \ -S (O) 2R 'and -S (O) 2NR'R ", wherein each of R 'and R" is the same or different and represents hydrogen or alkyl of 1 to 4 carbon atoms. Examples of preferred substituents on an aryl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (aikyl of 1 to 6 carbon atoms) amino, nitro and cyano. Particularly preferred substituents include fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms , haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, amino, mono (alkyl of 1 to 4 carbon atoms) amino, di (of 1 to 4 carbon atoms) amino, nitro , -CO2R ', -S (O) 2R' and -S (O) 2NH2, wherein R 'represents alkyl of 1 to 2 carbon atoms. Examples of particularly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. As used herein, references to an aryl group include fused ring system wherein an aryl group is fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group or a fused group that is a monocyclic carbocyclyl, heterocyclyl or heteroaryl group, which is fused to a phenyl ring.

Typically, such fused ring systems are systems wherein an aryl group is fused to a carbocyclyl, heterocyclic or monocyclic heteroaryl group. Preferred ring systems are those in which an aryl group is fused to a fused group, which is a monocyclic heterocyclyl or heteroaryl group or a monocyclic carboxylic group fused to a phenyl ring, particularly those wherein an aryl group is fused to a heterocyclyl or heteroaryl group. Examples of such a fused ring system are groups in which a phenyl ring is fused to a thienyl group or even a tetrahydrofuranyl group to form a benzothienyl or dihydrobenzofuranyl group. Other examples of such fused rings are groups in which a phenyl ring is fused to a dioxanyl group, a pyrrolyl group or a 2,3-dihydroinden-1-one group to form a benzodioxinyl, indolyl or 9H-fluoren-9-one group . As used herein, a carbocyclyl group is a non-aromatic, saturated or unsaturated, monocyclic hydrocarbon ring, typically having from 3 to 6 carbon atoms. Preferably, it is a saturated hydrocarbon ring (ie, a cycloalkyl group) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably cyclopentyl or cyclohexyl. A cycloalkyl group can be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents.

Suitable substituents on a carbocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, "nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 carbon atoms) carbamoyl, di (to 1 to 6 carbon atoms) carbamoyl , amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (of 1 to 6 carbon atoms) amino, oxo, -CO2R ', -CONR'R ", -S (O) R" , -S (O) 2R ', -S (O) NR'R ", -S (O) 2NR'R", -NH-S (O) 2R' or -NH-CO-R ', wherein each one of R 'and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms. Examples of suitable substituents on a carbocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl from 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 carbon atoms) carbamoyl, di (alkanoyl of 1 to 6 carbon atoms) carbamoyl, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, -CO2R ', -CONR'R ", -S (O) R', -S ( O) 2R ', -S (O) NR'R ", -NH-S (O) 2R' or -NH-CO-R ', wherein each of R' and R" is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms Preferred substituents on a carbocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (to 1 to 6 carbon atoms) amino, nitro, cyano and oxo. Preferred substituent examples in a carbocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino , nitro and cyano. Particularly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro and oxo. Examples of particularly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. Other examples of particularly preferred substituents include fluorine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. As used herein, a heterocyclyl group is a saturated or unsaturated, non-aromatic carbocyclic ring, typically having from 5 to 10 carbon atoms, wherein one or more, for example 1, 2 or 3, of the carbon atoms it is replaced by a heterogeneous atom selected from N, O and S. Saturated heterocyclyl groups are preferred. Examples include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl and thioxanyl. Other examples include dithiolanyl, oxazolidinyl, tetrahydrothiopyranyl and dithianyl. Piperazinyl, piperidinyl and morpholinyl are preferred. As used herein, references to a heterocyclyl group include fused ring systems wherein a heterocyclyl group is fused to a phenyl group. Preferred fused ring systems are those in which a 5- to 6-membered heterocyclyl group is fused to a phenyl group. An example of such fused ring systems is a group wherein a 1H-imidazole-2 (3H) -onyl group or an imidazolidin-2-onyl group is fused to a phenyl ring to form a 1-H-benzo group [cf. imidazole-2 (3H) -onyl. Very preferably, however, a heterocyclyl group is monocyclic. A heterocyclic group may be unsubstituted or substituted at any position. Typically, it carries 0, 1 or 2 substituents. Suitable substituents on a heterocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 carbon atoms) carbamoyl, di (alkanoyl of 1 to 6 carbon atoms) carbomil, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, oxo, -CO2R \ -CONR'R ", -S (O) R \ -S (O ) 2R ', -S (O) NR'R ", -S (O) 2NR'R", -NH- S (O) 2R 'or -NH-CO-R', wherein each of R 'and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms Examples of suitable substituents on a heterocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 carbon atoms) carbamoyl , di (alk i i of 1 to 6 carbon atoms) carbomil, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, -CO2R ', -CONR'R ", -S (O) R ', -S (O) 2R \ -S (O) NR'R", -NH-S (O) 2R' or -NH-CO-R ', in where each of R 'and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms. Preferred substituents on a heterocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, nitro, cyano and oxo. Examples of preferred substituents in a heterocyclyl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) amino, nitro and cyano. Particularly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, iron and oxo. Examples of particularly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. Other examples of particularly preferred substituents include fluorine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. Most preferably, a heterocyclyl group is unsubstituted or substituted by one or two alkyl groups of 1 to 2 carbon atoms. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine. Preferably it is chlorine, fluorine or bromine. Most preferably it is chlorine or fluorine. As used herein, an alkoxy group is typically an alkyl group attached to an oxygen atom. An alkyllithium group is typically the alkyl group attached to a thio group. A haloalkyl or haloalkoxy group is typically an alkyl or alkoxy group substituted by one or more halogen atoms. Typically, it is substituted by 1, 2 or 3 halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX3 and -OCX3 wherein X is a halogen atom, eg, chlorine or fluorine. Particularly haloalkyl groups are -CF3 and -CCI3. haloalkoxy groups in particular are -OCF3 and -OCCI3. As used herein, a heteroaryl group is typically a 5- to 10-membered aromatic ring, such as a 5- or 6-membered ring, containing at least one heterogeneous atom, for example 1, 2 or 3 heterogeneous atoms, selected of O, S and N.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrroyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. Other examples include oxazolyl and isothiazolyl. Preferred heteroaryl groups are pyridyl, thienyl, oxazolyl, isoxazolyl, furanyl and pyrazolyl. Examples of preferred heteroaryl groups are pyridyl, thienyl, isoxazolyl and furanyl. As used herein, references to heteroaryl groups include fused ring systems wherein a heteroaryl group is fused to a phenyl group. Preferred fused ring systems are those wherein a 5-6 membered heteroaryl group is fused to a phenyl group. Examples of such fused ring systems are benzofuranyl moieties, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, quinazolinyl and isoquinolinyl. Most preferably, however, a heterocyclyl group is monocyclic. A heteroaryl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents. Suitable substituents on a heteroaryl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (C1-C6 alkyl) carbamoyl, di (C1 to C6 alkoxy) carbamoyl, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (to Iq or 1 to 6 carbon atoms) amino, -CO2R ', -CONR'R ", -S (O ) R ', -S (O) 2R', -S (O) NR'R ", -S (O) 2NR'R ", -NH- S (O) 2R 'or -NH-CO-R', wherein each of R 'and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms Examples of suitable substituents on a heteroaryl group include halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono (alkyl of 1 to 6 atoms carbon) carbamoyl, di (to C 1 to 6 carbon atoms) carbamoyl, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (of 1 to 6 carbon atoms) amino , -CO2R ', -CONR'R ", -S (O) R \ -S (O) 2R \ -S (O) NR'R", -NH-S (O) 2R' or -NH-CO- R ', wherein each of R' and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms. Preferred substituents on a heteroaryl group include halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (C 1-6 -alkyl) amino, di (C 1-6 -alkyl) amino, nitro and cyano. Substituents particularly include fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. Other preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms and d i (alkoxy of 1 to 2 carbon atoms) amino. As used herein, references to a heteroaryl group include fused ring systems wherein one heteroaryl is fused to an aryl, carbocyclyl or monocyclic heterocyclyl group, or to another heteroaryl group. Preferred ring systems are those in which a heteroaryl group is fused to an aryl group, for example a phenyl group. An example of such a fused ring system which is a group in which a thienyl group is fused to a phenyl ring to form a benzothienyl ring. A further example wherein said fused ring system is a group wherein a furanyl group is fused to a phenyl ring to form a benzofuranyl group. When R in the formula (V) is an aryl or heteroaryl group, it is typically unsubstituted or substituted by one, two or three substituents selected from halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms or haloalkoxy of 1 to 6 carbon atoms. Preferably, it is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms or haloalkoxy of 1 to 4 carbon atoms. Most preferably, it is unsubstituted or substituted by a single one of fluorine, chlorine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms. carbon or haloalkoxy of 1 to 2 carbon atoms. Typically, R 1 in the formula (V) is an alkyl or aryl of 1 to 6 carbon atoms. Preferably, R1 is alkyl of 1 to 2 carbon atoms or aryl. Most preferably, R1 is alkyl or phenyl of 1 to 2 carbon atoms. Preferably, R1 is phenyl. Typically, R2 in formula (V) is hydrogen or alkyl of 1 to 4 carbon atoms. Preferably, R2 is hydrogen. Typically, R3 in the formula (V) is halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, amino, mono (alkyl of 1 to 4 carbon atoms) amino odi (to Iq uilo of 1 to 4 carbon atoms) amino. Preferably, R3 is fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, amino, mono (alkyl of 1 to 2 carbon atoms) amino odi (alkyl of 1 to 2 carbon atoms) amino. Most preferably, R3 is methyl, trifluoromethyl, fluorine, chlorine or bromine. Preferably, R3 is methyl or chloro. An example of a highly preferred group is when R3 is chlorine. Typically, n in formula (V) is 0, 1 or 2. Preferably, n is 0 or 1. Typically, R 4 in formula (V) is hydrogen or alkyl of 1 to 4 carbon atoms. Preferably, R 4 is hydrogen or alkyl of 1 to 2 carbon atoms. Most preferably, R 4 is hydrogen or methyl. Preferably, R 4 is hydrogen. When R5 in the formula (V) is a heterocyclyl group, it is typically linked through a carbon atom. Typically, R 5 is alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl alkyl of 1 to 4 carbon atoms, heteroaryl alkyl of 1 to 4 carbon atoms, carbocyclyl alkyl of 1 to 4 carbon atoms , heterocyclyl alkyl of 1 to 4 carbon atoms, aryl C (O) -C (O) -, heteroaryl-C (O) -C (O) - or -XR6. Examples of typical R5 groups are those in which R5 is alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl alkyl of 1 to 4 carbon atoms, heteroaryl alkyl of 1 to 4 carbon atoms, carbocyclyl alkyl from 1 to 4 carbon atoms, heterocyclyl alkyl of 1 to 4 carbon atoms or -XR6. Preferably, R 5 in the formula (V) is alkyl of 1 to 4 carbon atoms, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperidinyl, mofolinyl and piperazinium, phenyl alkyl of 1 to 2 carbon atoms, for example benzyl, heteroaryl alkyl of 1 to 2 carbon atoms, phenyl-C (O) -C (O) -, heteroaryl-C (O) -C (O) - or -XR6. Examples of preferred R5 groups are those in which R5 is alkyl of 1 to 4 carbon atoms, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperidinyl, mofolinyl and piperazinyl, phenyl alkyl of 1 to 2 carbon atoms, for example benzyl, heteroaryl alkyl of 1 to 2 carbon atoms or -XR6. Most preferably, R 5 in the formula (V) is alkyl of 1 to 4 carbon atoms, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH 2 -, furanyl-CH 2 -, phenyl- C (O) -C (O) -, thienyl-C (O) -C (O) - or -XR6. Examples of highly preferred groups R5 are those in which R5 is alkyl of 1 to 4 carbon atoms, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH2-, furanyl-CH2- or - XR6. Most preferably, R5 in the formula (V) is phenyl-CH2-, furani-CH2-, -C (O) -C (O) -thienyl or -XR6. Examples of highly preferred R5 groups are those in which R5 is phenyl-CH2-, furanyl-CH2- or -XR6. Typically, X in formula (V) is -CO-, -S (O) - or -S (O) 2-. Preferably, X is -CO- or -S (O) 2-, When R6 in the formula (V) is a group -NR'R "and either R 'or R "includes an aryl, heteroaryl, carbocyclyl or heterocyclyl moiety, typically unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro and cyano Preferably, the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon and nitro atoms An example of preferred substitution is when the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, lcoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro. Most preferably, the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms and nitro. A most preferred example of substitution is when the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by a single fluorine, chlorine, methyl, methoxy or nitro substituent. When R 'or R "is a heteroaryl or heterocyclyl group, it is attached through a carbon atom Typically, R' and R" in the group -NR'R "in the formula (V) both are not hydrogen. Typically, each of R 'and R "is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, aryl, heteroaryl, carbocyclyl, aryl alkyl of 1 to 4 carbon atoms or heteroaryl alkyl of 1 to 4 atoms of carbon. Examples of typical groups R 'and R "are those in which each of R' and R" is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, heteroaryl, for example thienyl, carbocyclyl, for example cyclohexyl or cyclopentyl, or phenyl, alkyl of 1 to 4 carbon atoms. Other examples of typical groups R 'and R "are those in which each of R' and R" is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl- ( CH2) -. Preferably, each of R 'and R "is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, phenyl-CH2-, cyclohexyl or cyclopentyl, most preferably one of R' and R" represents hydrogen. Preferably, one of R 'and R "is hydrogen and the other is alkyl of 1 to 4 carbon atoms, phenyl, phenyl-CH2-, cyclohexyl or cyclopentyl .. As a further preference, one of R' and R" is hydrogen and the other is alkyl of 1 to 4 carbon atoms, phenyl, thienyl or phenyl-CH2-. Typically, R6 in the formula (V) is alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl 1 to 4 carbon atoms, heteroaryl alkyl of 1 to 4 carbon atoms, carbocyclyl alkyl of 1 to 4 carbon atoms, heterocyclyl alkyl of 1 to 4 carbon atoms, aryl hydroxyalkyl of 1 to 4 carbon atoms, heteroaryl hydroxyalkyl of 1 to 4 carbon atoms, carbocyclyl hydroxyalkyl of 1 to 4 carbon atoms, heterocyclyl hydroxyalkyl of 1 to 4 carbon atoms, aryl alkyl of 1 to 4 carbon atoms-O- , heteroaryl alkyl of 1 to 4 carbon atoms) -O-, carbococlyl alkyl of 1 to 4 carbon atoms-O-, heterocyclyl alkyl of 1 to 4 carbon atoms-O- or -NR'R "where R ' and R "are as defined above. Examples of typical R6 groups are those in which R6 is alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl alkyl from 1 to 4 carbon atoms, heteroaryl alkyl of 1 to 4 carbon atoms, carbocyclyl alkyl of 1 to 4 carbon atoms, heterocyclyl alkyl of 1 to 4 carbon atoms or -NR'R "where R 'and R" they are as defined above. Preferably, R6 in the formula (V) is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, for example phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl and indolyl, heteroaryl, for example thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuranyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperazinyl, piperidinyl, mofolinyl and 1 -benzo [cf] imidazol-2 (3 / - /) - onyl, phenyl, alkyl of 1 to 2 carbon atoms, phenyl, alkyl of 1 to 2 carbon atoms-O-, phenyl hydroxyalkyl of 1 to 2 carbon atoms carbon, heteroaryl hydroxyalkyl of 1 to 2 carbon atoms, heteroaryl alkyl of 1 to 2 carbon atoms or -NR'R "wherein R 'and R" are as defined above. Examples of preferred R6 groups are those in which R6 is alkyl of 1 to 4 carbon atoms, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example N-heterocyclyl, phenyl, alkyl of 1 to 2 carbon atoms, for example benzyl, heteroaryl alkyl of 1 to 2 carbon atoms or -NR'R "wherein R 'and R" are as defined above. Most preferably, R6 in the formula (V) is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, thienyl, furanyl , oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl, alkyl of 1 to 2 carbon atoms, phenyl-CH2-CH (OH) -, phenyl-CH (OH) - CH2-, alkyl phenyl of 1 to 2 carbon atoms-O-, 1 H ~ benzo [c /] imidazole-2 (3H) -onyl or -NR'R "wherein R 'and R" are as defined above . Examples of highly preferred groups R6 are those in which R6 is alkyl of 1 to 4 carbon atoms, phenyl, thienyl, furanyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, isoxazolyl, piperidinyl, for example N-piperidinyl, morpholinyl, example N-morphounil, piperazinium, for example N-piperazinyl, or -NR'R "wherein R 'and R" are as defined above. Preferred compounds of the formula (V) are those wherein: R 1 is alkyl of 1 to 6 carbon atoms or aryl; - R2 is hydrogen or alkyl of 1 to 4 carbon atoms; - R3 is halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms carbon, amino, mono-alkyl amino of 1 to 4 carbon atoms or di-alkyl amino of 1 to 4 carbon atoms or, preferably, R 3 is fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, amino, mono-alkyl amino of 1 to 2 carbon atoms or di-alkyl amino of 1 to 2 carbon atoms; - n is 0, 1 or 2; - R4 is hydrogen or alkyl of 1 to 4 carbon atoms; - R5 is alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, carbocyclyl-alkyl of 1 to 4 carbon atoms, heterocyclyl alkyl of 1 to 4 carbon atoms, aryl-C (O) -C (O) -, heteroaryl-C (O) -C (O) - or -XR6; - X is -CO-, -S (O) - or -S (O) 2-; and - R6 is alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, arylalkyl of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, carbocyclyl-alkyl of 1 to 4 carbon atoms, heterocyclyl-alkyl of 1 to 4 carbon atoms, aryl-hydroxyalkyl of 1 to 4 carbon atoms, heteroaryl-hydroxyalkyl of 1 to 4 carbon atoms, carbocyclyl-hydroxyalkyl of 1 to 4 carbon atoms, heterocyclyl-hydroxyalkyl of 1 to 4 carbon atoms-, aryl-alkyl of 1 to 4 carbon atoms-O-, heteroaryl-alkyl of 1 to 4 atoms of carbon-O-, carbocyclyl-alkyl of 1 to 4 carbon atoms-O-, heterocyclyl-alkyl of 1 to 4 carbon atoms- O- or -NR'R ", wherein each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, aryl, heteroaryl, carbocyclyl, aryl-alkyl of 1 to 4 carbon atoms- or heteroaryl 1- alkyl of 1 to 4 carbon atoms, the aryl portion in the group R1 is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms or haloalkoxy of 1 to 6 carbon atoms; the aryl and heteroaryl moieties in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono-alkyl carbamoyl of 1 to 6 carbon atoms , di-alkyl carbamoyl of 1 to 6 carbon atoms, amino, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, -CO2R ', -CONR'R ", -S (O) R \ -S (O) 2R', -S (O) NR 'R', -S (O) 2NR'R ', -NH-S (O) 2R' or -NH-CO-R ', wherein each of R' and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms; the carbocyclyl and heterocyclyl moieties in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro, cyano, carbamoyl, mono-alkyl carbamoyl of 1 to 6 carbon atoms , di-alkyl carbamoyl of 1 to 6 carbon atoms, amino, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, oxo, -CO2R \ -CONR'R ", -S (O) R ', -S (O) 2R', -S (O) NR'R ", -S (O) 2NR'R", -NH- S (O) 2R 'or -NH-CO -R ', wherein each of R' and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms; and alkyl portions in the aryl-alkyl groups of 1 to 4 carbon atoms, heteroaryl-alkyi of 1 to 4 carbon atoms, carbocyclyl-alkyl of 1 to 4 carbon atoms, heterocyclyl-alkyl of 1 to 4 carbon atoms of R6 are unsubstituted or substituted by one or two hydroxy substituents. Preferably, in these preferred compounds of the formula (V), the aryl, heteroaryl and carbocyclyl moieties in the R 'and R "groups are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl from 1 to 6. carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, nitro and cyano Other preferred compounds of the formula (V) are those in which: R 1 is alkyl of 1 to 2 carbon atoms or phenyl, R 2 is hydrogen or alkyl of 1 to 4 carbon atoms, R 3 is methyl, trifluoromethyl, fluorine, chlorine or bromine; n is 0 or 1, - R 4 is hydrogen or alkyl of 1 to 2 carbon atoms, R 5 is alkyl of 1 to 4 carbon atoms, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, Example piperidinyl, morpholinyl and piperazinyl, phenyl-alkyl of 1 to 2 carbon atoms, for example benzyl, heteroaryl-alkyl of 1 to 2 carbon atoms, phenyl-C (O) -C (O) -, heteroaryl-C (O) -C (O) - or -XR6, provided that when R5 is heterocyclyl, it is attached through a carbon atom; - X is -CO-, -S (O) - or -S (O) 2-; and - R6 is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, for example phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl and indolyl, heteroaryl, for example thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuranyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperazinyl, piperidinyl, morpholinyl and 1 H-benzofofimidazole-2 (3H) -onyl, phenyl-alkyl of 1 to 2 carbon atoms, phenylalkyl of 1 to 2 carbon atoms-O-, phenyl-hydroxyalkyl of 1 to 2 carbon atoms, heteroaryl-hydroxyalkyl of 1 to 2 carbon atoms, heteroaryl- alkyl of 1 to 2 carbon atoms or -NR'R "wherein each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, heteroaryl, for example thienyl, carbocyclyl, for example cyclohexyl or cyclopentyl, or phenyl-alkyl of 1 to 4 carbon atoms, the phenyl portion in group R1 is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms or haloalkoxy of 1 to 4 carbon atoms; the aryl portions in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, acyl of 2 to 7 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio from 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, amino, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, nitro , cyano, -CO2R ', -S (O) R', - S (O) 2R 'and -S (O) 2NR'R ", wherein each of R' and R" is the same or different and represents hydrogen or alkyl of 1 to 4 carbon atoms; the heteroaryl moieties in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, nitro and cyano; and the carbocyclyl and heterocyclyl moieties in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, nitro, cyano and oxo; and the alkyl portion in the phenyl-alkyl groups of 1 to 2 carbon atoms and heteroaryl-alkyl of 1 to 2 carbon atoms of R6 are unsubstituted or substituted by a single hydroxy substituent. Preferably in these further preferred compounds of the formula (V), the phenyl, heteroaryl and carbocyclyl moieties in the R 'and R "groups are unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, alkyl of 1 at 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms and nitro. Formula (V) are compounds of the formula (Va) and their pharmaceutically acceptable salts, wherein: - R1 is phenyl or methyl; - R3 is methyl or chloro; - n is 0 or 1; R 4 is hydrogen or methyl; R5 is phenyl-CH2-, furanyl-CH2-, thienyl-C (O) -C (O) - or -XR6.

- X is -CO- or -S (O) 2-; and - R6 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl-alkyl of 1 to 2 carbon atoms, phenyl-CH2-CH (OH) -, phenyl-CH (OH) -CH.2-, phenyl -alkyl of 1 to 2 carbon atoms-O-, 1 H-benzo [c midazoi-2 (3H) -onyl or -NR'R "wherein each of R 'and R" are the same or different and represent hydrogen , alkyl of 1 to 4 carbon atoms, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl- (CH2) -, the phenyl portion in the group R1 is unsubstituted or substituted by a single substituent fluorine, chlorine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms or haloalkoxy of 1 to 2 carbon atoms; the Amino portions in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, hydroxy , alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, amine, mono-alkyl amino of 1 to 4 carbon atoms , di-alkyl amino of 1 to 4 carbon atoms, nitro, -CO2R \ -S (O) 2R 'and -S (O) 2 NH2, where R' represents alkyl of 1 to 2 carbon atoms; the heteroaryl moieties in the groups R5 and R6 are unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms and di-alkyl amino of 1 to 2 carbon atoms; and the heterocyclyl and carbocyclyl moieties in the R6 group are unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro.

Preferably, R1 in the formula (Va) is phenyl, n is 0, R4 is hydrogen and R5 is -CO-phenyl or -CO-NH-phenyl, wherein the phenyl group in R5 is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms, -CO2R 'or -S (O) 2R', wherein each R 'is the same or different and represents alkyl of 1 to 2 carbon atoms. The compounds of formulas (I), (II), (III) or (V) which contain one or more chiral centers can be used in an enantiomeric or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the chemical structures illustrated herein are intended to encompass all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and enantiomers and / or diastereoisomers.

The preferred compounds of the formula (V) are optically active isomers. Thus, for example, the preferred compounds of the formula (V) containing only one chiral center include an R-enantiomer in substantially pure form, an S-enantiomer in substantially pure form and enantiomeric mixtures containing an excess of the R-enantiomer or an Excess of the S-enantiomer. For the avoidance of doubt, the compounds of the formula (V) may, if desired, be used in the form of solvates. As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. The pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acids, and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic. Acceptable pharmaceutical bases include alkali metal hydroxides (for example sodium or potassium) and alkaline earth metal (for example calcium or magnesium) and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. Most preferably, component (b) is: N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 1, 1-D-ethyl-3- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] d-yzepin-3-yl) -urea; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -butyramide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -isobutyramide; 2,2-Dimethyl-N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaze? In-3-yl) -propionamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of cyclopentanecarboxylic acid; 2-oxo-5-phenyl-2,3-ihydro-1 H -benzo [e] [1,4] diazepin-3-yl) cyclohexanecarboxylic acid; 3- Metoxy N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 4- Metoxy N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [4] diazepin-3-yl) -benzamide; 2-Methoxy N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-trifluoromethyl-benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-amide of thiophene-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of furan-2-carboxylic acid; (2-oxo-5-f in i 1-2, 3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of piperidine-1-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of morpholine-4-carboxylic acid; 4-Nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-N itro-N- (2-oxo-5-f eni I-2, 3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 4-Methyl-piperazine-1-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; 3,4-Dichloro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-trifluoromethylbenzamide; 4-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2- eti l-N- (2-oxo-5-f eni l-2, 3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Chloro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-4-nitro-N- (2-oxo-5-f eni I-2, 3-d i hydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Methoxy-4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide (2 Benzo [b] thiophene-3-carboxylic acid-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] di azepin-3-yl) -amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amidoxazole-5-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amino benzo [b] thiophene-2-carboxylic acid amide; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of thiophene-3-carboxylic acid; N- (2-Oxo-5-f eni I-2, 3-dihydro-1H-benzo [e] [1,4] diazep i n-3-ll) -isonicotinamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -methanesulfonamide; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of propane-1-sulfonic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of butan-1-sulfonic acid; 2-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 3-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 4-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 2-FI uoro-N- (2-oxo-5-f eni I-2, 3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 3- (2-Nitro-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (3-Nitro-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (4-N -itro-benzylamino) -5-phen-1, 3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (2-Methoxy-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (3-Methoxy-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (2-trifluoromethyl-benzylamino) -1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (3-trifluoromethyl-benzylamino) -1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (4-trifluoromethyl-benzylamino) -1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3 - [(Furan-2-ylmethyl) -amino] -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -isobutyramide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -methane sulfone mid a; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of furan-2-carboxylic acid; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of thiophen-2-carboxylic acid; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of cyclohexanecarboxylic acid; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -2-methoxy-benzamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -4-methoxy-benzamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -2-nitro-benzamide; 2- (2-Methoxy-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (3-Methoxy-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (4-Methoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (4-Nitro-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (3-Nitro-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2- (2-trifluoromethyl-phenyl) -acetamide; N- (2-Oxo-5-phenyI-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2- (3-trifluoromethyl-phenyl) -acetamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2- (4-trifluoromethyl-phenyl) -acetamide; 1- (2-Methoxy-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Nitro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Chloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Chloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-p-tolyl-urea; 1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; (S) -1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 4-Methanesulfonyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -4-Methanesulfonyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] di azepin-3-yl) -benzamide; 5-Acetyl-2-ethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -5-Acetyl-2-ethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of 6-fluoro-4H-benzo [1, 3] dioxin- 8-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid; (S) -2-Methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -4-tri-fluoro methyl- benzamide; 2,4,5-Trifluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] "diazepin-3-yl) -benzamide; (S) - 2,4,5-Trifluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Hydroxy-N - (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Hydroxy-N- (2- oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of a-idol H-indole-7-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1] , 4] diazepin-3-yl) -amide of (S) -1H-indole-7-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1 , 4] diazepin-3-yl) -amide of 3-methoxy-naphthalene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1] , 4] diazepin-3-yl) -amide of (S) -3-methoxy-naphthalene-2-carboxylic acid; N- [7-Chloro-5- (2-fluoro-phenyl) -2-oxo- 2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -4-methoxy-benzamide; 1- (2-Fluoro-benzyl) -3- (2-oxo-5-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Methoxy-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (3-Methyl-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-trifluo-rom ethyl-ethyl) -urea; 4-Chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 4-Methoxy-3-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) benzamide; 3-Methoxy-2-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 5-Chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) benzamide; 5-Fluoro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; -Methoxy-2-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-Methoxy-4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 3- (2-Methoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) propionamide; 3- (3-Methoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide; 3- (4-Methoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide; N- [5- (3-C-lor-f-enyl) -2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -2-methoxy-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -4-methoxy-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -2-nitro-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -4-nitro-b Enzyme; 4- Methoxy-N- [2-oxo-5- (4-trif luoromethyl-f-enyl) -2, 3-dihydro-1H-benzo [e] [1,4] di-azepin-3-yl] -benzamide; 2-Methoxy-N- [2-oxo-5- (3-trifluoromethyl-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -benzamide; 4-Methoxy-N- [2-oxo-5- (3-trifluoromethyl-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -benzamide; 2-Ethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,4-Dimethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Bromo-5-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-N- [5- (3-methoxy-phenyl) -2-oxo-2,3-dihydro-1 H-benzo [e] [1,4] diazepin-3-yl] -benzamide N- [5- (3-Methoxy-f-enyl) -2-oxo-5-f eni I-2, 3-dihydro-1 H-benzo [e ] [1,4] diazepin-3-i I] -4- nor tro -benzamide; 2-Methoxy-N- (8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Chloro-4-methanesulfonyl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Dimethylamino-N- (2-oxo-5-phenyI-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; benzyl ester of (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; 1- (3,5-Dimethyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-trifluoromethoxy-phenyl) -urea; 1 - (4-Bromo-2-trif luoromethyl-f-enyl) -3- (2-oxo-5-f eni I -2, 3-d ihydro- 1 H -benzo [e] [1,4] diazepin- 3-yl) -urea; 1- (4-Bromo-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1 - . 1 - (2,3-D-chloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dih id ro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2,6-Dimethyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Chloro-6-methyl-phenyl) -3- (2-oxo-5-phenyI-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Nitro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Methylsulfanyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2,6-Dichloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 5-tert-Butyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,5-Dimethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 1- (2,6-Difluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (3-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (3-Methoxy-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] d.azepin-3-yl) -3- (3-trifluoromethyl-phenyl) -urea; 1- (3-Chloro-phene) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 2-Methoxy-4-methylsulfanyl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 4-Methanesulfonyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepin-3-yl) terephthalamic acid methyl ester; 2-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,6-Difluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] '[1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-propoxybenzamide; 2-lodo-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -terephthalamic acid methyl ester; 4-Amino-5-chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -benzamide; 1- (2-Oxo-5-f eni [-2,3-d ihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-m-tolyl-urea; 2-Methylsulfanyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -5-sulfamoyl-benzamide; 2-Hydroxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-phenyl-propionamide 3-Hydroxy-N - (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-phenyl-propionamide; 3- (2-Fluoro-phenyl) -1-methyl-1- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 2-Methoxy-N-methyl-4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 1-tert-Butyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1-Cyclohexyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1-Ethyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1-Butyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 4,5-Dimethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) amide; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amido of piperidin-1-carboxylic acid; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) acetamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -isobutyramide; [5- (3-chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of furan-2-acid carboxylic; [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of thiophen-2-acid carboxylic; [5- (3-chloro-phenyl) -2-oxo-5-f eni I-2, 3-d i hydro-1 H -benzo [e] [1,4] diazepin-3-yl] -amide cyclohexanecarboxylic acid; [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of piperidin-1-acid carboxylic; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] isonicotinamide; (2-Methyl-2-furan-2-carboxylic acid 2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of pyrazine-2-carboxylic acid; N- [5- (3-Methoxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -isobutyramide; [5- (3-methoxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of thiophenic acid 2-carboxylic; [5- (3-methoxy-phenyI) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of cyclohexanecarboxylic acid; [5- (3-methoxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of piperidin-1-acid carboxylic; [5- (3-methoxy-f-enyl) -2-oxo-5-f-eni I-2, 3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of acid piperidine-4-carboxylic; (8-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of cyclohexanecarboxylic acid; (8-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of thiophen-2-carboxylic acid; 1- (2-Oxo-5-phenyl-2,3-ihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-thiophen-2-ylurea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-thiophen-3-ylurea; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of pyridine-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of a-idol H-Pyrazole-4-carboxylic acid; 6-Dimethylamino-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -nicotinamide; 2-Ethoxy-naphthalene-1-carboxylic acid 2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; 9-Oxo-9H-fluoren-1-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-M) -amide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -amide of 2-oxo-2,3-dihydro-benzoimidazole -1-carboxylic; tert-butyl ester of (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) carbamic acid ester; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -4,5-dibromo-furan-2 -carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -benzofuran-2-carboxylic acid; methyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H- benzp [e] [1,4] diazepin-3-yl) -carbamic acid ester; ethyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; isobutyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; and 2-Oxo-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-thiophene-2-i I-aceta mid a, or a pharmaceutically acceptable salt thereof. The compounds of formulas (I), (II), (III) and (IV) are known compounds. They are described in, for example, WO 00/195910, WO 00/004900, WO 03/053344, US-A-4324794 and WO 01/00612, and can be prepared through the procedures presented in those documents. WO 00/195910, WO 00/004900, WO 03/053344, US-A-4324794 and WO 01/00612 are incorporated herein by reference. Any of the compounds described as fusion protein inhibitors in those documents can be used in the present invention. The compounds of the formula (V) can be prepared by reacting glyoxylic acid (HCO-CO2H), benzotriazole and a suitable benzyl carbamate at reflux in toluene, under Dean-Stark conditions providing the key protected amino acid of the formula (II ') ) The amino acid thus obtained of the formula (II ') can then be reacted with a suitable chlorinating agent, such as oxalyl chloride, followed by the reaction with a 2-aminobenzophenone of the formula (III') to give the intermediate amide of the formula (IV) which does not need to be characterized. The compound of the formula (IV) can then be subjected to ammonolysis followed by ring closure in acetic acid containing ammonium acetate to obtain the protected benzodiazepine of the formula (V) The compound of the formula (V) can then be deprotected using hydrogen bromide in acetic acid to produce the deprotected amine of the formula (VI ').

The compounds of the formula (V), wherein R5 is XR6 and X is -CO- can be prepared by reacting a compound of the formula (VI '), as defined above, with an acid anhydride in the appropriate solvent, preferably pyridine at room temperature, or with an acid chloride in a suitable solvent in the presence of a base, preferably in THF at room temperature with triethylamine present. Alternatively, the compounds can be produced through the reaction of a compound of the formula (Vf) with an acid in a suitable solvent in the presence of a base and a coupling agent, preferably in THF at room temperature with triethyloamine and hexaf The rof osf ato of O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium (HBTU) present. If the acid chloride used is amino carbonyl chloride, the compound of the formula (V) is a tertiary urea. In the case where R6 is NH-R ', said compounds can be prepared through the reaction of a compound of the formula (VI ') with an isocyanate. This reaction is preferably carried out in THF at room temperature. Alternatively, the isocyanate can be prepared in situ from the relevant amine and phosgene, in the presence of a base, usually triethyloamine, again in THF. The compounds of the formula (V), wherein R5 is -XR6 and X is -S (O) 2- can be prepared through the reaction of a compound of the formula (VI ') with a suitable sulfonyl chloride.

Similarly, the compounds of the formula (V), wherein R5 is XR6 and X is -S (O) - can be prepared through the reaction of a compound of the formula (VI ') with a suitable sulfinyl chloride. The compounds of the formula (V) wherein R5 is not XR6 can be prepared by known methods. For example, a compound of the formula (VI ') can be reacted with a compound of the formula R5-L, wherein L is a leaving group such as a chlorine atom, a mesylate group or a triflate group. When R5 is aryl or heteroaryl, L can be -B (OH) 2 and the reaction can occur in the presence of copper acetate. Said boronic acid coupling reactions, of course, will be familiar to those skilled in the art. Compounds wherein R5 is aryl or heteroaryl can also be prepared through a Buchwaid reaction or through the reaction of a compound of the formula (VI ') with an appropriate fluoroaryl or fluoroheteroaryl compound. The compounds wherein R 5 is a heteroaryl group can also be prepared through the reaction of a compound of the formula (VI ') with a suitable chloroheteroaryl or bromoheteroaryl compound. Compounds wherein R5 is a carbocyclyl group can also be prepared by known methods, for example, a compound wherein R5 is cyclohexyl can be prepared through the reaction of a compound of the formula (VI ') with cyclohexanone in presence of a reducing agent. The compounds of the formula (V) wherein the group R5 is arylalkyl of 1 to 6 carbon atoms, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl-alkyl of 1 to 6 carbon atoms can also be prepared through the reaction of a compound of the formula (VI ') with an aldehyde in the presence of a reducing agent. Preferably, said reactions between the compounds of the formula (VI ') and aldehydes are carried out in a mixture of dichloromethane and acetic acid in the presence of sodium (triacetoxy) borohydride at room temperature. In the preparation of the benzodiazepine structure, where possible commercially available aminobenzophenone compounds of the formula (III ') can be used, the compounds of the formula (III'), which are not commercially available, can be prepared by known methods, for example through the reaction of a Weinreb-type amide of the formula (VII ") with a R1-Li group or a Grignard reagent such as R1-MgBr. Preferably, this reaction is carried out in THF at -100 ° C. The compounds of the formula (Vil ') are known compounds or can be prepared by analogy with known methods. For example, they can be prepared through the reaction of isatoic anhydrides of the formula (VIII ') with N, O-dimethyl hydroxylamino under standard reaction conditions. The starting materials of the formula (II '), (III'), (Vil1), and (HIV ') are known compounds, they can be prepared by analogy with known methods. Another synthetic manipulation of the compounds thus obtained of the formula (V) can be carried out by conventional methods to obtain other compounds of the formula (V). The benzodiazepines of the formula (V) can be salified by treatment with an appropriate acid or base. Although the route described for the claimed compounds provides an adequate synthesis for laboratory scale preparations, an alternative route was sought, which has potential as a manufacturing route. The same starting material (2-amino-benzophenone) (1) was used, however, both in the alternative route, where the benzodiazepine ring system was formed through the initial reaction with bromoacetyl bromide (or a equivalent reagent) followed by ring closure with ammonia. These reactions were carried out in a suitable solvent, such as dichloromethane, and at a suitable temperature, which can vary from -20 to 150 ° C. In order to protect NH functionality, at this stage, the unsubstituted benzodiazepine was reacted with a base, and an alkylating agent. For example, sodium hydride in DMF followed by the addition of 4-methoxybenzyl chloride gave rise to intermediate (2) shown below. Another reaction of this material with a base (for example potassium tert-butoxide) in a suitable solvent (for example THF or DMF) followed by extinction with isoamyl nitrite (or an alternative similar reagent) developed the oxime intermediate (3) which can be converted to the primary racemic amine through methods that include the use of hydrogen and a suitable catalyst. This amine then underwent a Dynamic Kinetic Resolution (DKR) procedure through which the racemic amine in the presence of a suitable optically active acid, and a suitable aldehyde gave rise to the precipitation of the salt of the (S) -amine (4). ) desired in a good yield and an exceptionally high enantiomeric excess. A suitable acid for this conversion can be, for example, camphor sulfonic acid, Boc-phenyl alanine or the like, and a suitable aldehyde can be a benzaldehyde such as 3,5-dichloro salicylaldehyde.

The optically pure amine thus formed can then be transformed to a desired derivative, such as an amide or urea. The amide formations can be made using a suitable carboxylic acid and a coupling agent, or a carbonyl chloride or other suitable reagent, and the ureas prepared using either a suitable isocyanate, or alternatively the reaction with phosgene followed by a suitable amine. These derivatives thus formed can then have the protective group removed. This can be done in the presence of a Lewis acid, such as aluminum chloride, boron trifluoride, titanium tetrachloride, or the like. These reactions can be carried out in a suitable solvent, such as dichloromethane. The reaction temperatures can vary from -20 to 150 ° C, but typically it is carried out at room temperature or below.

In a particularly embodiment of the invention, component (a) is 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-imidazo [4 , 5-c] pyridin-2-one, 2- [2- (1,2-dihydro-benzotriazol-1-ylmethyl) -benzoimidazol-1-yl]] ethyl} -diethyl-amine,. { 2- [2- (3-iodo-2,3-dihydro-indazol-1-ylmethyl) -benzimidazol-1-yl] -ethyl} -dimethylamine or a pharmaceutically acceptable salt thereof and component (b) is (S) -1- (2-fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1) H-benzo [e] [1,4] diazepin-3-yl) -urea, (S) -2-methoxy-4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H -benzo [e] [1,4] diazepin-3-yl) -benzamide, (S) -4-methanesulfonii-2-methoxy-N- (2-oxo-5-phenyl-2,3-ihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition according to the invention, for use in the treatment of the body of a human or animal. Also provided is the use of (a) an RSV fusion protein inhibitor and (b) the benzodiazepine derivative, in the manufacture of a medicament for use in the treatment or prevention of an RSV infection. The present invention also provides a method for treating or preventing an RSV infection in a patient, said method comprising administering to the patient of (a) an inhibitor of RSV fusion protein and (b) a benzodiazepine derivative. Typically, the amount of component (a) in the composition of the invention is 0.025 wt% to 10 wt%, preferably 0.25 wt% to 5 wt%, preferably 1 wt% to 3. 5% by weight, for example about 2.5% by weight, based on the total weight of the composition. Typically, the amount of component (b) in the composition of the invention is 0.025 wt% to 10 wt%, preferably 0.25 wt% to 5 wt%, most preferably 1 wt% to 3.5 wt%. % by weight, for example about 2.5% by weight, based on the total weight of the composition. Typically, the total amount of the components (a) and (b) in the composition of the invention is from 0.05 to 20% by weight, preferably from 0.5 to 10% by weight, preferably from 2 to 7% by weight, for example about 5% by weight, based on the total weight of the composition. RSV is prevalent among children under two years of age, adults who suffer from asthma, chronic obstructive pulmonary disorder (COPD) or immunodeficiency and old age. It is a particularly serious risk among children who suffer from chronic lung disease. Accordingly, said composition or medicament is typically for use in the treatment of a patient who is a child under 2 years of age, patients with asthma, COPD or immunodeficiency, elderly persons or persons in long-term care facilities. Typically, the child suffers from chronic lung disease. In addition, anti-RSV prophylaxis is recommended for newborn infants at 32 weeks gestation or before, until they reach 6 months of age, the elderly, people with immunodeficiency and those who are in health care facilities. a lot of time. Therefore, said composition or medication is typically used to prevent RSV infection in a child under 6 years of age, who was born after 32 weeks of management or less, elderly people, people with immunosuppression and those who are in facilities of health care for a long time. As described above, RSV strains after exposure to fusion inhibitors known in the art rapidly develop resistance. In order to minimize the risk of developing resistance to fusion inhibitors, it is desirable to combine them with another RSV replication inhibitor with a different mode of action. For the knowledge, the benzodiazepine derivatives described above are the first class of compounds with a novel mode of action. Accordingly, the compositions of the invention are characterized by a very low resistance profile, which makes them particularly suitable for both epepatic and prophylactic applications. The present invention also covers situations where components (a) and (b) are administered separately. In this way, for example, component (a) can be administered up to 24 hours before component (b). Alternately, component (b) can be administered up to 24 hours after component (a). More usually, when components (a) and (b) are administered separately, they will be administered in 12 hours, preferably in 6 hours, in each case. In addition, the present invention also provides a product comprising (a) a fusion protein inhibitor of RSV and (b) a benzodiazepine derivative for separate, simultaneous and sequential use in the irradiation of the body of a human or animal. Typically, said product is for separate, simultaneous or sequential use to eradicate or prevent an RSV infection. The use of an RSV fusion protein inhibitor is also provided in the manufacture of a medicament for use in the treatment or prevention of RSV infection through co-administration with a benzodiazepine derivative. The present invention also provides the use of a benzodiazepine derivative in the manufacture of a medicament for use in the treatment or prevention of an RSV infection, through co-administration with an RSV fusion protein inhibitor. When components (a) and (b) are administered separately, typically they are formulated as described above. The amount of the active ingredient in each separate formulation, of course, will correspond to the nature of the component (a) or (b) given above for the combined formulation. In this way, when components (a) and (b) are administered separately, typically a first formulation containing 0.025% by weight to 10% by weight, preferably 0.25% by weight, is provided. % by weight, preferably from 1% by weight to 3.5% by weight, for example about 2.5% by weight, of said RSV fusion protein inhibitor, based on the total weight of the formulation. Similarly, a second formulation conferring from 0.025% by weight to 10% by weight, preferably from 0.25% by weight to 5% by weight, preferably from 1% by weight to 3.5% by weight, for example around 10% by weight, is provided. 2.5% by weight, of a benzodiazepine derivative, based on the total weight of the formulation. The two formulations can be administered separately in any order. Preferably, the compositions and medicaments of the invention have a greater activity than the combined individual activities of the compounds (a) and (b). In this way, components (a) and (b) typically interact in synergistic fashion. Preferably, in the formulations and medicaments of the invention, component (a) and component (b) each is present in a quantity that produces a synergistic therapeutic effect to treat or prevent an RSV infection. The anti-RSV compositions of the invention can be administered in a variety of dosage forms. In this way they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, granules or dispersible powders. The compounds of the invention can also be administered parenterally, either subcutaneously, intravenously, inramuscularly, intraeserially, inimerically or through infusion techniques. Composites can also be administered as suppositories. In a preferred embodiment, the administration is through an intravenous, intranasal or intrabronchial means. In particular, formulations for bringing or preventing RSVs that are most expensive can be administered in an initial way. The present invention also provides an inhaler or nebulizer containing a medicament comprising (i) a composition of the invention comprising component (a) and component (b), as defined above, and (ii) ) a pharmaceutically acceptable vehicle or fluid. The ani-RSV compositions of the invention are typically formulated for administration with a pharmaceutically acceptable vehicle or diluent. For example, the oral dosage forms may contain, in June, the compound (s) acíivo, diluyeníes, for example lacíosa, dexírosa, sucrose, cellulose, corn starch or potato starch, lubricaníes, for example silica, íalco, esieraic acid , magnesium or calcium stearate, and / or polyethylene glycols; agglutinan agents; for example starches, gum arabic, gelaíina, meyilcelulosa, carboximeilcelulosa or polyvinyl pyrrolidone; disaggregation agents, for example starch, alginic acid, alginates or sodium glycolate and starch; effervescent mixtures; colorants; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in general, pharmacologically inactive and non-toxic substances used in pharmaceutic formulations. Said pharmaceutical preparations can be manufactured in a known manner, for example, by mixing, granulating, blending, coating with sugar, or film coating processes. The liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups can be used as carriers, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbiol. The suspensions and emulsions may contain as a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl alcohol, glycols, for example propylene glycol, and if desired, a suitable amount of water. lidocaine chloride. The solutions for injection or infusion can contain, for example, sterile water or preferably they can run in the form of saline, sterile, aqueous and isotonic solutions. Preferably, the anti-RSV compositions of the invention are solubilized in a carrier containing (a) a pharmaceutically acceptable oil selected from oil-glyceride esterification or polyether products of vegetable oil fatty acids with a chain length of from 8 to 10. carbon atoms and (b) a pharmaceutically acceptable tensioactive agent selected from oleate and laurel esters of a polyalcohol copolymerized with ethylene oxide. The most preferred vehicles contain Labrafil as the oil and Tween 20 or Tween 80 as the tensio-active agent. The ani-RSV compositions of the invention can also be suspended in PEG 400 for oral administration. A therapeutically effective amount of an anti-RSV composition of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg, typically from 0.5 to 30 mg, preferably from 1 to 20 mg of active ingredient per kg of body weight, according to the activity of the specific composition, age, weight and conditions of the subject to be brought, the type and severity of the disease and the frequency and route of administration. Preferably, the daily dose levels are from 5 mg to 2 g of active ingredient. The following Examples illustrate the invention. However, they do not limit the invention in any way. In this regard, it is important to understand that the parlicular assays used in the example section are designed only to provide an indication of antiviral activity. Many available assays exist to determine the activity of data compounds against RSV, and a negative result in any particular assay, so it is not deficient.

EXAMPLES Example 1 3- [1- (3-meiiI-buyl) -1H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazole-1-sulfonic acid dimethylamide, 1-methylsulfonyl-3- [1- ( 3-meti! -buti!) - 1 H- benzo i mid azo! - 2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 3- [1- (3-meiyl-builyl) - 1H-benzoimidazol-2-ylmeiyl] -2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid benzyl amide, 5-. { 3- [1- (3-menesulfonyl-propyl) -1 H -benzoimidazol-2-ylmeiyl I] -2-oxo-2,3-dihydro-benzoimidazol-1-yl} -penianyl, 7- [2- (3-isopropenyl-2-oxo-2,3-dihydro benzo imidazo l-1-ylmethyl) -benzoimidazo-1-1-yl] -hephenyiyl, 1-ylyo-3- [1 - (4-hydroxybuyyl) -1H-benzoi mid azo l-2-ylmethyl] -1,3-dihydrobenzoimidazol-2-one, 1-ethyl-3- [1- (2 -hydroxy-2-phenyl-ethyl) -1 H -benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 1-isopropenyl-3- [1- (3-oxo-butyl) -1H -benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 1- (4-hydroxy-benzyl) -3- [1- (3-methyloxy) -1H-benzoimidazole-2-ylmeityl ] -1,3-dihydro-benzoimidazol-2-one, 1-lsopropenyl-3- [1- (3-meityl-buyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazole-2- Ona, 1-cyclopropyl-3- [1- (4-hydroxy-buÍiI) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-imidazo [4,5-c] pyridin-2-one and 1- isopropenyl-3- (1-propyl-1 H-benzoimidazol-2-ylmelyyl) -1,3-dihydro-imidazo [4,5-c] pyridin-2-one were prepared as described in WO00 195910.

Example 2 { 2-β2- (1,2-dihydro-benzoyriazol-1-methylmethyl) -benzoy-1-azole-1-yl]] ethyl) -diethylamine was prepared as described in WO00004900.

Example 3 (2-r2- (3-iodo-2,3-dihydro-indazol-1-ylmethiD-benzimidazol-1-ip-ethylD-dimethyl-amine was prepared as described in WO03053344.

Example 4 Bis (5-amidino-2-benzimidazolyl) methane was prepared as described in US4, 324794.

Example 5 2-. { 2-p-M- (2-amino-ethyl) -piperidin-4-ylamino-1-4-methyl-benzoimidazoi-1-ylmethi) -6-methyl-pyridin-3-ol was prepared as described in WO0100612.

Example 6 The compounds of the general formula (V) were prepared as described in PCT / GB03 / 04050. In particular, (S) -1- (2-fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] benzodiazepin-3- il-urea and (S) -4-methanesu! fonyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzora] [1,4] diazepin-3-yl) -benzamide were prepared according to the protocols described in Examples 75b and 73b of PCT / GB03 / 04050.

Example 7 Determination of the Activity of the RSV Fusion Inhibitor RSV enraces the host cell through the binding to and fusion with the membrane of the host cell. The effect of an inhibitor on the virus-cell fusion event can be qualitatively eliminated by using a fluorescence de-excretion system. The design of this trial comes from the fact that RSV binds to cells at 4 ° C and 37 ° C, but that fusion occurs only at concentrations above 18 ° C. RSV labeled with octadecyl-rhodamine coloran (R18) was pre-incubated with Hep-2 cells seeded in a 6-well plate for 1 hour at 4 ° C to allow binding to occur. The untreated virus was joined by washing the cell monolayer. Then, the inhibitor was added to the virus-cell complexes and transferred to the plates at 37 ° C for 1 hour in order to reduce the fusion. The virus-cell fusion could be observed directly under a fluorescence microscope. The fluorescence emission was extinguished with 2 identical fluorophores that are in close proximity. After the fusion of the labeled virus with the cell membrane, the enamel dissipation of the fluorophores was increased due to the expansion of the coloran and a reduction in the extinction occurred. This was observed as an increase in the fluorescence intensity of R18. Therefore, the inhibition of the fusion could lead to a reduction of the fluorescence of R18 compared to the non-irradiated control. When the fluorescent performance of R18 in the presence of the inhibitor was comparable with the unfractionated conírol, esio suggested that the inhibitor did not exert its effects on the fusion prophecy.

Example 8 Determination of RSV replication inhibitory activity The 60 infernal cavities of 96-cavity stool plates were seeded with Hep-2 cells at 4x104 cells / well for studies of compound activity and toxicity in 100μl of the medium and incubated at 37 ° C overnight or until to confluence. The cells were infected with 25 μl RSV, for example the RSS strain, previously rinsed to give 80% cell annihilation. To each well, 25μM of the test compound was added. The final DMSO concentration was 0.5%. Some 200 μl of sterile distilled water was added to the outer cavities of the plate and incubated at 37 ° C for 6 days. Some 0.25 μl / ml PMS was added to the supply XTT solution, final concentration. 25 μM PMS. Then, 25 μl of a hot XTT / PMS solution was added to each well and incubated for 1 hour at 37 ° C. The maximum reading of OD 50n (uncontrolled, non-infected conírol cells) corresponds to 100% inhibition. The minimum leures of OD450nm (infected control cells) correspond to a 0% inhibition. The Log10 concentration will be graphical OD450nm and the IC50 values were calculated from the reading with a value of 50% of the graph or using regression analysis.

Example 9 Synergistic action between the RSV fusion inhibitor and anti-RSV benzodiazepines ELISA experiments were performed on the combined effect of the benzodiazepine RSV replication inhibitor potenie (S) -1- (2-fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -urea (Compound A) with an RSV fusion inhibitor selected from 1- Cyclopropyl-3- [1- (4-hydroxybuyl) -1 H -benzoimidazol-2-ylmefyl] -1,3-dihydro-imidazo [4,5-c] pyridin-2-one (Compound B) or 1 isopropenyl-3- (1-propyl-1 H-benzoimidazole-2-i I meti I) -1,3-dihydro-imidazo [4,5-c] pyridine-2-one (compound B).

ELISA PROTOCOL Mouse monoclonal antibodies were used for the phosphoprotein (P), nucleocapsid (N) and fusion proteins (F) of RSV and a secondary antibody conjugated to horseradish peroxidase (HRP) of rabbit ani-raíón to demonstrate a reduction in the RSV aniigen to the conversion of o-phenylene diamine dihydrochloride substrate (OPD) to a colored product. This was quantified through an optical density (OD) measurement.

This trial was carried out using 96 cavities of 96-well round-bottom plates. The outer cavities were not subjected to any greater amount of evaporation than the internal cavities on day 3 of the test period, (ie, no "edge effect" was seen). The plates were placed one day before the addition of the virus and compound. The trial then ran for 3 days with ELISA development appearing in the 4th. day.

Day 0 Preparation of Test Plates The 96 wells of a microtitre plate were seeded at a density of 5x103 Hep-2 cells / well in 10Oμl / well of a Growth Medium (GM) consisting of Dulbecco's MEM (DMEM) with Glutamax -1, Sodium pyruvate, 1000 mg / l glucose and pyridoxine (Invitrogen, catalog number 21885-025) and supplemented with 10% FBS. (See Plate 1). In the tissue culture, the cells were adhered to the tissue culture flask and developed at 37 ° C, 5% CO2 until a confluence of 90%. The monolayers were washed with 20 ml of sterile PBS to remove serum and rinsed with 1 ml of syringe to separate the cells from the flask. The cells were suspended in a known small volume of growth medium and concentrated using a hemocytometer.

The cell suspension was developed at the desired concentration in the growth medium and added to cavities through a multichannel pipette. In summary, moderate agitation encouraged the cells to disperse more uniformly through the cavity.

Plate 1 The plates were maintained undisturbed at 37 ° C in a 5% CO2 atmosphere for 24 hours, during which time the cells were sedimented to form a uniform cell monolayer.

Day 1 Virus addition A frozen vial of an RSV supply solution (RSS strain provided by Virogen Ltd) was removed from the -80 freezer or liquid nitrogen store and diluted to a Known Infection Multiplicity (moi) in the Medium of Increase.

The m.o.i. was calculated before the virus virus test (Throughout the ELISA test period) since the virus challenge was required to achieve a window of at least 0.8 OD units between infected and uninfected control cells.

Multiplicity of Infection = Plaque Numbing units per cavity (pfu / cavity) cell numbers per cavity 25μl (50μl in Example 9c) of diluted virus was added to infected cavities through a multichannel pipette; 25μl (50μl in Example 9c) of Growth Medium was added to uninfected cell control cavities through a multipath pipette. The sides of the plates were marked with stripes to idenify the plates in the event that the plates were separated. Plates were incubated at 37 ° C for 1 hour to allow virus uptake.

Dilutions of the Compound Compound "A" was tiiulized horizontally through the plate and Compound "B" was titled vertically down the plate, creating a checker board. The 2 compounds were labeled Y? -log or double dilutions either vertically (horizontally) or below the plate (vertically) in the presence of the virus. Each dilution of the compound was fixed in duplicate or triplicate. For triplicates, 3 identical plates were formed. The duplicates were formed as cavities in duplicate on the same plate. The dilution scale covered concentrations just above the IC50 of the compound below the 1C50 of the compound and OμM of conírol was included for each compound. The compounds were formed in a separate microliter plate at 8x strength in GM containing 2% DMSO (a final concentration of DMSO in the 0.5% assay). Then 12.5μM (25μl in Example 9c) of the dilution series of Compound "A" and 12.5μl (25μl in Example 9c) of the "B" dilution series were transferred to the appropriate wells of the plaque. trial through a pipette of multiple channels, according to the marking on the checker board. 12.5μl (25μl in Example 9c) of GM (containing 2% DMSO) were added to the cavities receiving OμM Compound "A" or OμM Compound "B". 25μl (50μl in the Example 9c) of GM (containing 2% DMSO) to cavities did not condense any compound. The untreated cavities, infected with viruses served as virus control (VC); the untrained, non-infected cavities served as the cell conirol (CC). The difference in absorbance between the CC and VC cavities constitutes the test window. Plates were incubated at 37 ° C, 5% CO2 for 3 days.

ELISA stage Day 4 The media were placed in the indirectly directed cavities in Virkon (1% solution in water) and the plates were washed by immersing in a plastic box confining PBS. 50μi / 75% / 25% vol / vol cavity of fixed oil / methanol was added through a multichannel pipette and left for 3 minutes. The acetone / meianol was discarded from the cavities to Virkon and the cavities were washed with PBS as above. Some 200μl of blocking solution (2% Marvel in PBS containing 0.05% Tween) per cavity was added via a multichannel pipette. The plates were incubated at 37 ° C in a shaking incubator for 60 minutes. The blocking solution was discarded from the manifold and a primary antibody diluted directly into the wells (ie, without a required wash) was added. The RSV mouse monoclonal antibody NCL-RSV3 (Novocastra) was diluted 1/400 in PBS / 2% Marvel / 0.05% Tween and 50μl per well was added. The plates were incubated at 37 ° C in a shaking incubator for 90 minutes. The antibody was discarded from the collector and the plates were washed 4 times by immersion in PBS / 0.05% Tween. The HRP conjugate of rabbit anti-mouse DAKo (DAKO catalog number P0260) 1/1000 was diluted in PBS / 2% Marvel / 0.05% Tween and 50μl were added per well. The plates were incubated 37 ° C in a shaking incubator for 60 minutes. The antibody was discarded from the collector and the plates were washed 6 times by immersion in PBS / 0.05% Tween. A substrate (SigmaFasí OPD) was prepared earlier by dissolving 1 urea in 20mL of water. The OPD was added to the urea solution after use (NB, slightly sensitive OPD) and swirled to mix. They added 50μl of the substratum per cavity. The reaction was stopped by the addition of 25μl / cavity of % sulfuric acid, once a sufficient color developed, but while the cell control ancestor remained low (~ 5 minutes). The plates were read in a SpectraMax spectrophotometer (Molecular Devices) at a wavelength of 490nm and used the SOFTmax Pro software package. The cavities were emptied, washed with running water and the monolayers were stained with 50μl / 2% cavity. of crystal violet in % methanol / water for at least 1 hour. The wells were then washed and air dried and the monolayers examined under the microscope for indications of cell toxicity.

Results The SOFTmax data files were exported to Excel. Damage management used Excel templates written at home to plot dose-response curves graphically and calculate values of IC50 of the curves obtained. All the replica cavities were mediated. The assay window was calculated by subtracting the medium cell (CC) control from the medium virus (VC) control. For each compound, the average CC was subtracted from the mean values for each concentration point. The control percentage was then calculated for each concentration point as a percentage of the window. The percentage of conírol is plotted with the concentration of compounds. A strong line was fixed to the curve and the slope and intersection functions were used to calculate the IC50. The IC 50 for Compound "A" was calculated for each previous concentration of Compound "B". Similarly, the IC50 for Compound "B" was calculated for each prior concentration of Compound "A".

Example 9a (S) -1- (2-Fluoro-phenin-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [eU1, 41diazepin-3-yl) -urea (Compound B) in combination with 1-isopropenyl-3- (1-ropil-1H-benzoimidazol-2-ylmethyl) -1,3-dihydro-imidazorr4.5-clpyridine-2-one (Compound A) Compound B has an IC50 of 2μM ELISA against the RSV RSS strain. Compound A has an ELISA IC50 of 0.5μM against the RSV RSS strain. In combination, concentrations of Compound A below its IC50 (1, 0.3, 0.1μM) the IC50 of Compound B was reduced from 0. 5μM to at least 0.16μM (3.2 times reduction). At concentrations of Compound B below its 1C50 (0.3, 0.1μM) the IC50 of Compound A was reduced from 2μM to at least 0.65μM (3 times reduction).

Example 9b (S) -1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreip. 41diazepin-3-yl) -urea (Compound B) in combination with 1-cyclopropyl-3-f1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmeiyl] -1,3-dihydro-imidazo [4,5-clpiridin-2-one (Compound A) Compound B has an IC50 of 1.4μM ELISA with the RSS strain of RSV. Compound A has an IC50 of ELISA of 0.015μM with the RSS strain of RSV. In combination, concentrations of Compound B below its IC50 (1, 0.3, 0.1, 0.03μM), the IC50 of Compound A was reduced from 0.015μM to at least 0.0007μM (reduction of 21.4 times). At concentrations of Compound A below its IC 50 (0.01, 0.003, 0.001, 0.0003 μM) the IC 50 of Compound B was reduced from 1.4 μM to at least 0.26 μM (5.4 fold reduction).

Example 9c (S) -4-Methanesulfonyl-2-meioxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e1 [1,4-diazepin-3-yl] -benzamide (Compound A) in combination with 1-cyclopropyl-3-M- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmein-1,3-dihydro-imidazoyl-4-pyridin-2-one (Compound B) Compound A has an IC50 of 1μM ELISA with the RSS strain of RSV. Compound B has an ELISA IC50 of O.OdμM against the RSV RSS strain. In combination, at concentrations of Compound A below its IC50 the IC50 of Compound B was reduced from O.OdμM to at least 0. 03 μM (reduction of 2.66 times). At concentrations of Compound B below its IC50 The IC50 of Compound A was reduced from 1μM to at least 0.3μM (3.33 fold reduction). The formula presented below can be used to identify a synergistic interaction.

FIC = Fractional inhibitory concentration. Compare the activity of a compound in combination (Compound A + Compound B) with the acíividad of the compound only (Compound A or Compound B).

IC50 Cpd A '1C50 Cpd B ONLY where the FIC value < 0.5 SYNERGY 0.5 - 1.0 ADDITION 1.0 - 2.0 INDIFFERENCE '> 2.0 ANTAGONISM FIC for (S) -1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl ) -urea in combination with 1- isopropenyl-3- (1-propyl-1 H -benzoimidazol-2-methylmethyl) -1,3-dihydro-imidazo [4,5-c] pyridine-2-one: < 0.25 FIC for (S) -1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzofe] [1,4] diazepin-3-yl) -urea (Compound B) in combination with 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-imidazo [4,5-c] pyridine -2-ona: < 0.04 FIC for (S) -4-Methanesulfonyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide in combination with 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1 H -benzoimidazol-2-ylmethyl] -1, 3-dihydro-imidazo [4,5-c] pyridin-2- ona: 0.0675

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and: (a) an inhibitor of the RSV fusion protein; and (b) a benzodiazepine derivative capable of inhibiting RSV replication.

2. A composition according to claim 1, wherein the component (b) is a compound of the formula (V), or a pharmaceutically acceptable salt thereof, wherein: - R1 represents alkyl of 1 to 6 carbon atoms, aryl or heeroaryl; R2 represented hydrogen or alkyl of 1 to 6 carbon atoms; - each R3 is the same or different and represents halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy from 1 to 6 carbon atoms, amino, mono- (alkyl of 1 to 6 carbon atoms) amino, d i- (alkyl of 1 to 6 carbon atoms) amino, ni, cyano, -CO2R \ -CONR 'R', -NH-CO-R ', -S (O) R \ -S (O) 2R', -NH-S (O) 2R ', -S (O) NR'R "or -S ( O) 2NR'R ", wherein each of R 'and R" is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms; n is from 0 to 3; R4 represented hydrogen or alkyl of 1 to 6 carbon atoms; R5 represents alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heeroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms. carbon, heterocyclyl-alkyl of 1 to 6 carbon atoms, aryl-hydroxyalkyl of 1 to 6 carbon atoms, heeroaryl-hydroxyalkyl of 1 to 6 carbon atoms, carbocyclyl-hydroxyalkyl of 1 to 6 carbon atoms, heteroaryl-hydroxyalkyl 1 to 6 carbon atoms, aryl-C (O) -C (O) ~, heeroaryl-C (O) -C (O) -, carbocyclyl-C (O) -C (O) -, heierocyclyl-C ( O) -C (O) - or -XR6; X represented -CO-, -S (O) - or -S (O) 2-; and R6 represented alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heteroaryl, aryl-alkyl of 1 to 6 carbon atoms , heleroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl-alkyl of 1 to 6 carbon atoms, aryl- (1 to 6 carbon atoms) -O- , heeroaryl- (alkyl of 1 to 6 carbon atoms) -O-, carbocyclyl- (alkyl of 1 to 6 carbon atoms) -O-, heyerocyclyl- (alkyl of 1 to 6 carbon atoms) -O- , or -NR'R "wherein each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 6 carbon atoms, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl of 1 to 6 atoms of carbon, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms or heterocyclyl-alkyl of 1 to 6 carbon atoms.

3. A composition according to claim 2, wherein: each R3 is the same or different and represents halogen, hydroxy, alkyl of 1 to 6 carbon atoms, akoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 atoms carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, amino, mono-alkyl amino of 1 to 6 carbon atoms, di-alkyl amino of 1 to 6 carbon atoms, nitro, cyano , -CO2R ', -CONR'R ", -NH-CO-R', -S (O) R ', -S (O) 2R', -NH-S (O) 2R ', -S (O) NR'R "or -S (O) 2NR'R", wherein each of R 'and R "is the same or different and represents hydrogen or alkyl of 1 to 6 carbon atoms; R5 represents alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 atoms of carbon, heyerocyclyl-alkyl of 1 to 6 carbon atoms, or -XRd ', - X represents -CO-, -S (O) - or -S (O) 2-; and - R6 represents alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heeroaryl, carbocyclyl, heterocyclyl, arylalkyl of 1 to 6 carbon atoms, heteroaryl-alkyl of 1 to 6 carbon atoms, carbocyclyl-alkyl of 1 to 6 carbon atoms, heterocyclyl-alkyl of 1 to 6 carbon atoms, or -NR'R "wherein each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 6 carbon atoms, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl of 1 to 6 carbon atoms, or heteroaryl-alkyl of 1 to 6 carbon atoms.

4. A composition according to claim 2 or claim 3, wherein R1 is alkyl of 1 to 2 carbon atoms or aryl.

5. A composition according to any of claims 2 to 4, wherein R2 is hydrogen.

6. A composition according to any of claims 2 to 5, wherein R3 is halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, amino, mono-alkyl amino of 1 to 4 carbon atoms or di-alkyl amino of 1 to 4 carbon atoms.

7. A composition according to claim 6, wherein R3 is fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, amino, mono-alkyl amino of 1 to 2 carbon atoms or di-alkyl amino of 1 to 2 carbon atoms.

8. A composition according to any of claims 2 to 7, wherein R4 is hydrogen or alkyl of 1 to 2 carbon atoms.

9. A composition according to any of claims 2 to 8, wherein R5 is alkyl of 1 to 6 carbon atoms, aryl, heeroaryl, carbocyclyl, heteroaryl, aryl-alkyl of 1 to 4 carbon atoms, heteroaryl-alkyl from 1 to 4 carbon atoms, carbocyclyl-alkyl of 1 to 4 carbon atoms, heterocyclylalkyl of 1 to 4 carbon atoms, apy-C (O) -C (O) -, heteroaryl-C (O) -C ( O) - or -XR6.

10. A composition according to claim 9, wherein R5 is alkyl of 1 to 4 carbon atoms, aryl, heeroaryl, carbocyclyl, heteroaryl, phenyl-alkyl of 1 to 2 carbon atoms, heteroaryl-alkyl of 1 to 2. carbon atoms, phenyl-C (O) -C (O) -, heteroaryl-C (O) -C (O) - or -XR6.

11. A composition according to claim 10, wherein R5 is alkyl of 1 to 4 carbon atoms, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH2-, furanyl-CH2 -, phenyl-C (O) -C (O) -, thienyl-C (O) -C (O) - or -XR6.

12. A composition according to any of claims 2 to 11, wherein X is -CO- or -S (O) 2-.

13. A composition according to any of claims 2 to 12 wherein, when R6 is a group NR'R "wherein each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 4 atoms carbon, aryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 4 carbon atoms or hepheroaryl-alkyl of 1 to 4 carbon atoms.

14. A composition according to claim 13, wherein when R6 is a group -NR'R "each of R 'and R" is the same or different and represents hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-CH2-.

15. A composition according to claim 14, wherein when R6 is a group -NR'R "and one of R 'and R" is hydrogen.

16. A composition according to any of claims 2 to 15, wherein R6 is alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-alkyl of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, carbocyclyl-alkyl of 1 to 4 carbon atoms, heterocyclyl-alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, heeroaryl-hydroxyalkyl of 1 to 4 carbon atoms, carbocyclyl-hydroxyalkyl of 1 to 4 carbon atoms, heteroaryl-hydroxyalkyl of 1 to 4 carbon atoms, aryl-alkyl 1 to 4 carbon atoms-O-, heeroaryl-alkyl of 1 to 4 carbon atoms-O-, carbocyclyl-alkyl of 1 to 4 carbon atoms-O-, heteroaryl-alkyl of 1 to 4 carbon atoms-O - or -NR'R "

17. A composition according to claim 16, wherein R6 is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, aryl, heteroaryl, carbocyclyl, heterocyclyl, phenyl-alkyl of 1 to 2 carbon atoms, phenyl-alkyl of 1 to 2 carbon atoms-O-, heteroaryl-alkyl of 1 to 2 carbon atoms, phenyl-hydroxyalkyl of 1 to 2 carbon atoms, heeroaryl-hydroxyalkyl of 1 to 2 carbon atoms or -NR'R ".

18. A composition according to claim 17, wherein R6 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl , thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenylalkyl of 1 to 2 carbon atoms, phenyl-CH2-CH (OH) -, phenyl-CH ( OH) -CH2-, phenyl-C1-C2-alkyl- O-, 1H-benzo [d] imidazole-2 (3H) -onyl or -NR'R "

19. A composition according to any of claims 2 to 18, wherein the benzodiazepine derivative of the formula (V) is a benzodiazepine derivative of the formula (Va): nde: - R1 is phenyl or methyl; - R3 is methyl or chloro; n is 0 or 1; - R4 is hydrogen or me yl; - R5 is phenyl-CH2-, furanyl-CH2-, thienyl-C (O) -C (O) - or -XR6; - X is -CO- or -S (O) 2-; and - R6 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, naphyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, ynyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl-alkyl of 1 to 2 carbon atoms, phenyl-CH2-CH (OH) -, phenyl-CH (OH) -CH2-, phenyl-alkyl of 1 to 2 carbon atoms-O-, 1H-benzo [d] imidazole-2 (3H) -onyl or -NR'R "wherein each of R 'and R" are the same or different and represent hydrogen, alkyl from 1 to 4 carbon atoms, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl- (CH2) -, the phenyl portion in the group R1 is unsubstituted or substituted by a single substituent fluoro, chloro, alkyl of 1 to 2 atoms of carbon, alkoxy of 1 to 2 carbon atoms, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms or haloalkoxy of 1 to 2 carbon atoms; the aryl portions in the groups R5 and R6 are unsubstituted or substituted by 1, 2 or 3 selected compounds of fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, hydroxy , alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloaicoxy of 1 to 4 carbon atoms, amino, mono-alkyl amino of 1 to 4 carbon atoms , di-alkyl amino of 1 to 4 carbon atoms, nitro, -CO2R ', -S (O) 2R' and -S (O) 2 NH2, wherein R 'represented alkyl of 1 to 2 carbon atoms; the heeroaryl moieties in the groups R5 and R6 are not substituted or substituted by 1 or 2 selected sulfur, chlorine, bromine, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms and di-alkyl amino of 1 to 2 carbon atoms; and the heterocyclic and carbocyclyll moieties in the R6 group are unsubstituted or substituted by 1 or 2 susíiuuyeníes selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and nitro.

20. A composition according to claim 1, wherein the benzodiazepine derivative of the formula (V) is: 2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin- 3-yl) -cyclohexanecarboxylic acid amide; 3- Meioxy N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 4- Meioxy N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2- Methoxy N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-ylfluoromethyl-benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-phenyl-2,3-dihydro-H-benzo [e] [1,4] diazepin-3-yl) -3-amide of iophene-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of furan-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of piperidine-1-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of morpholin-4-carboxylic acid; 4-Niio-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-Niio-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] d-azepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of 4-methyl-piperazine-1-carboxylic acid; 3,4-Dichloro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-ylfluoromethylbenzamide; 4-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2- Meti l-N- (2-oxo-5-f eni I-2, 3-di hydro-1 H -benzo [e] [1,4] diazep i n-3-yl) -benzamide; 2-Chloro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-4-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Meioxy-4-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide (2 Benzo [b] thiophene-3-carboxylic acid-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] di azepin-3-yl) -amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of isoxazole-5-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amino benzo [b] thiophene-2-carboxylic acid amide; (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of thiophene-3-carboxylic acid; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -isonicotinamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -methanesulfonamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of propane-1-sulfonic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of butan-1-sulfonic acid; 2-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 3-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 4-Bromo-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 2-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzensulfonamide; 3- (2-Nitro-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (3-Nitro-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (4-Nitro-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (2-Methoxy-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3- (3-Meioxy-benzylamino) -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (2-trifluoromethyl-benzylamino) -1, 3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (3-trichloro-methyl-1-benzylamino) -1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 5-Phenyl-3- (4-trifluoromethyl-benzylamino) -1,3-dihydro-benzo [e] [1,4] diazepin-2-one; 3 - [(Furan-2-ylmethyl) -amino] -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -acetamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -isobutyramide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -methanesulfonamide; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of furan-2-carboxylic acid; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of thiophen-2-carboxylic acid; (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of cyclohexanecarboxylic acid; N- (7-Chloro-2-oxo-5-phenyl-2,3-d-hydro-1 H-bznzo [e] [1,4] d-azepin-3-yl) -2-methoxy-benzamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -4-methoxy-benzamide; N- (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-nitrobenzamide; 2- (2-Methoxy-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (3-Meioxy-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (4-Meioxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; 2- (4-Niio-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -acetamide; 2- (3-Nitro-phenyl) N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -acetamide; N- (2-Oxo-5-f eni I-2, 3-d-hydro-1 H -benzo [e] [1,4] diazepin-3-yl) -2- (2-ylfluoromethyl-phenyl) - acetylamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2- (3-trifluoromethyl-phenyl) -acetamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2- (4-ylfluoromethyl-phenyl) -acelamide; 1- (2-Methoxy-phenyl) -3- (2-oxo-5-phenyl-2,3-ihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Nitro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Chloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Chloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1 - (2-oxo-5-f eni I-2, 3-d-hydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-p-folyl-urea; 1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] d.azepin-3-yl) -urea; (S) -1- (2-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 4-Mefansulfomí-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -4-Methanesulfonyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 5-Acetyl-2-ethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dlazepin-3-yl) -benzamide; (S) -5-Acetyl-2-ethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of 6-fluoro-4H-benzo [1,3] dioxin- 8-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid; (S) -2-Methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -4-trifluoromethyl-benzamide; 2,4,5-Trifluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -benza mida; (S) -2,4,5-Trifluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Hydroxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Hydroxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-f in yl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of ididol H-indole-7-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide (S) -1 H -indole-7-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of 3-methoxy-naphthalene-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amido of (S) -3-meloxy-naphthalene-2-carboxylic acid; N- [7-Chloro-5- (2-fluoro-phenyl) -2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-ii] -4-mexoxoi-benzamide; 1- (2-Fluoro-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Meioxy-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3? I) -urea; 1- (3-Meilyl-benzyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-trifluoromethylphenyl) -urea; 4-Chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 4-Methoxy-3-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) benzamide; 3-Methoxy-2-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 5-Chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) benzamide; 5-Fluoro-2-methoxy-N- (2-oxo-5-phenyl-2,3-ihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-4-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 5-Methoxy-2-nifro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-Meioxy-4-niiro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 3- (2-Methoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) propionamide; 3- (3-Me-phoxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide; 3- (4-Meioxy-phenyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide; N- [5- (3-Chloro-phenyl) -2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -2-methoxy-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -4-methoxy-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -2-nitro-benzamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phene-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -4-niiro-b Enzyme; 4- M ethoxy-N - [2-oxo-5- (4-trif luoromethyl-f in yl) -2, 3-d ihydro-1 H -benzo [e] [1,4] di azepin-3-yl ]-benzamide; 2-Methoxy-N- [2-oxo-5- (3-ylfluoromethyl-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -benzamide; 4-Methoxy-N- [2-oxo-5- (3-trifluoromethyl-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -benzamide; 2-Eioxy-N- (2-oxo-5-phenyI-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,4-Dimethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Bromo-5-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Methoxy-N- [5- (3-methoxy-phenyl) -2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-i I] -benzamide N- [5- (3-Meioxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepin-3-yl] -4-nitro-benzamide; 2-Methoxy-N- (8-meityl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Chloro-4-methanesulfonyl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2-Dimethylamino-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benza-t-ida; benzyl ester of (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; 1- (3,5-Dimethyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-trifluoromethyloxy-phenyl) -urea; 1- (4-Bromo-2-trif luoromethyl-f eni l) -3- (2-oxo-5-f in i I-2, 3-d ihydro-1 H-benzo [e] [1, 4] di azepin-3- i I) - urea; 1- (4-Bromo-benzyl) -3- (2-oxo-5-phenyI-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2,3-Dichloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2,6-Dimethyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Chloro-6-methyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (4-Nitro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Methylsulfanyl-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2,6-Dichloro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 5-tert-Butyl-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,5-Dimethoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; 1- (2,6-Difluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (3-Fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (3-Methoxy-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (3-ylluoromethylphenyl) -urea; 1- (3-Chloro-phene) -3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 2-Meioxy-4-methylsulfanyl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 4-Menesulfonyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) terephthalamic acid methyl ester; 2-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 2,6-Difluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-propoxybenzamide; 2-lodo-N- (2-oxo-5-phenyl-2,3-d-hydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 3-meioxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-ii) -terephthalamic acid meitylic acid ester; 4-Amino-5-chloro-2-methoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-m-ioyyl-urea; 2-Melylsulfanyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia zepin-3-yl) -benza mida; 2-Meioxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -5-sulfamoyl-benzamide; 2-Hydroxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-phenyl-propionamide 3-Hydroxy-N - (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -3-phenyl-propionamide; 3- (2-Fluoro-phenyl) -1-methyl-1 - (2-oxo-5-phen i I-2, 3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl )-urea; 2-Methoxy-N-methyl, -4-nitro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; 1-tert-Butyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1-Cyclohexyl-3- (2-oxo-5-phenyl-2,3-dlhydro-1H-benzo [e] [1,4] diazepin-3-yl) -urea; 1-Ether l-3- (2-oxo-5-f eni 1-2, 3-d-hydro-1 H -benzo [e] [1,4] diazepin-3-yl) -urea; 1-Butyl-3- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] d.azepin-3-yl) -urea; 4,5-Dimethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl); (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of piperidin-1-carboxylic acid; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) acedamide; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -isobutyramide; [5- (3-chloro-f-enyl) -2-oxo-5-f eni I-2, 3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide acid furan-2-carboxylic; [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of thiophen-2-acid carboxylic; [5- (3-chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide, cyclohexanecarboxylic acid; [5- (3-Chloro-phenol) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of piperidin-1-acid carboxylic; N- [5- (3-Chloro-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] isonicotinamide; (5-Methyl-furan-2-carboxylic acid 2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of pyrazine-2-carboxylic acid; N- [5- (3-Meioxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -isobutyramide; [5- (3-meioxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of thiophen-2-acid carboxylic; [5- (3-methoxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of cyclohexanecarboxylic acid; [5- (3-meioxy-f-enyl) -2-oxo-5-f-eni I-2, 3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of acid piperidine-1-carboxylic acid; [5- (3-methoxy-phenyl) -2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl] -amide of piperidin-4-acid carboxylic; (8-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of cyclohexanecarboxylic acid; (8-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of thiophen-2-carboxylic acid; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-thiophen-2-ylurea; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3-thiophen-3-ylurea; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of pyridine-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of 1H-Pyrazole-4-carboxylic acid; 6-Dimethylamino-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nichoinamide; (2-Ethoxy-naphthalene-1-carboxylic acid 2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide; 9-Oxo-9H-fluoren-1-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of 2-oxo-2,3-dihydro-benzoimidazole-1 -carboxylic; tert-butyl ester of (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) carbamic acid ester; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -4,5-dibromo-furan-2 -carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -benzofuran-2-carboxylic acid; methyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; etyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; isobutyl ester of (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -carbamic acid ester; and 2-Oxo-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-iiophen-2-yl-acetamide.

21. A composition according to any of claims 2 to 20, wherein the benzodiazepine derivative of the formula (V) is 1- (2-fluoro-phenyl) -3- (2-oxo-5-phenyl-2) , 3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -urea, 2-methoxy-4-nitro-N- (2-oxo-5-phenyl-2,3-di idro- 1 H-benzo [e] [1,4] diazepin-3-yl) -benzamide or 4-menesulfonyl-2-mephoxy-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] -diazepin-3-yl) -benzamide.

22. A composition according to claim 21, wherein the benzodiazepine derivative of the formula (V) is 1- (2-fluoro-phenyl) -3- (2-oxo-5-phenyl-2,3-dihydro) -1 H-benzo [e] [1,4] diazepin-3-yl) -urea.

23. A composition according to any of the preceding claims, wherein compound (a) is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: - X is a direct or alkyl bond of 1 to 6 carbon atoms; the alkyl of 1 to 6 carbon atoms is optionally substituted with halogen, oxo, cyano, hydroxyl, OCOR4 or S (O) n-alkyl of 1 to 6 carbon atoms; Y is R4, NR4R5, NCOR4, = N-OR4, -CONHR4, COOR4, -OR4, aryl, heeroaryl, cyclyl or heyerocyclyl, wherein R4 and R5 are H or alkyl of 1 to 6 carbon atoms; Z is CR6R ', wherein R6 and R7 are independently H, or straight-chain, branched or cyclic alkyl of 1 to 6 carbon atoms; - n is 1-2; - R-i is CONR4R5, CO2R4 or alkyl of 1 to 6 carbon atoms, the alkyl of 1 to 6 carbon atoms may optionally be susíiuuido with OR4 or NR8R9; - R8 and Rg are each independently H, alkyl of 1 to 6 carbon atoms, SO2R5, CO2R4 or COR4; - R2 is selected from the group consisting of NH2, CONR6R7, heteroaryl, alkenyl of 2 to 6 carbon atoms, CO2R4, N = CPh2, C (= NH) NH2 and alkyl of 1 to 6 carbon atoms; said alkyl optionally may be substituted with a member selected from the group consisting of halogen, CN, NR10R-α, OSO 2 R 4 and OR 4; - Rio and R11 are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, CO2R4, COR4 and SO2R4; - R3 is selected from the group consisting of (1) CO2R9; (2) alkyl of 1 to 6 carbon atoms optionally substituted with CN, OR 4 or NR 6 R 7; and (3) alkenyl of 2 to 6 carbon atoms substituted with CN; - Q is a member selected from the group consisting of A is C or N, optionally substituted with H, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyanoalkyl of 1 to 6 carbon atoms, CO2R4, aryl, benzoaminocarbonyl, hydroxybenzyl, SO2NR4R5 or cycloalkyl of 3 to 6 carbon atoms, where A is a carbon, can also optionally be substituted by O or S through a double bond; B is C or N; wherein B is C and may optionally be substituted by H, alkyl of 1 to 6 carbon atoms, NO2, CN, halogen, COR4, COOR4, CONHR4C (= NH) NH2 or C (= NOH) NH2.

24. A composition according to any of claims 1 to 22, wherein the component (a) is a compound of the formula (I), as defined earlier or a pharmaceutically acceptable salt thereof, wherein at least two of Ri, R2 and R3 are hydrogen, and the oire is hydrogen or -C (NH) -NH2 and / or either -XY is H, or X is an alkylene group of 1 to 6 carbon atoms which is unsubstituted or substituted by a hydroxy group and Y is H, OH, CN, -NR'R ", -COR ', -SO2R' or phenyl, wherein R 'and R" are the same or different and represented an alkyl group of 1 to 4 carbon atoms and / or Z is -CH2- and / or Q is a portion: wherein B is -CH- or -N-, A- is -C (O) - or -NH- and A2 is -CH; -CHR'- or -NR "-, wherein R 'is a halogen atom and R" represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, -SO2- (alkyl of 1 to 6 carbon atoms), -SO2-N (alkyl of 1 to 6 carbon atoms) 2 or - (CO-NH) a- (alkyl of 1 to 4 carbon atoms) -phenium, where a is 0 or 1, said group is unsubstituted or is substituted by a hydroxy or cyano substituent.

25. A composition according to any of claims 1 to 22, wherein the component (a) is a compound of the formula (II), or a pharmaceutically acceptable salt thereof: where: - !_! is -CH2- or -CHIR2-CO- - each X is the same or different and is CH or N; - each R1 is the same or different and is alkyl of 1 to 6 carbon atoms, halogen, hydroxy, phenyl or (CH2) m = NH2; - n is 1 or 2; - R2 is alkoxy of 1 to 6 carbon atoms or akoxy-phenyl of 1 to 6 carbon atoms; - R3 is alkyl of 1 to 6 carbon atoms; - L2 is -CH2- or -NH-; - Y is alkyl of 1 to 6 carbon or alkenyl atoms of 1 to 6 carbon atoms; - Z is H, N (R4) 2-, -C (= O) -R5, -C (= CH2) -R5, -CH (OH) -R5, -CH (CH3) -R5, -CH (OCH3 ) - R5; - each R4 is the same or different and is H, alkyl of 1 to 6 carbon atoms. - R5 is alkylcarbonyl of 1 to 6 carbon atoms, amino, hydroxyl, cele, heteroapion, carbocyclyl, heteroaryl; and - m = 1-6

26. A composition according to any of claims 1 to 22, wherein component (a) is: 1-cyclopropyl-3- [1- (4-hydroxybuile) -1 H -benzoimidazole-2-I I-I I, 1,3-dihydro-imidazo [4,5-c] pyridin-2-one. { 2- [2- (1,2-Dihydro-benzotriazol-1-ylmethyl) -benzoimidazol-1-yl]] ethyl} -dielylamine. { 2- [2- (3-lodo-2, 3-d ihydro-i ndazol-1-ylmethyl) -benzimidazol-1-yl] -ethyl} -dimethylamine 1-lsopropenyl-3- [1- (3-methyl-butyl) -1 H -benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1- (4-Hydroxy-benzyl) -3 - [1- (3-methyl-buyl) -1H-benzo imidazo I-2-ylmethyl] -1,3-dihydro-benzoimidazole -2-lona-1-lsopropenyl-3- [1- (3-oxo-butyl) -1 H-benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1-Ethyl-3- [1- (2-h idroxy-2-f-enyl-ethyl) -1H-benzol-mid-azole -2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1-Ethyl-3- [1- (4-hydroxy-bulyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydrobenzoimidazole-2 -one 7- [2- (3-lsopropenyl-2-oxo-2,3-dihydrobenzoimidazol-1-ylmethyl) -benzoimidazol-1-yl] -hephen-nifril 5-. { 3- [1- (3-Mefansulfonyl-propyl) -1H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazol-1-yl} -penia-nitrile benzylamide of 3- [1- (3-Meily-butyl) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid 1-methanesulfonyl-3- [ 1- (3-Methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-d-hydroxybenzoimidazo-l-2-one dimethylamide of 3- [1- (3-Methyl-butyl) - 1 H-benzoimidazol-2-ylmethyl] -2-oxo-2, 3-dihydrobenzoimidazole-1-sulfonic acid 1-lsopropenyl-3- (1-propyl-1H-benzoimidazol-2-ylmethyl) -1,3-dihydro-imidazo [4,5-c] pyridin-2-one Bis (5) -amidino-2-benzimidazolyl) -melanic acid 2-. { 2- [1- [1- (2-Amino-ethyl) -piperidin-4-ylamino] -4-meityl-benzoimidazoI-1-ylmellyl} -6-meylyl-plridin-3-ol, or a pharmaceutically acceptable salt thereof.

27. A composition according to any of claims 1 to 22, wherein component (a) is 1-cyclopropyl-3- [1- (4-hydroxy-builyl) -1H-benzoimidazol-2-ylmefyl] - 1, 3-d-hydroimidazo [4,5-c] pyridin-2-one,. { 2- [2- (1, 2-dihydro-benzoyriazol-1-ylmethyl) -benzoimidazol-1-yl]] ethyl} -diethyl-amine,. { 2- [2- (3-iodo-2,3-dihydro-indazol-1-ylmethyl) -benzimidazol-1-yl] -ethyl} dimethylamine or a pharmaceutically acceptable salt thereof.

28. A composition according to any of claims 1 to 22, wherein the component (a) is 1-cyclopropyl-3- [1- (4-hydroxybuyl) -1H-benzoimidazol-2-ylmethyl] -1 , 3-dihydro-imidazo [4,5-c] pyridin-2-one or 1-isopropenyl-3- (1-propy1o-1 H -benzoimidazol-2-ylmethyl) -1, 3-dihydro-imidazo [4, 5-c] pyridin-2-one or a pharmaceutically acceptable salt thereof.

29. A composition according to any of the preceding claims, wherein the compound (a) is present in an amount of 0.025% by weight to 10% by weight.

30. A composition according to any of the preceding claims, wherein component (b) is present in an amount of 0.025% by weight to 10% by weight.

31. A composition according to any of the preceding claims, for use in the treatment of the body of a human or animal.

32. The use of: (a) an RSV fusion protein inhibitor as defined in any of claims 1 and 21 to 28; and (b) a benzodiazepine derivative defined in any of claims 1 to 22, in the manufacture of a medicament for use in the treatment or prevention of an RSV infection.

33. The use according to claim 31, wherein the medicament is a composition as defined in the claim. 29 or 30.

34. A product comprising: (a) an RSV fusion protein inhibitor as defined in any of claims 1 and 21 to 28; and (b) a benzodiazepine derivative as defined in any of claims 1 to 22; for the separate, simultaneous or sequential use in the body of a human or animal.

35. A product according to claim 34, for separate, simultaneous or sequential use in the treatment or prevention of RSV infection.

36. A method for treating or preventing RSV infection in a patient, the method comprising administering to said patient: (a) an RSV fusion protein inhibitor as defined in any of claims 1 and 21 to 28; and (b) a benzodiazepine derivative as defined in any of claims 1 to 22.

37. The use of an RSV fusion protein inhibitor as defined in any of claims 1 and 21 to 28, in the manufacture of a medicament for use in the prevention or prevention of an RSV infection, upon co-administration with a benzodiazepine derivative as defined in any of claims 1 to 22.

38. The use of a benzodiazepine derivative as defined in any of claims 1 to 22, in the manufacture of a medicament for use in the treatment or prevention of an RSV infection, through co-administration with an RSV fusion protein inhibitor as defined in any of claims 1 and 21 to 28.