MXPA06010709A

MXPA06010709A - Pharmaceutical composition comprising a benzodiazepine derivative and a inhibitor of the rsv fusion protein

Info

Publication number: MXPA06010709A
Application number: MXPA/A/2006/010709A
Authority: MX
Inventors: Powell Kenneth; Kelsey Richard; Carter Malcolm; Dowdell Verity; Alber Dagmar; Henderson Elisa
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 anergic 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 palivizumab. 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 repiration. 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 which contains, 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 because 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 (eg, medium of growth with 10% fetal bovine serum and DIVISO) is used in step (d) instead 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%, protein inhibition. RSV fusion as determined by the previous test. 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 with halogen, oxo, cyano, hydroxyl, OCOR4 or S (0) 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, C02R4 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, S02R5, C02R4 or COR4; - R2 is selected from the group consisting of NH2, CONR6R ', heteroaryl, alkenyl of 2 to 6 carbon atoms, C02R4, 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, 0S02R4 and OR4; - R10 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, C02R4, COR4 and S02R4; - R3 is selected from the group consisting of (1) C02R9; (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, alkenyl of 2 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, C02R4, aryl, benzoaminocarbonyl, hydroxybenzyl, S02NR4R5 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, N02, 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 ', -S02R' or phenyl, wherein R 'and R "are the same or different and represent an alkyl group of 1 to 4 carbon atoms. Typically, Z is -CH2-. Typically, Q is a portion where B is -CH- or -N-, A! 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, -S02- (alkyl of 1 to 6 carbon atoms), -S02-N (alkyl of 1 to 6 atoms) carbon) 2 or - (CO-NH) a- (alkyl of 1 to 4 carbon atoms) -phenyl, wherein a is 0 or 1, said group is unsubstituted or 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, benzylaminocarbamoyl or para-hydroxybenzyl Component (a) can also be a compound of the formula (II), or a pharmaceutically acceptable salt thereof, where: - each X is the same or different and is CH or N; - each R is the same or different and is alkyl of 1 to 6 carbon atoms, halogen, hydroxy, phenyl or (CH 2) m = NH 2; - 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 (= 0) -R5, -C (= CH2) -R5, -CH (OH) -R5, -CH (CH3) -R5, -CH (OCHs) ) - R5; - each R4 is the same or different and is H, alkyl of 1 to 6 atoms of carbon. - R5 is alkylcarbonium 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 carbonyl 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; 1 R 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 (= 0) -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-ethyl) -sulfamoyl] -phenylamino] - [1] , 3,5] triazin-2-ylamino) -biphenyl-2,2'-disulfonic acid. Preferably, component (a) is: 1-Cyclopropyl-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} -diethiamine. { 2- [2- (3-lodo-2,3-dihydro-indazol-1-ylmethyl) -benzimidazol-1-yl] -ethyl} -dimethylamine 1-lsopropenyl-3- [1- (3-methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one 1- (4-Hydroxy-benzyl) -3- [ 1- (3-methyl-butyl) -1 H -benzoimidazole-2-yl methylene] -1,3-dihydro-benzoimidazol-2-one 1-lsopropenyl-3- [1- (3-oxo-butyl) -1 H-benzoimidazol-2-ylmethyl] -1,3-dihydrobenzo-mide zol-2-one 1-Ethyl-3- [1- (2-hydroxy-2-phenyl-ethyl) -1H-benzoimidazole-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-lsopropenyl-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) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydrobenzoimidazole-1-carboxylic acid 1-methanesulfonyl-3- [ 3- (1- (3-Methyl-butyl) -1H-benzoimidazole 1- (3-methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one dimethylamide -2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazole-1-sulphonic 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) -methane 2-. { 2- [1- [1- (2-Amino-ethyl) -piperidin-4-lamino] -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, nde: - 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 from 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, -C02R ', -CONR 'R', -NH-CO-R ', -S (0) R \ -S (0) 2R \ -NH-S (0) 2R \ -S (0) NR'R' or -S (0) 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 represents hydrogen or alkyl of 1 to 6 carbon atoms; - X represents -CO-, -CO-NR'-, -S (O) - or -S (0) 2-, wherein R 'is hydrogen or an alkyl group of 1 to 6 carbon atoms; Y - R 5 represents an aryl, heteroaryl or heterocyclyl group, which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (C 1 -C 4 alkyl) -X 1 - (C 1 -C 4 alkyl) -X 2 - ( C1-C4 alkyl), where X! represents -O-, -S- or -NR ', wherein R' represents H or an alkyl group of 1 to 4 carbon atoms, and X2 represents -CO-, -SO- or -S02-, or R5 represents - A -, - Y-A2, wherein: - Ai is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; Y represents a direct bond or an alkylene portion of 1 to 4 carbon atoms, -S02-, -CO-, -O-, -S- or -NR'- wherein R 'is an alkyl group of 1 to 6 carbon atoms; and - A2 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group. As used herein, an alkyl group of 1 to 6 carbon atoms or portion is a group or linear or branched alkyl portion containing 1 to 6 carbon atoms, such as a group or alkyl portion of 1 to 4 carbon atoms . Examples of alkyl groups and portions of 1 to 4 carbon atoms include methyl, ethyl, n-propyl, / -propyl, n-butyl, / -butyl and butyl. To avoid any 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 that is substituted by one or more hydroxy groups.

Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group. A preferred hydroxyalkyl group is -CH 2 -OH.

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 (C 1-6 alkyl) amino, di (C 1-6 alkyl) amino, -C02R? -CRR? R, S (0) R? -S (0) 2R? , -S (0) NR'R ", -S (0) 2NR'R" -NH-S (0) 2R 'or -NH-CO-R', where each of R 'and R "is equal 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, -C02R ', -S (0) R', -S (0) 2R 'and -S (0) 2NR'R ", wherein each of R 'and R" is the same or different and represents hydrogen or alkyl of 1 to 4 carbon atoms. Particularly preferred substituents include fluorine, chlorine, bromine, iodine, cyano, 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 atoms carbon, 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 (alkyl of 1 to 4 carbon atoms) amino, nitro , -C02R \ -S (0) 2R 'and -S (0) 2 NH2, where R' represents alkyl of 1 to 2 carbon atoms. Highly preferred substituents include chlorine, fluorine, cyano, alkyl of 1 to 4 carbon atoms and 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 monocyclic carbocyclyl, heterocyclyl or heteroaryl group. Preferred ring systems are those in which an aryl group is fused to a fused group, which is a group heterocyclyl or monocyclic heteroaryl 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 . Most preferably, however, an aryl group, as used herein, is not fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group or said fused 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 cyclopropyl, cyclopentyl or cyclohexyl, most preferably cyclopropyl. 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 atoms carbon, 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 (a 1 to 6 carbon atoms) carbamoyl, di (C 1-6 alkyl) carbamoyl, amino, mono (C 1-6) alkyl amino, di (C 1-6 alkyl) amino), oxo, -C02R \ -CONR'R ", -S (0) R ', -S (0) 2R', -S (0) NR'R ", -S (0) 2NR'R", -NH-S (0) 2R 'or -NH-CO-R', where each of R 'and R "is equal 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 carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, d i (some 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, d (alkyl of 1 to 6 carbon atoms) amino, nitro, cyano and oxo. 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. Most preferably, a carbocyclyl group is not replaced. 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. Piperidinyl, thiomorpholinyl, imidazolidinyl and morpholinyl groups 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-imidazo! -2 (3H) -onyl group or an imidazolidin-2-onyl group is fused to a phenyl ring to form a 1-H-benzo group [c /] imidazole-2 (3H) -onyl. Most 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 (alkyl of 1 to 6 carbon atoms) carbomil, amino, mono (alkyl of 1 to 6 carbon atoms) amino, di (a l or uyl of 1 to 6 carbon atoms) amino, oxo, -C02R ', -CONR'R ", -S (0) R', - S (0) 2R ', -S (0) NR'R ", -S (0) 2NR'R", -NH- S (0) 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 in a heterocyclic 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. 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. Most preferably, a heterocyclyl group is unsubstituted or substituted by one or two alkyl groups of 1 to 2 carbon atoms or oxo. An example of a substituted heterocyclic group is S, S-dioxothiomorpholino. 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 alkylthio 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. Haloalkyl groups in particular are -CF3 and -CCi3. haloalkoxy groups in particular are -OCF3 and -OCCl3. 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 from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. . Other examples include oxazolyl and isothiazolyl. Preferred heteroaryl groups are pyridyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, furanyl and pyrazolyl. As used herein, references to a heteroaryl group include fused ring systems wherein a heteroaryl group is fused to a phenyl group or a heterocyclyl group monocyclic Preferred fused ring systems are those in which a 5- to 6-membered heteroaryl group is fused to a phenyl group or a 5- to 6-membered heterocyclyl group. Examples of such fused ring systems are benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, quinazolinyl, isoquinolinyl and 1H-imidazole moieties. [4,5-b] pyridin-2 (3 H) -one. Most preferably, said fused ring system is a 1 H-imidazo [4,4-b] pyridin-2 (3H) -one moiety. 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 (alkyl of 1 to 6 carbon atoms) carbamoyl, di (alkalyl of 1 to 6 carbon atoms) carbamoyl, amino , mono (C 1-6 -alkyl) amino, di (C 1-6) alkyl amino, -C02R? -CRR, -S (0) R ', -S (0) 2R ', -S (0) NR'R ", -S (0) 2NR'R", -NH- S (0) 2R' or -NH-CO-R ', 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 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, haloaikyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono (alkyl of 1 to 6 carbon atoms) amino, di (of 1 to 6 carbon atoms) amino, nitro and cyano. Highly preferred substituents include fluorine, chlorine, bromine, alkyl of 1 to 2 carbon atoms, and haloalkyl of 1 to 2 carbon atoms. When R1 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 an unsubstituted phenyl group.

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 or di (alkyl of 1 to 4 carbon atoms) amino. Preferably, R3 is fluorine, chlorine, bromine, alkyl 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, l < RTI ID = 0.0 > alkoalkyl < / RTI > of carbon atoms, haloalkoxy of 1 to 2 carbon atoms, amino, mono (alkyl) 1 to 2 carbon atoms) amino or di (alkyl of 1 to 2 carbon atoms) ammo. Most preferably, R3 is methyl, trifluoromethyl, fluorine, chlorine or bromine. Preferably, R3 is methyl or chloro. Typically, n in formula (V) is 0, 1 or 2. Preferably, n is 0 or 1. Most preferably, n is 0. 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. Typically, X in formula (V) is -CO-, -S (0) 2- or -CO-NR'-, wherein R 'represents hydrogen or an alkyl group of 1 to 2 carbon atoms. Preferably, X is -CO- or -CO-NR '. When R5 in the formula (V) is a heterocyclyl or a heterocyclyl group which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (C 1 -C 4 alkyl) -X 1 - (C 1 -C 4 alkyl) -X 2 - (C 1 -C 4 alkyl), the heterocyclyl or heteroaryl group is typically a 5- or 6-membered ring. Preferably, it is a heteroaryl group of or 6 members, for example, a furanyl group. Typically, the hydroxyalkyl group of 1 to 6 carbon atoms in the formula (V) is a -CH 2 -OH group. Typically, X in formula (V) is -NR ', wherein R' is hydrogen or alkyl of 1 to 2 carbon atoms. Typically, X2 in formula (V) is -S (0) 2. Typically, A-i in the formula (V) is an aryl or heteroaryl group. Preferably A- is a monocyclic aryl or heteroaryl group, a naphthyl group or a heteroaryl group fused to a heterocyclyl group substituted with monocyclic oxo. Most preferably, A ^ e is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group or a 5- to 6-membered heteroaryl group fused to a 5- to 6-membered heterocyclyl group substituted with monocyclic oxo (e.g., a substituted imidazolidibide group) with oxo). Most preferably, A-i is a phenyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thienyl or 1 H-imide [4,5-b] pyridin-2- (3H) -one moiety. Typically, the portion Ai in the formula (V) is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkyl halo of 1 to 4 carbon atoms and alkoxy substituents. from 1 to 4 carbon atoms. Preferably, the substituents are selected from the substituents halogen, cyano, alkyl of 1 to 2. carbon atoms, haloalkyl of 1 to 2 carbon atoms and alkoxy of 1 to 2 carbon atoms. Typically, Y in the formula (V) represents a direct bond, an alkylene group of 1 to 2 carbon atoms, -S02- or -O-. Typically, A2 in the formula (V) is a phenyl group, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or cycloalkyl having 3 to 6 carbon atoms. Preferably, A2 is a piperazinyl, pyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl or phenyl group. Typically, when A2 in the formula (V) and sun heterocyclyl group, it is attached to the Y portion through an N atom. Typically, the A2 portion in the formula (V) is unsubstituted or substituted by one or two substituents that Alkyl substituents of 1 to 4 carbon atoms and halogen are selected when A2 is a heteroaryl or aryl group and selected from alkyl substituents of 1 to 4 carbon atoms, halogen and oxo when A2 is a carbocyclic or heterocyclyl group. Most preferably, A2 in the formula (V) is a piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thiomorpholino group, said group is unsubstituted or substituted by an alkyl group of 1. to 2 carbon atoms. 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 , amino, mono (alkyl of 1 to 4 carbon atoms) amino or di (alkyl of 1 to 4 carbon atoms) amino, 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 of 1 to 2 carbon atoms or di (alkyl of 1 to 2 carbon atoms) amino; n is 0, 1 or 2; R 4 is hydrogen or alkyl of 1 to 4 carbon atoms; -X is -CO-, -CO-NR 'or -S (0 ) 2-, wherein R * is hydrogen or an alkyl group of 1 to 2 carbon atoms, and R5 is a 5- or 6-membered heterocycle or heteroaryl ring, which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (C1-C4 alkyl) -X1 (d-C4 alkyl) -X2- (d-C4 alkyl), wherein Xi and X2 are as defined above, or R5 represents -A-, -Y-A2, where: Ai e sun aryl or heteroaryl group; Y is a direct bond, an alkylene group of 1 to 2 carbon atoms, -S02- or -O-; and - A2 is an aryl, heteroaryl, heterocycle or carbocyclic group, the aryl moiety in the group R1 is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen groups, 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 and haloalkoxy of 1 to 6 carbon atoms, the portion Ai is unsubstituted or substituted by 1 or 2 substituents selected from substituents halogen, cyano, nitro, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and the A2 portion is unsubstituted or substituted by one or more substituents which are selected from C 1 -C 4 alkyl substituents and halogen when A2 is a heteroaryl or aryl group and which are selected from alkyl substituents of 1 to 4 atoms of carbon, halogen and oxo when A2 is carbocyclic or heterocyclyl ungroup. Other preferred compounds of the formula (V) are those wherein: - R 1 is alkyl of 1 to 2 carbon atoms or phenyl; - R2 is hydrogen or alkyl of 1 to 4 carbon atoms; - R3 is methyl, trifluoromethyl, fluorine, chlorine or bromine; - n is 0 or 1; - R4 is hydrogen or alkyl of 1 to 2 carbon atoms; - X is -CO-, -CO-NR'- or -S (0) 2, wherein R 'is hydrogen or an alkyl group of 1 to 2 carbon atoms; and R5 is a 5- or 6-membered heterocyclyl or heteroaryl group, the which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (alkyl of 1 to 4 carbon atoms) -NR'- (alkyl of 1 to 4 carbon atoms) -S02- (alky1 to 4 carbon atoms), wherein R 'is hydrogen or alkyl of 1 to 2 carbon atoms, or R 5 represents -Ai-Y-A2, wherein: Ai is ungroup phenyl, a 5- or 6-membered heterocyclic monocyclic group or a 5- or 6-membered heteroaryl group fused to a 5- to 6-membered heterocyclyl group substituted with monocyclic oxo; - Y represents a direct link, an alkylene portion of 1 to 2 carbon atoms, -S02- or -0-; and A2 is a phenyl, heteroaryl group of 5 to 6 members, heterocyclyl of 5 to 6 members or cycloalkyl of 3 to 6 carbon atoms, the phenyl portion in the group R '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 portion Ai is unsubstituted or substituted by 1 or 2 substituents selected from substituents halogen, cyano, nitro, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and the portion A2 is unsubstituted or substituted by 1 or 2 substituents which are selected from alkyl substituents from 1 to 4 carbon, halogen and oxo atoms when A2 is a heterocyclyl or cycloalkyl group and which are selected from alkyl substituents of 1 to 4 atoms, carbon and halogen when A2 is a phenyl or heteroaryl group. Particularly preferred compounds of the formula (V) are compounds of the formula (Va) and their pharmaceutically acceptable salts, wherein: X is -CO- or -CO-NH-; and R 5 is a 5- to 6-membered heteroaryl group, for example, a furanyl group, which is substituted by -CH 2 -OH or - (C 1 -C 4 alkyl) -N (CH 3) - (C 1 -C 4 alkyl) -S02- (C 1 -C 4 alkyl) or R 5 represents -A -? - Y-A2, wherein: Ai is a phenyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thienyl or 1 H-imidazo moiety 4,5-b] pyridin-2- (3H) -one, which is unsubstituted or substituted by 1 or 2 substituents selected from the substituents halogen, cyano, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon and alkoxy atoms of 1 to 2 carbon atoms; And it's a direct link, an alkylene group of 1 to 2 carbon atoms, -S02- or -O-; and A2 is a piperazinyl, pyridyl, morpholinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo, thiomorpholino group, which is unsubstituted or substituted by an alkyl group of 1 to 2 carbon atoms. In the compounds of the formula (Va), typically n is 0 and R is hydrogen. Preferably, in the compounds of the formula (Va), Ai is a phenyl or furanyl group, which is unsubstituted or substituted by a chlorine atom. Preferably, Y is a direct bond or a methylene group. Preferably, A2 is a morpholino group or S, S-dioxo-thiomorpholino. The compounds of formula (V) which contain one or more chiral centers may 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, 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. To avoid any doubt, the compounds of the formula (V) can, 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. Particularly preferred compounds of the formula (V) include: 6- (4-Methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [ 1,4] diazepin-3-yl) -nicotinamide; 3,4,5,6-tetrahydro-2H- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide. , 2 '] bipyridinyl-5'-carboxylic acid; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-1-2,3-dihydro-1H-benzo [e] [1 , 4] diazepin-3-yl-benzamide; (S) -2-Chloro-4-morpholin-4-yl-N- (2-oxo-5-phene-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -4-fluoro- (2-oxo-5-phenyl) -2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl-benzamide; (S) -5-Chloro-2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-ii) -amide of (S) -5- (4-methyl-piperazin- 1-ylmethyl) -furan-2-carboxylic acid; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-pyrrolidin-1-methylmethyl-furan -2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-Piperidin-1-ylmethyl-furan -2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-Dimethylaminomethyl-furan-2-carboxylic acid; (S) -4-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperidin-1-yl -benzamide; (S) -4-Fluoro-2-morpholino-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl -benzamide; (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -piperidin-1-yl-benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl-4-trifluoromethyl -benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperidin-1-yl-4-trifluoromethyl -benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H- benzo [e] [1,4] diazepin-3-yl) -4-trifluoromethyl-benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl-5-trifluoromethyl -benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -5-trifluoromethyl -benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1 H- benzo [e] [1 , 4] diazepin-3-yl) -nicotinamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -2-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -4-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -6-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2-Chloro-6- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -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 (S) -3-Cyclopropyl-2-oxo-2, 3-dihydro-imidazo [4,5-b] pyridine-1-carboxylic acid; (S) -3- (4-Methyl-piperazin-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3 -yl) -benzamide; (S) -4- (4-Methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H- benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (piperidin-1-sulfonyl) -benzamide; (S) -3- (Morpholin-4-sulfonyl) -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 (S) -5-morpholin-4-ylmethyl-furan- 2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-hydroxymethyl-furan-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5- (1, 1-dioxo-1) 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid; (S) -2-Chloro-4- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [ e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Chloro-5- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -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 (S) -5-. {[[(2-methanesulfonyl- ethyl) -methyl-amino] -methi.}. -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl. ) - (S) -2-pyridin-3-yl-thiazole-4-carboxylic acid amide: (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1, 4] diazepin-3-yl) -amide acid (S) -2-pyridin-4-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [ 1,4-diazepin-3-yl) -amide of (S) -4-methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -2-morpholin-4-ylmethyl-furan- 3-carboxylic; (S) -3-Morpholin-4-ylmethyl-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 (S) -5-morpholin-4-ylmethyl-isoxazole- 3-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -3-morpholin-4-ylmethyl-furan- 2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-pyridin-2-yl-thiophene 2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -2-methyl-4- (morpholine- 4-sulfonyl) -furan-3-carboxylic acid; (S) -6-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -3-morpholin-4-ylmethyl-thiophene 2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-morpholin-4-ylmethyl-thiophene 2-carboxylic; 2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-phenyl-oxazole-4-carboxylic acid; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-phenoxy-phenyl) -urea; or a pharmaceutically acceptable salt thereof. The compounds of the 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-C02H), benzotriazole and a benzyl carbamate appropriate to 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 X is -CO- or -CO-NR '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 hexaflorophosphate of 0-benzotpazol-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 urea. In the case where R 'in the X portion is hydrogen, 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 presence of a base, usually triethyloamine, again in THF. The compounds wherein R 'is different from hydrogen can, of course, be prepared by reacting a corresponding compound wherein R' is hydrogen with an appropriate alkylating agent, for example, L- (C- | -C6 alkyl), where L is a leaving group, for example chlorine. The compounds of the formula (V), wherein X is -S (0) 2- can be prepared through the reaction of a compound of the formula (VI ') with a suitable sulfonyl chloride. Similary, the compounds of the formula (V), wherein X is -S (O) - can be prepared through the reaction of a compound of the formula (VI ') with a suitable sulfinyl chloride. 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 (Vil ') 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 (VII ') are known compounds or they can be prepared through analogy with known methods. For example, they can be prepared through the reaction of isatoic anhydrides of the formula (HIV ') with N, 0-dimethyl hydroxylamino under standard reaction conditions. The starting materials of the formula (II '), (IIP), (Vil'), and (HIV ') are known compounds, can be prepared through 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 of formula (V) 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-methoxy-benzyl 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 racemic primary 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. Amide formations can be made using an acid 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 inert 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) -1 H- benzoimidazoI-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) -2-chloro-4-morpholin-4-yl-N (2-oxo-5-phenyl-2,3-dihydro- 1H-benzo [e] [1, 4] diazepin-3-yl) -benzamide or (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) (1,1-dioxo-1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid 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 from 0.025 wt% to 10 wt%, preferably from 0.25 wt% to 5 wt%, preferably from 1 wt% to 3.5 wt% 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%. by weight, for example about 2.5% by weight, based on the total weight of the composition. - Typically, the total amount of 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 around 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 of gestation or before, until they reach 6 months of age, the elderly, people with immunodeficiency and those who are in health care facilities during long time. Therefore, said composition or medication is typically to be used to prevent RSV infection in a child under 6 years of age, who was born after 32 weeks of gestation or less, elderly people, people with immunosuppression and those who are in care facilities of the health 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 therapeutic 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). Alternatively, component (b) can be administered up to 24 hours before component (a). More usually, when components (a) and (b) are administered separately, they are administered in 12 hours, preferably in 6 hours, with each other.

Therefore, 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 treatment of the body of a human or animal. Typically, said product is for separate, simultaneous or sequential use to treat or prevent infection by RSV. The use of an RSV fusion protein inhibitor in the manufacture of a medicament for use in the treatment or prevention of an RSV infection is also provided 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, they are typically formulated as described above. The amount of the active ingredient in each separate formulation, of course, will correspond to the amount of component (a) or (b) given above for the combined formulation. Thus, when components (a) and (b) are administered separately, a first formulation containing 0.025% by weight to 10% by weight, preferably 0.25% by weight to 5% by weight, is typically provided. weight, preferably from 1% by weight to 3.5% by weight, for example about 2.5% by weight, of said protein inhibitor of RSV fusion, based on the total weight of the formulation.

Similarly, a second formulation containing 0.025 wt% to 10 wt%, preferably of 10% by weight, is typically provided. 0. 25% by weight to 5% by weight, preferably from 1% by weight to 3.5% by weight, for example about 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 higher activity than the individual combined 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 an amount that produces a synergistic therapeutic effect for treating or preventing 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, intramuscularly, intrasternally, intradermally or through infusion techniques. The compounds can also be administered as suppositories.

In a preferred embodiment, the administration is through an intravenous, intranasal or intrabronchial means. In particular, formulations for treating or preventing RSV can advantageously be administered in intranasal form. The present invention, therefore, 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 carrier or diluent. The anti-RSV compositions of the invention are typically formulated to be administered with a pharmaceutically acceptable carrier or diluent. For example, oral dosage forms may contain, together with the active compound (s), diluents, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch, lubricants, eg, silica, talc, stearic acid. , magnesium or calcium stearate, and / or polyethylene glycols; binding agents; for example, starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose 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 pharmaceutical formulations. Said pharmaceutical preparations can be manufactured in a known manner, for example, through of mixing, granulating, tabletting, sugar coating, or film coating processes. Liquid dispersions for oral administration can be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. 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 oleate, glycols, for example propylene glycol, and if desired, an appropriate amount of lidocaine chloride. The solutions for injection or infusion may contain, for example, sterile water or preferably they may be in the form of saline solutions, sterile, watery and isotonic. Preferably, the anti-RSV compositions of the invention are solubilized in a carrier containing (a) a pharmaceutically acceptable oil selected from esterification or polyether products of vegetable oil fatty acid glycerides with a chain length of from 8 to 10. carbon atoms and (b) a pharmaceutically acceptable surfactant selected from oleate and laurate esters of a polyalcohol copolymerized with ethylene oxide. The vehicles particularly Preferred products contain Labrafil as the oil and Tween 20 or Tween 80 as the surfactant. The anti-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 treated, 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 particular assays used in the examples section are designed only to provide an indication of antiviral activity. There are many assays available to determine the activity of compound data against RSV, and a negative result in any particular assay, therefore, is not determinative.

EXAMPLES Intermediary 1 2-Chloro-4- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid A mixture of 4-amino-2-chlorobenzoic acid (172 mg) and etensulfonyl-ethene (0.15 ml) in Water (3 ml) containing sodium carbonate (212 mg) was heated at 100 C for 18 h. The mixture was allowed to cool and acidified with 2N HCl. The off-white precipitate was collected and dried (263 mg). LC / MS RT = 4.09 mins, ES- 288,290 Intermediary 2 2-Chloro-5- (1,1-di-oxo-1? 6-thiomorpholin-4-yl) -benzoic acid A mixture of 5-amino-2-chlorobenzoic acid (172 mg) and etensulfonyl-ethene (0.15 ml) in water (3 ml) it was heated to 100 C for 18 h. The mixture was allowed to cool and extracted with dichloromethane. The dried extracts were evaporated to give a pale brown solid (265 mg). LC / MS RT = 4.13mins, ES- 288,290 Intermediary 3 2- (1,1-Dioxo-1? 6-thiomorpholin-4-ip-nicotinic acid) This material was prepared as described for Intermediate 1 except that 2-amino-nicotinic acid (138 mg) was used. title was isolated as an off-white solid (93 mg) Intermediary 4 2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -3-methyl-benzoic acid This material was prepared as described for Intermediate 2 except that 2-amino-3-methylbenzoic acid was used ( 302 mg). The title compound was isolated as a pale brown solid (486 mg).

Intermediary 5 2- (1, 1-d i oxo-1? 6-thiomorph i n-4-i I) -4-methyl I-benzoic acid This material was prepared as described for the Intermediary 2 except that 2-amino-4-methylbenzoic acid (302 mg) was used. The title compound was isolated as a brown solid (430 mg) Intermediary 6 2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -6-methyl-benzoic acid This material was prepared as described for Intermediate 2 except that 2-amino-6-methylbenzoic acid was used (302 mg). The title compound was isolated as a brown solid (490 mg) Intermediate 7 3- (4-Methyl-piperazin-1-sulfonyl) -benzoic acid A solution of 3-chlorosulfonyl-benzoic acid (89 mg) 4-dimethylamino-pyridine (catalytic amount) and N-methylpiperazine (0.045 ml) in dichloromethane (10 mL) was heated to reflux for 2 h. The solvent was then evaporated and the raw material was used without purification or characterization in the next synthetic step.

Intermediary 8 3-piperidin-1-sulfonyl-benzoic acid This material was prepared as described for the Intermediary 7 except that piperidine was used as the nucleophile. As for Intermediary 7, the material was used raw.

Intermediary 9 3- (Morpholin-4-sulfonyl) -benzoic acid This material was prepared as described for Intermediary 7 except that morpholine was used as the nucleophile. As for Intermediary 7, the material was used raw.

Intermediary 10 2-Chloro-6- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid This material was prepared as described for Intermediate 2 except that 2-amino-6-chlorobenzoic acid was used ( 343 mg). The title compound was isolated as a yellowish solid (405 mg) Intermediary 11 -Chloro-2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid This material was prepared as described for Intermediate 2 except that 2-amino-5-chlorobenzoic acid was used (200 mg). The title compound was isolated as a white solid (233 mg) 1 H NMR (DMSO, d) 3.25 (brs, 4 H) 3.47 (brs, 4 H) 7.31 (d, 1 H) 7.54 (dd, 1H) 7.71 (d, 1H) LC / MS RT = 4.66 min ES + = 290.292 was found Intermediary 12 2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -5-fluoro-benzoic acid This material was prepared as described for Intermediate 2 except that 2-amino-5-fluorobenzoic acid was used ( 200 mg). The title compound was isolated as a white solid (310 mg) 1 H NMR (DMSO, d) 3.28 (m, 4 H) 3.42 (m, 4 H) 7.33-7.56 (m, 3 H) LC / MS RT = 4.28 min. ES "= 272 Intermediary 13 4-Fluoro-2-thiomorpholin-4-yl-benzoic acid A mixture of 2,4-difluoro-benzoic acid (0.5 g), thiomorpholine (0.33 ml) and triethylamine (0.88 ml) in acetonitrile (2 ml) was heated to 200 ° C in a microwave reactor for 20 mins. The residue was partitioned between water and dichloromethane. The dried organic layer was evaporated and then purified on an SPE cartridge of silica gel. Elution with dichloromethane followed by a gradient of dichloromethane: ethanol: 0.880 ammonia; 800: 8: 1 to 200: 8: 1 gave the title material as a white solid (292 mg) 1 H NMR (DMSO, d) 2.81 (m, 4 H) 3.27 (m, 4 H) 7.11 (m, 1 H) 7.40 (dd, 1H) 7.95 (m, 1H) Intermediary 14 2- (1,1-di-oxo-4-oxy-1? 6-thiomorphyl-n-4-yl) -4-fluo-benzoic acid Intermediate 11 (262mg) and potassium peroxymonosulfate (1.34 g) in methanol (5 ml) and water (2.5 ml) were stirred at room temperature for 6 h. The formed precipitate was collected by filtration, then dissolved in aqueous sodium bicarbonate. Acidification at pH 3 with 1M HCl led to the formation of a white precipitate, which was collected and dried (194 mg). 1H NMR (DMSO, b) 3.2-3.48 (brm, 4H) 3.59 (t, 2H) 3.89 (t, 2H) 6.96 (m, 1H) 7.30 (dd, 1H) 7.85 (m, 1H) Intermediary 15 6-Chloro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreip, 4-diazepin-3-yl) -nicotinamide A mixture of 3-amino-5-phenyl-1,3-dihydro- Racemic benzo [e] [1,4] diazepin-2-one (1 g), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (1.51 g), triethylamine (0.83 ml) ) and 6-chloro-nicotinic acid (0.63 g) in dry DMF (20 ml) was stirred at room temperature for 1.5 h. Then water (200 ml) was added and the mixture was stirred vigorously for 10 mins. The colorless precipitate was collected by filtration and dried (1.1 g). 1 H NMR (DMSO,?) 5.50 (d, 1H) 7.28-7.71 (m, 10H) 8.42 (dd, 1H) 9.01 (d, 1H) 9.99 (d, 1H) 10.95 (s, 1H) LC / MS RT = 4.96mins, ES + 391,393 Intermediary 16 Tiomorpholin-1, 1-dioxide 9.98 g of thiomorpholine and 14.8 g of triflic anhydride in DCM were stirred together at room temperature for 2 hours. The reaction was then divided between 1 M K2C03 (ac) and DCM. The organic layer was separated and dried by passing it through a hydrophobic frit, then concentrated in vacuo. 13.82 g of the resulting oil were stirred with 85.2 g of oxone in 50 mL of methanol and 50 mL of water for 18 h at room temperature. The reaction was then filtered and washed with methanol and the filtrate was concentrated. This was then partitioned between water and EtOAc and the aqueous layer was washed 3 times with EtOAc. The combined organic extracts were then dried (MgSO4) and concentrated to yield a white solid. This was then stirred at room temperature with 40 g of K2CO3 in 80 mL of methanol for 18 h. The methanol was then removed in vacuo and the rest was partitioned between DCM and sat. K2C03 (ac) - The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo to yield the title compound, 3.51 g. 1 H NMR (CDCl 3, d) 1.54 (s, 1 H), 2.93-2.97 (m, 4 H), 3.24-3.28 (m, 4 H).

Intermediary 17 Ethyl ester of 5- acid. { ((2-methanesulfonyl-ethyl) -methyl-amino-1-methyl-furan -2-carboxylic 0.5 g of 5-chloromethyl-furan-2-carboxylic acid ethyl ester and 20 ml of 2 M of a solution of methylamine in THF were stirred at room temperature for 5 days under nitrogen. The solution was then concentrated and purified by SPE. The resulting oil was heated at 200 ° C in a microwave with 0.2 mL of methanesulfonyl-ethene in 3 mL of acetonitrile for 1 h. The solution was concentrated and purified by chromatography to yield the title compound as a colorless oil. LC / MS RT = 3.55 min, ES + = 290 1H NMR (CDCI3, d) 1.29 (t, 3H), 2.25 (s, 3H), 2.92-2.88 (m, 2H), 2.99 (s, 3H), 3.06-2.99 (t, 2H ), 3.6 (s, 2H), 4.26 (q, 2H), 6.28 (d, 1H), 7.04 (d, 1H).

Intermediary 18 -Dimethylaminomethyl-furan-2-carboxylic acid 0.16 ml of a 2 M solution of dimethylamine was added to a stirred suspension of 19.2 mg of sodium hydride in 2 mL of DMF under a nitrogen atmosphere at room temperature for 30 min. Then a solution of 5-chloromethyl-furan-2-carboxylic acid ethyl ester in 2 mL of DMF was added dropwise. during a period of 30 min. The reaction was then allowed to stir for 2 days. The solvent was then removed under vacuum and 5 mL of EtOH and 0.35 mL of 2 M NaOH were added and stirred at 80 ° C for 40 min. After returning, the reaction was acidified below a pH 5.0 and the solvent was removed in vacuo to yield the title compound that will be hydrolyzed and then used crude in the next step.

Intermediates 19-23 were prepared in an analogous manner and used without characterization in the next synthetic step.

Intermediary 19 -Morpholin-4-ylmethyl-furan-2-carboxylic acid Intermediary 20 - (1,1-Dioxo-1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid Intermediary 21 - (4-M ethyl-pi-erazin-1-ylmethyl) -fura n-2-carboxylic acid Intermediary 22 - (Piperidin-1-ylmethyl) -furan-2-carboxylic acid Intermediary 23 - (Pirrol i din -1 -i l meti l) -fu ran-2-carboxylic acid Intermediary 24 3-Cyclopropyl-1,3-dihydror4,5-b1pyridin-2-one A mixture of 2-chloro-3-nitro-pyridine (2g), cyclopropylamine (1.13 ml) and potassium carbonate (3.48 g) in acetonitrile (30 ml) was stirred at room temperature for 18 h. The mixture was then partitioned between water and ethyl acetate. The dried extracts were evaporated giving a bright yellow solid (2.1g). This material was then hydrogenated at atmospheric pressure in ethanol (150 ml) on a palladium on carbon catalyst (10%, 100 mg). When the hydrogen consumption ceases, the mixture is filtered through celite and evaporated giving a dark gum (1.7 g). This material was then dissolved in dry THF (40 ml) and treated with carbonyl diimidazole (2.2 g) at reflux for 2.5 h. The mixture was then partitioned between water and ethyl acetate. The dried organic extract was evaporated leaving a dark gum, which was crystallized from ethyl acetate / petrol to give a colorless solid (1-2 g). 1 H NMR (DMSO, d) 0.97-1.04 (m, 4H) 2.92 (m, 1H) 6.97 (dd, 1H) 7.22 (dd, 1H) 7.92 (dd, 1H) 10.95 (brs, 1H) Intermediary 25 2-Morpholin-4-ylmethyl-furan-3-carboxylic acid methyl ester A mixture of 2-chloromethyl-furan-3-carboxylic acid methyl ester (100 mg) and morpholine (0.08 ml) in acetonitrile (4 ml) stirred at room temperature for 2 h. The mixture was then partitioned between dichloromethane and an aqueous solution of sodium bicarbonate. The dried organic layer was evaporated giving a yellow oil (75 mg) 1 H NMR (CDCl 3, d) 2.57 (m, 4 H) 3.74 (m, 4 H) 3.86 (s, 3 H) 3.97 (s, 2 H) 6.70 (d, 1 H 7.38 (d, 1H) Intermediary 26 3-Morpholin-4-ylmethyl-benzoic acid methyl ester This material is prepared as for Intermediary 25. The product was a colorless oil (210 mg). 1 H NMR (CDCl 3, d) 2.43 (m, 4 H) 3.53 (s, 2 H) 3.70 (m, 4 H) 3.91 (s, 3 H) 7.39 (t, 1 H) 7.42 (dd, 1 H) 7.93 (dt, 1 H) 7.99 (brs, 1H) Intermediary 27 -Morpholin-4-ylmethyl-isoxazole-3-carboxylic acid methyl ester 5-Methyl-isoxazole-3-carboxylic acid methyl ester (200 mg), N-bromosuccinimide (252 mg) and benzoyl peroxide (30 mg) were stirred. mg) in dry chloroform (4 ml) and heated at 85 ° C for 5 h. The solution was cooled to room temperature and triturated with morpholine (0.27ml). Stirring was continued for 20 h and the mixture was then partitioned between water and dichloromethane. The dried organic extract was evaporated and the residue was purified on an SPE cartridge of silica gel. Elution with dichloromethane followed by dichloromethane: ethanol: 0.880 ammonia; 200: 8: 1 gave a colorless oil (50 mg). 1 H NMR (CDCl 3, d) 2.46 (m, 4 H) 3.64 (m, 4 H) 3.67 (s, 2 H) 3.90 (s, 3 H) 6.55 (s, 1 H) Intermediates 28-30 were prepared in a method analogous to Intermediary 25 Intermediary 28 3-Morpholin-4-ylmethyl-furan-2-carboxylic acid methyl ester This compound was isolated as a yellow oil (189 mg) 1 H NMR (CDCl 3, d) 2.45 (m, 4 H) 3.65 (m, 4 H) 3.71 ( s, 2H) 3.85 (s, 3H) 6.56 (d, 1H) 7.45 (d, 1H) Intermediary 29 3-Morpholin-4-ylmethyl-thiophene-2-carboxylic acid methyl ester This compound was isolated as a yellow oil (197 mg). 1 H NMR (CDCl 3, d) 2.50 (m, 4 H) 3.69 (s, 2 H) 3.72 (m, 4 H) 3.86 (s, 3 H) 6.90 (d, 1 H) 7.64 (d, 1 H) Intermediary 30 -Morpholin-4-ylmethyl-thiophene-2-carboxylic acid methyl ester This compound was isolated as a yellow oil (214mg). 1 H NMR (CDCl 3, d) 2.44 (m, 4 H) 3.64 (m, 4 H) 3.79 (s, 3 H) 3.84 (s, 2 H) 7.15 (d, 1 H) 7.36 (d, 1 H) Intermediates 25-30 were hydrolysed to the corresponding carboxylic acids before being used in the final coupling step of the synthetic sequence.

Intermediary 31 4-Fluoro-2-morpholin-4-yl-benzoic acid 2,4-difluoro-benzoic acid (50 mg) and morpholine (0.03 ml) were heated in acetonitrile (0.5 ml) in microwaves at 200 ° C for 15 minutes. mins The solvent was evaporated leaving a dark gum, which was used without purification in the next synthetic step.

Intermediary 32 4-Fluoro-2-piperidin-1-yl-benzoic acid This is prepared in a procedure analogous to Intermediate 31.

Intermediates 33-5 were prepared in a procedure analogous to Intermediate 31 except that 2-fluoro-4-trifluoromethyl-benzoic acid was used.

Intermediary 33 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid Intermediary 34 2-piperidin-1-yl-4-trifluoromethyl-benzoic acid Intermediary 35 2-Morpholin-4-yl-4-trifluoromethyl-benzoic acid Intermediates 36 and 37 were prepared in a procedure analogous to Intermediary 31 except that 2-fluoro-5-trif-I uoro-methyl-benzoic acid was used.

Intermediary 36 2-pyrrolidin-1-yl-5-trifluoromethyl-benzoic acid Intermediary 37 2-Morpholin-4-yl-5-trifluoromethyl-benzoic acid Intermediates 38 and 39 were prepared in a procedure analogous to Intermediate 31 except that 4-cyano-2-fluoro-benzoic acid was used.

Intermediary 38 4-Cyano-2-pyrrolidin-1-yl-benzoic acid Intermediary 39 4-Cyano-2-piperidin-1-yl-benzoic acid Example 1 6- (4-Methyl-piperazin-1-y-N- (2-oxo-5-phenyl-2,3-dihydro-1H- benzofeip, 41diazepin-3-yl) -nicotinamide Intermediate 15 (50 mg) and N-methylpiperazine (0.022 ml) in acetonitrile (1 ml) containing triethylamine (0.027 ml) was heated in a microwave at 200 ° C for 10 mins. The mixture was then partitioned between water and dichloromethane. The dried organic layer was evaporated and the residue was purified on an SPE cartridge of silica gel. Elution with gradient of 5-10% methanol in dichloromethane gave a colorless solid (10 mg) 1 H NMR (DMSO, d) 2.28 (s, 3 H) 2.45 (m, 4 H) 3.68 (m, 4 H) 5.56 (d, 1H) 6.93 (d, 1H) 7.32-7.72 (m, 10H) 8.20 (dd, 1H) 8.82 (d, 1H) 9.42 (d, 1H) 10.94 (s, 1H) RT = 3.94mins, ES + 455 Example 2 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [eU1,41diazepin-3-yl) -amide 3,4,5,6-tetrahvdro-2H-ri, 2'1b-pyridinyl amide -5'-carboxylic This material was prepared as in Example 1 except that piperidine was used as the nucleophile. The product was a colorless solid (15 mg) 1 H NMR (DMSO, d) 1.54-1.63 (brm, 6H) 3.65 (m, 4H) 5.48 (d, 1H) 6.86 (d, 1H) 7.25-7.65 (m, 10H ) 8.11 (dd, 1H) 8.75 (d, 1H) 9.32 (d, 1H) RT = 4.54 mins, ES + 440 Example 3 (S) -2- (1.1-Dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzorel, 41diazepin-3-yl-benzamide) (S) -3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (100mg), O-benzotriazol-1-yl-NNN 'hexafluorophosphate. N'-tetramethyluronium (150 mg), 2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid (102 mg) and triethylamine (0.083 ml) in dry DMF (1 ml) at room temperature After 1 h water was added (10 ml) and the stirring was continued for 10 min.The colorless precipitate was collected by filtration and then partitioned between dichloromethane and water.The dried organic phase was evaporated and the residue was purified on a silica gel SPE cartridge Elution with ethyl acetate: petrol 1: 1 gave the title compound as a colorless solid (140 mg) 1 H NMR (DMSO, d) 3.49 (brs, 8H) 5.48 (d. , 1H) 7.31-7.95 (m, 13H) 10.86 (d, 1H) 11.18 (s, 1H) Example 4 (S) -2-Chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreiri, 41diazepin-3-yl) -benzamide This material is prepared as Example 3 except that 2-chloro-4-morpholin-4-yl-benzoic acid (86 mg) was used. The title compound was a colorless solid (112mg). 1 H NMR (DMSO, d) 3.21 (m, 4 H) 3.70 (t, 4 H) 5.36 (d, 1 H) 6.90-6.97 (m, 2H) 7.21-7.66 (m, 10H) 9.21 (d, 1H) 10.86 (s, 1H) Example 5 (S) -2- (1,1-Dioxo-4-oxy-1? 6-thiomorpholin-4-yl) -4-fluoro- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoyl) , 41-diazene-3-yl-benzamide This material was prepared as Example 3 except that 2- (1,1-dioxo-4-oxy-1? 6-thiomorpholin-4-yl) -benzoic acid was used (Intermediate 14 30 mg) The title compound was a colorless solid (29 mg). 1 H NMR (DMSO, d) 3.32-3.98 (m, 8H) 5.34 (d, 1H) 6.99 (dt, 1H) 7.16-7.65 (m, 11H) 9.51 (d, 1 H) 10.98 (s, 1H) RT = 5.09 mins, ES + 523 Example 6 (S) -5-Chloro-2- (1,1-dioxo-1? 6-thiomorpholin-4-ih-N- (2-oxo-5-phenyl-1-2.3-dihydro-1H-benzo reU1.4 ] diazepln-3-yl) -benzamide This material was prepared as in Example 3 except that 5-chloro-2- (1,1-dioxo-1,6-thiomorpholin-4-yl) -benzoic acid was used (Intermediary 11, 58 mg). The title compound was a colorless solid (70 mg). 1 H NMR (DMSO, d) 3.54 (s, 8 H) 5.53 (d, 1 H) 7.37-7.75 (m, 11 H) 7.90 (d, 1H) 10.84 (d, 1H) 11.24 (s, 1H) RT = 5.38mins, ES + 523,525 Example 7 (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-in-5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreir, 41diazepin -3-yl) -benzamide This material was prepared as in Example 3 except that 5-fluoro-2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid was used (Intermediary 12, 54 mg). The title compound was a colorless solid (70 mg). 1H NMR (DMSO, d) 3.49 (m, 8H) 5.47 (d, 1H) 7.34-7.69 (m, 12H) 11.12 (d, 1H) 11.20 (s, 1H) RT = 5.19 mins, ES + 507 Example 8 (S) -5- (4-Methyl-piperazin-1-ylmethip-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo reU1.41diazepin-3-yl) -amide This material was prepared as Example 3 except that 5- (4-methyl-piperazin-1-ylmethyl) -furan-2-carboxylic acid was used (Intermediary 21). The title compound was a colorless solid (15 mg). 1 H NMR (CDCl 3, d) 2.23 (s, 3 H), 2.43-2.51 (m, 8 H), 3.56 (s, 2 H), 5.65 (d, 1 H), 6.29 (d, 1 H), 7.05-7.51 (m, 11H), 7.92 (d, 1H). RT = 4.10 mins, ES + 458 Example 9 (2-OXQ-5 -f in 1,2-dihydr or-1 H-benzore-1, 41-diazepin-3-yl) -amide of (S) -5-Pyrrolidin-1-ylmethyl-furan-2- carboxylic This material was prepared as Example 3 except that 5- (pyrrolidin-1-ylmethyl) -furan-2-carboxylic acid (Intermediate 23) was used. The title compound was a colorless solid (52 mg). 1H NMR (CDCIs, d) 1.76-1.77 (m, 4H), 2.60-2.62 (m, 4H), 3.71 (s, 2H), 5.64 (d, 1H), 6.31 (d, 1H), 7.05-7.50 ( m, 10H), 7.98 (d, 1H), 8.04 (s, 1H). RT = 4.09 mins, ES + 403 Example 10 (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzofeU1,4-diazepin-3-yl) -amide acid (S) -5-iperidin-1-ylmethyl-furan-2-carboxylic acid This material is prepared as Example 3 except that 5- (piperidin-1-ylmethyl) -furan-2-carboxylic acid (Intermediary 22) was used. The title compound was a colorless solid (21 mg). 1 H NMR (CDCl 3, d) 1.36-1.45 (m, 2H), 1.53-1.60 (m, 4H), 2.45-2.55 (m, 4H), 3.62 (s, 2H), 5.65 (d, 1H), 6.34 ( d, 1H), 7.06-5.52 (m, 10H), 7.81-7.89 (m, 1H), 7.96 (d, 1H). RT = 4.16 mins, ES + 443 Example 11 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzore1H, 4ldiazepin-3-yl) -amide acid (S) -5-dimethylaminomethyl-furan-2-carboxylic acid This material was prepared as Example 3 except that 5-dimethylaminomethyl-furan-2-carboxylic acid (Intermediate 18) was used. The title compound was a colorless solid (5 mg). 1 H NMR (DMSO, d) 2.35 (s, 6 H), 3.69 (s, 2 H), 5.56 (d, 1 H), 6.65 (d, 1 H), 7.48-7.85 (m, 10 H), 9.1 (d, 1 H) , 11.13 (s, 1H). RT = 4.09 mins, ES + 403 Example 12 (S) -4-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41 diazepin-3-yl) -2-piperidin-1-yl-benzamide This material was prepared as Example 3 except that 4-fluoro-2-piperidin-1-yl-benzoic acid (Intermediary 32) was used. The title compound was a colorless solid (58 mg). 1 H NMR (DMSO, d) 1.62-1.67 (m, 2H) 1.91-1.99 (m, 4H) 3.08-3.16 (m, 4H) 5.56 (d, 1H) 7.15-7.79 (m, 11 H) 8.10-8.13 (m, 4H) m, 1H) 11.08 (syd, 2H) RT = 6.02 mins, ES + 457 Example 13 (S) -4-Fluoro-2-morpholino-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzophe-1M, 41-diazepin-3-yl) -benzamide This material was prepared as Example 3 except that 4-fluoro-2-morfoiin-4-yl-benzoic acid (Intermediate 31) was used. The title compound was a colorless solid (19mg). 1 H NMR (DMSO, d) 2.94-3.00 (m, 4H) 3.71-3.82 (m, 4H) 5.35 (d, 1H) 6.98-7.85 (m, 12H) 10.52 (d, 1H) 10.90 (s, 1H) RT = 5.34 mins, ES + 459 Example 14 (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1.4I diazepin-3-yl) -2-pyrrolidin-1-yl-benzamide This material was prepared as in Example 3 except that 4-cyano-2-pyrrolidin-1-yl-benzoic acid (Intermediary 38) was used. The title compound was a colorless solid (13 mg). H NMR (DMSO, d) 1.87 (brs, 4H) 3.29 (brs, 4H) 5.37 (d, 1H) 7.01-7.65 (m, 12H) 9.60 (d, 1H) 10.88 (s, 1H) RT = 5.45 mins, ES + 450 Example 15 (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreiri, 4] diazepin-3-yl) -piperidine-1-yl-benzamide This material was prepared as Example 3 except that 4-cyano-2-piperidin-1-yl-benzoic acid (Intermediate 39) was used. The title compound was a colorless solid (27 mg). 1 H NMR (DMSO, d) 1.32-1.36 (m, 2H) 1.58-1.67 (m, 4H) 2.81-2.89 (m, 4H) 5.25 (d, 1H) 7.10-7.83 (m, 12H) 10.70 (d, 1H ) 10.81 (s, 1H) RT = 5.88mins, ES + 464 Example 16 (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-H-benzoreip, 4-diazepin-3-yl) -2-pyrrolidin-1-yl-4-trifluoromethyl-benzamide This material was prepared as Example 3 except that 2-pyrroic acid was used! id in- 1 -yl-4-trifluoromethylbenzoic (Intermediary 33). The title compound was a colorless solid (5 mg). 1H NMR (DMSO, d) 1.89-1.92 (brs, 4H) 3.29-3.32 (brs, 4H) 5.40 (d, 1H) 6.88 (s, 1H) 6.94 (d, 1H) 7.24-7.67 (m, 10H) 9.56 (d, 1H) 10.89 (s, 1H) RT = 5.91 mins, ES + 493 Example 17 (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41-diazepin-3-yl) -2-piperidin-1-yl-4-trifluoromethyl-benzamide This material was prepared as Example 3 except that 2-piperidin-1-yl-4-trifluoromethylbenzoic acid (Intermediate 34) was used. The title compound was a colorless solid (14 mg). 1 H NMR (DMSO, d) 1.53-1.57 (m, 2H) 1.80-1.91 (m, 4H) 3.00-3.14 (m, 4H) 5.46 (d, 1H) 7.30-7.72 (m, 11 H) 8.09 (d, 1H) 10.98 (d, 1H) 10.99 (s, 1H) RT = 6.39 mins, ES + 507 Example 18 (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1.4l d-azepin-3-p-4-trifluoromethyl-benzamide This material is prepared as Example 3 except that 2-morpholin-4-yl-4-trifluoromethylbenzoic acid (Intermediate 35) was used.The title compound was a colorless solid (14 mg). 1H NMR (DMSO, d) 3.18-3.24 ( m, 4H) 3.90-3.96 (m, 4H) 5.52 (d, 1H) 7.36-8.10 (m, 12H) 10.59 (d, 1H) 11.10 (s, 1H) RT = 5.72 mins, ES + 509 Example 19 (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoreip, 41-diazepin-3-in-2-pyrrolidin-1-yl-5-trifluoromethyl-benzamide This material was prepared as in Example 3 except that 2-pyrrolidin-1-yl-5-trifluoromethylbenzoic acid (Intermediate 36) was used.The title compound was a colorless solid (8 mg) .1H NMR (DMSO, d) 2.00-2.02 (brs, 4H) 3.40-3.43 (brs, 4H) 5.48 (d, 1H) 6.90 (d, 1H) 7.34-7.74 (m, 11 H) 9.71 (d, 1H) 10.98 (s, 1H) RT = 5.84 mins , ES + 493 Example 20 (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1.4l diazepin-3-yl) -5-trifluoromethyl-benzamide This material was prepared as Example 3 except that 2-morpholin-4-yl-5-trifluoromethylbenzoic acid (Intermediate 37) was used. The title compound was a colorless solid (19 mg). 1 H NMR (DMSO, d) 3.13-3.18 (m, 4H) 3.85-3.90 (m, 4H) 5.46 (d, 1H) 7.30-7.69 (m, 10H) 7.88 (dd, 1H) 8.04 (d, 1H) 10.37 (d, 1H) 11.04 (s, 1H) RT = 5.72mins, ES + 509 Example 21 (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,5-phenyl-2H-benzofe1f1.41 diaze in-3-ip-nicotinamide This material was prepared as the Example 3 except that 2-morpholin-4-yl-nicotinic acid was used The title compound was a colorless solid (45 mg) 1 H NMR (DMSO, d) 3.30-3.36 (m, 4H) 3.82-3.85 (m , 4H) 5.45 (d, 1H) 7.14-7.17 (m, 1H) 7.18-7.71 (m, gH) 8.07 (dd, 1H) 8.44 (dd, 1H) 10.00 (d, 1H) 11.05 (s, 1H) RT = 4.86 mins, ES + 442 Example 22 (S) -2- (1,1-Pioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreiri, 41diazepin-3-yl) ) -nicotinamide This material was prepared as Example 3 except that 2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -nicotinic acid (Intermediate 3) was used. The title compound was a colorless solid (10mg). 1H NMR (DMSO, d) 3.25 (t, 2H) 3.40 (t, 2H) 3.75-3.88 (m, 4H) 5.47 (d, 1H) 6.67-6.72 (m, 1H) 7.28-7.67 (m, 8H) 8.24 -8.38 (m, 3H) g.56 (d, 1H) 10.92 (s, 1H) RT = 4.43 mins, ES + 508 Example 23 (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -3-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H- benzoreiri, 4-diazepin-3-yl) -benzamide This material was prepared as in Example 3 except that 2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -3-methyl-benzoic acid was used (Intermediary 4). The title compound was a colorless solid (65 mg). 1 H NMR (DMSO, d) 2.36 (s, 3 H) 3.24 (brs, 4 H) 3.49 (brs, 4 H) 5.43 (d, 1 H) 7.11-7.68 (m, 12 H) 9.61 (d, 1 H) 10.99 (s, 1 H ) RT = 5.04 mins, ES + 503 Example 24 (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -4-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoyl) -1,41 diazepin -3-yl) -benzamide This material was prepared as in Example 3 except that 2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -4-methyl-benzoic acid was used (Intermediary 5). The title compound was a colorless solid (72 mg). 1 H NMR (DMSO, d) 2.39 (s, 3 H) 3.44-3.54 (brm, 8 H) 5.46 (d, 1 H) 7.14 (d, 1 H) 7.31-7.69 (m, 10 H) 7.86 (d, 1 H) 10.94 (d , 1H) 11.17 (s, 1H) RT = 5.20 mins, ES + 503 Example 25 (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -6-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzofe1f1.41diazepin -3-yl) -benzamide This material was prepared as in Example 3 except that 2- (1,1-dioxo-1α-6-thiomorph i n-4-i I) -6-methyl I -benzoic acid was used. ico (Intermediary 6). The title compound was a colorless solid (32 mg). H NMR (DMSO, d) 2.27 (s, 3H) 3.24-3.27 (m, 4H) 3.41-3.43 (m, 4H) 5.56 (d, 1H) 7.03 (d, 1H) 7.11 (d, 1H) 7.25-7.68 (m, 10H) 9.44 (d, 1H) 10.96 (s, 1H) RT = 5.03 mins, ES + 503 Example 26 (S) -2-Chloro-6- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreiri, 41diazepin -3-yl) -benzamide This material was prepared as Example 3 except that 2-chloro-6- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid was used (Intermediary 10). The title compound was a colorless solid (51 mg). 1H NMR (DMSO, d) 3.43-3.47 (m, 4H) 3.59-3.61 (m, 4H) 5.63 (d, 1H) 7.39-7.83 (m, 12H) 9.86 (d, 1H) 11.14 (s, 1H) RT = 5.07 mins, ES + 523, 525 Example 27 (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzore1M, 41 diazepin-3-yl) -amide of (S) -3-Cyclopropyl-2-oxo-2,3-dihydro-imidazoic acid , 5-b1pyridine-1-carboxylic acid 3-Cyclopropyl-1,3-dihydro [4,5-b] pyridin-2-one was stirred (Intermediate 24, 35 mg), triethylamine (0.028 ml) and triphosgene (20 mg) at room temperature in dichloromethane (3 ml) for 1 h. Then (S) -3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (50 mg) was added and the stirring was continued for 18 h. The solvent was evaporated and the residue was purified on an SPE cartridge of silica gel. Elution with dichloromethane: ethanol: 0.880 ammonia; 200: 8: 1 gave a colorless solid (3 mg) 1H NMR (DMSO, d) 0.88-1.09 (m, 4H) 2.92 (m, 1H) 5.25 (d, 1H) 7.06-7.71 (m, 10H) 8.08 ( m, 2H) 9.94 (d, 1 H) 11.08 (s, 1 H) RT = 4.90 mins, ES + 453 Example 28 (S) -3- (4-Methyl-pi erazine-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzofeU1,41diazepin-3-yl) -benzamide This material was prepared as in Example 3 except that 3- (4-methyl-piperazin-1-sulfonyl) -benzoic acid (Intermediate 7) was used. The title compound was a pale yellow solid (23 mg). 1 H NMR (CDCl 3, d) 2.19 (s, 3 H), 2.39-2.43 (m, 4 H), 2.95-3.05 (m, 4H), 5.68 (d, 1H), 6.5 (s, 1H), 7.13 (t, 2H), 7.19 (s, 1H), 7.32-7.83 (m, 8H), 8.08-8.11 (m, 2H), 8.28-8.29 (m, 1H). RT = 4.25 mins, ES + 518 Example 29 (S) -4- (4-Methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41diazepin-3-yl) -benzamide This material is prepared as Example 3 except that 4- (4-methyl-piperazin-1-yl) -benzoic acid was used. The title compound was a colorless solid (46 mg). 1 H NMR (CDCl 3, d) 2.30 (s, 3 H), 2.50-2.54 (m, 4 H), 3.26-3.30 (m, 4H), 5.70 (d, 1H), 6.86 (d, 2H), 7.14 (t, 1H), 7.17-7.50 (m, 8H), 7.74 (d, 1H), 7.80 (d, 2H), 8.25-8.40 (m, 1H). RT = 4.16 mins, ES + 454 Example 30 (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoreU1.4ldiazepin-3-yl) -3- (piperidin-1-sulfoniD-benzamide) This material was prepared as Example 3 except that 3-piperidin-1-sulfonyl-benzoic acid (Intermediate 8) was used.The title compound was a colorless solid (35 mg) .1H NMR (CDCl3, d) 1.35-1.38 (m, 2H), 1.57-1.65 ( m, 4H), 2.91-2.99 (m, 4H), 5.70 (d, 1H), 7.14 (t, 2H), 7.19 (s, 2H), 7.31-7.84 (m, 7H), 8. 04-8.12 (m, 2H), 8.28-8.29 (m, 1H), 8.41 (s, 1H). RT = 5.47 mins, ES + 503 Example 31 (S) -3- (Morpholine-4-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreiri, 41diazepin-3-yl) -benzamide This material was prepared as Example 3 except that 3- (morfoiin-4-sulfonyl) -benzoic acid (Intermediate 9) was used. The title compound was a colorless solid (29 mg). 1 H NMR (CDCl 3, d) 2.97-3.00 (m, 4 H), 3.66-3.70 (m, 4 H), 5.68 (d, 1 H), 7.10-8.18 (m, 13 H), 8.29-8.31 (m, 2 H). RT = 5.06 mins, ES + 505 Example 32 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo feiri, 41-diazepin-3-yl) -amide of (S) -5-Morpholin-4-ylmethyl-furan-2-carboxylic acid This material is prepared as Example 3 except that 5-morpholin-4-ylmethyl-furan-2-carboxylic acid (Intermediate 19) was used. The title compound was a colorless solid (35 mg). 1 H NMR (CDCl 3, d) 2.46-2.49 (m, 4 H), 3.55 (s, 2 H), 3.66-3.70 (m, 4H), 5.65 (d, 1H), 6.30 (d, 1H), 7.06-7.51 (m, 10H), 7.95 (d, 1H), 8. 38 (s, 1H). RT = 4.28 mins, ES + 445 Example 33 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzofeiri, 4-diazepin-3-yl) -amido of (S) -5-Hydroxymethyl-furan-2-carboxylic acid This material was prepared as Example 3 except that The hydrolysis product of 5-chloromethyl-furan-2-carboxylic acid ethyl ester was used. The title compound was a colorless solid (48 mg). H NMR (CDCl 3, d) 2.78 (s, 1 H), 4.55-4.56 (m, 2 H), 5.63 (d, 1 H), 6.25 (d, 1 H), 7.00 (d, 1 H), 7.09 (t, 2 H) , 7.15-7.49 (m, 7H), 8.10 (d, 1H), 8.46 (s, 1H). RT = 4.54 mins, ES + 376 Example 34 (2-oxo-5-phenyl-2,3-dihydro-1H-benzofe-1, 41-iazepin-3-yl) -ad ida of (S) -5- (1,1-Dioxo-1? 6-thiomorpholin-4ylmethylphuran- 2-carboxylic This material was prepared as Example 3 except that 5- (1,1-dioxo-1,6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid was used.

(Intermediary 20). The title compound was a colorless solid (192 mg). 1 H NMR (CDCl 3, d) 3.00-3.10 (m, 8 H), 3.68 (s, 2 H), 5.65 (d, 1 H), 6.32 (d, 1 H), 7.06-7.50 (m, 10 H), 7.95 (d, 1H), 8.08-8.16 (s, 1H). RT = 4.65 mins, ES + 493 Example 35 (S) -2-Chloro-4-M, 1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1.41 diazepin- 3-yl) -benzamide This material was prepared as Example 3 except that 2-chloro-4- (1,1-dioxo-1,6-thiomorpholin-4-yl) -benzoic acid was used (Intermediary 1). The title compound was a colorless solid (41 mg). 1H NMR (DMSO, d) 3.15 (brs, 4H) 3.92 (brs, 4H) 5.41 (d, 1H) 7.10-7.68 (m, 12H) 9.26 (d, 1H) 10.92 (s, 1H) RT = 4.70 mins, ES + 523, 525 Example 36 (S) -2-Chloro-5- (1,1-dioxo-1? 6-thiomorpholin-4-in-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzofe-1, 41-diazepin- 3-yl) -benzamide This material was prepared as Example 3 except that 2-chloro-5- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -benzoic acid was used (Intermediary 2). The title compound was a colorless solid (69 mg). 1H NMR (DMSO, d) 3.14 (brs, 4H) 3.81 (brs, 4H) 5.37 (d, 1H) 7.08-7.63 (m, 12H) 9.56 (d, 1H) 10.84 (s, 1H) RT = 4.76 mins, ES + 523,525 Example 37 (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzorel H.41 diazepin-3-yl-amide of (S) -5- (r (2-methanesulfonyl-ethyl) -methyl-aminol- methyl > -furan-2-carboxylic acid This material was prepared as in Example 3 except that 5- [{[[(2-methanesulfonyl-ethyl) -methyl-amino] -methyl] -furan acid ethyl ester was used. -2-carboxylic acid (Intermediate 17.) The title compound was a colorless solid (87 mg), 1 H NMR (DMSO, d) 2.05 (s, 3H), 2.61 (t, 2H), 2.84 (s, 3H), 3.12 (t, 2H), 3.48 (s, 2H), 5.21 (d, 1H), 6.34 (d, 1H), 7.05-7.39 (m, 9H), 7.50 (td, 1H), 8.77 (d, 1H) 10.78 (s, 1H) RT = 4.78 mins, ES + 495 Example 38 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzop-1,41-diazepin-3-yl) -amido (S) -2-pyridin-3-yl-t-azol-4-carboxylic acid material was prepared as in Example 3 except that 2-pyridin-3-yl-thiazole-4-carboxylic acid was used. The title compound was a colorless solid (55 mg). 1 H NMR (DMSO, d) 5.64 (d, 1 H) 7.48-7.86 (m, 10 H) 8.66 (dt, 1 H) 8.73 (s, 1 H) 8.93 (dd, 1 H) 9.31 (d, 1 H) 9.47 (d, 1 H ) 11.28 (s, 1H) RT = 4.70 mins, ES + 440 Example 39 (2-Oxo-d -f-enyl -2, 3-dihydro-1H-benzoreir, 41-diazepin-3-yl) -amide of (S) -2-pyridin-4-yl-t-azol-4-carboxylic acid material was prepared as in Example 3 except that 2-pyridin-4-yl-thiazole-4-carboxylic acid was used. The title compound was a colorless solid (54 mg). H NMR (DMSO, d) 5.36 (d, 1H) 7.19-7.58 (m, 9H) 7.6 (dd, 2H) 8.53 (s, 1H) 8.6g (dd, 2H) 9.02 (d, 1H) 11.01 ( s, 1H) RT = 4.69 mins, ES + 440 Example 40 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoyrie, 41-diazepin-3-yl) -amide acid (S) -4-Methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid This material was prepared as in Example 3 except that 4-methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid was used. The title compound was a colorless solid (67 mg). 1H NMR (DMSO, d) 2.56 (s, 3H) 5.25 (d, 1H) 7.10-7.49 (m, gH) 8.58-8.63 (s + dd, 2H) 9.16 (d, 1H) 9.38 (d, 1H) 10.78 (s, 1H) RT = 4.82 mins, ES + 455 Example 41 (S) -2- orpholin-4-ylmethyl-furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzoreU1,4ldiazepin-3-yl) -amide This material was prepared as Example 3 except that 2-morpholin-4-ylmethyl-furan-3-carboxylic acid (Intermediate 25) was used. The title compound was a colorless solid (24 mg). 1 H NMR (DMSO, d) 2.58 (brm, 4H) 3.67 (brm, 4H) 3.81 (s, 2H) 5.45 (d, 1H) 6.88 (d, 1H) 7.33-7.75 (m, 10H) 10. g5 (s) , 1H) 11.01 (d, 1H) RT = 5.04 mins, ES + 445 Example 42 (S) -3-Morpholin-4-ylmethyl-N- (2-oxo-5-phenyl-2,3-dihydro-H-benzoreI ri, 41diazepin-3-yl) -benzamide This material was prepared as Example 3 except that 3-morpholin-4-ylmethyl-benzoic acid (Intermediary 26) was used. The title compound was a colorless solid (24 mg). 1H NMR (DMSO, d) 2.3g (brm, 4H) 3.55 (s, 2H) 3.60 (brm, 4H) 5.51 (d, 1H) 7.28-7.71 (m, 11 H) 7.g3 (s, 1H) 7 7 (s, 1H) g.50 (d, 1H) 10.93 (s, 1H) RT = 4.86 mins, ES + 455 Example 43 (2-Oxo-5-phenyl-2,3-dihydro-H-benzoreU1, 41-diazepin-3-yl) -amide acid (S) -5-morpholin-4-ylmethyl-isoxazole-3-carboxylic acid This material was prepared as Example 3 except that 5-morpholin-4-ylmethyl-isoxazole-3-carboxylic acid (Intermediate 27) was used. The title compound was a colorless solid (11 mg). 1 H NMR (DMSO, d) 2.93 (m, 4H) 3.46 (m, 4H) 3.66 (brs, 2H) 5.26 (d, 1H) 6.77 (s, 1H) 7.13-7.38 (m, 9H) g.17 (d , 1H) 10. g? (s, 1H) RT = 4.75mins, ES + 446 Example 44 (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzoreir, 41-diazepin-3-yl) -amide of (S) -3-morpholin-4-ylmethyl-furan-2-carboxylic acid This material is prepared as Example 3 except that 3-morpholin-4-ylmethyl-furan-2-carboxylic acid (Intermediate 28) was used. The title compound was a colorless solid (20 mg). 1 H NMR (DMSO, d) 2.52 (brm, 4H) 3.62 (brs, 4H) 3.67 (m, 2H) 5.39 (d, 1H) 6.67 (d, 1H) 7.25-7.71 (m, 9H) 7.84 (d, 1H ) 10. g3 (s, 1H) 11.34 (d, 1H) RT = 4.g6 mins, ES + 445 go Example 45 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41diazepin-3-yl) -amide (S) -5-pyridin-2-yl-thiophene-2-carboxylic acid This material is prepared as Example 3 except that 5-pyridin-2-yl-thiophene-2-carboxylic acid was used. The title compound was a colorless solid (32 mg). H NMR (DMSO, d) 5.58 (d, 1H) 7.37-7.77 (m, 10H) 7.g6-7.gg (m, 2H) 8.10 (d, 1H) 8.32 (d, 1H) 8.67 (d, 1H ) 9.81 (d, 1H) 11.03 (s, 1H) RT = 4.91 mins, ES + 43g Example 46 (S-2-methyl-4- (morpholin-4-sulfonyl) -furan (2-Oxo-5-phenyl-2,3-dihydro-1H-benzore-1, 1,4-diazepin-3-yl) -amide) -3-carboxylic acid This material was prepared as in Example 3 except that 2-methyl-4- (morpholin-4-sulfonyl) -furan-3-carboxylic acid was used. The title compound was a colorless solid (75 mg). 1 H NMR (DMSO, d) 2.77 (s, 3 H) 3.26 (m, 4 H) 3.85 (m, 4 H) 5.60 (d, 1 H) 7.43-7.83 (m, g H) 8.23 (s, 1 H) g.68 (d , 1H) 11.07 (s, 1H) RT = 4.90 mins, ES + 509 Example 47 (S) -6-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzore 1,4l diazepin-3-yl) -nicotinamide This material was prepared as Example 3 except that 6-morpholin-4-nicotinic acid was used. The title compound was a colorless solid (28 mg). 1H NMR (DMSO, d) 3.58-3.61 (m, 4H) 3.70-3.73 (m, 4H) 5.51 (d, 1H) 6.89 (d, 1H) 7.24-7.71 (m, 9H) 8.19 (dd, 1H) 8.80 (d, 1H) 9.3g (d, 1H) 10.8g (s, 1H) RT = 4.59 mins, ES + 442 Example 48 (2-Oxo-5-phenyl-2,3-dihydro-1 H-benzo re1H, 41-diazepin-3-yl) -amide of (S) -3-Morpholin-4-ylmethyl-thiophene-2-carboxylic acid This material is prepared as Example 3 except that 3-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (Intermediate 29) was used. The title compound was a colorless solid (34 mg). 1 H NMR (DMSO, d) 2.43 (m, 4 H) 3.59 (m, 4 H) 3.70 (s, 2 H) 5.45 (d, 1 H) 7.05 (d, 1 H) 7.24-7.70 (m, 9 H) 8.05 (d, 1 H ) g.54 (d, 1H) 10.92 (s, 1H) RT = 5.02 mins, ES + 461 Example 49 (2 -Oxo -5-phen i 1-2,3 -di-hi-dro-1-H-benzo-REU-1,4-diazepin-3-p -amide of (S) -5-morpholin-4-ylmethyl-thiophen-2 -amide carboxylic This material was prepared as in Example 3 except that 5-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (Intermediate 30) was used.The title compound was a colorless solid (41 mg) .1H NMR (DMSO) , d) 2.28 (brm, 4H) 3.38 (brm, 4H) 3.56 (s, 2H) 5.16 (d, 1H) 6.90 (d, 1H) 7.04-7.44 (m, 9H) 7.52 (d, 1H) 10.68 (s) , 1H) 11.82 (d, 1H) RT = 5.33 mins, ES + 461 Example 50 2-Morpholm-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41 diazepin-3-yl) -benzamide This material was prepared as Intermediary 15 except that 2-morpholin-4-yl-benzoic acid (49 mg). The product was a colorless solid (33 mg) 1H NMR (DMSO, d) 3.01-3.12 (m, 4H) 3.86-3.93 (m, 4H) 5.44 (d, 1H) 7.21-7.71 (m, 12H) 7.93 (dd , 1H) 10.99 (d, 1H) 11.02 (s, 1H) RT = 5.47, ES + 441 Example 51 (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoreU1,41-diazepin-3-in-benzamide of (S) -5-phenyl-oxazole-4-carboxylic acid) (S) -3-amino was stirred -5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (60 mg), triethylamine (0.037 ml) and 5-phenyl-oxazole-4-carbonyl chloride (50 mg) ) in THF (3 ml) at room temperature for 2 h The mixture was then partitioned between water and dichloromethane The dried organic phase was evaporated and the residue was purified on a SPE silica gel cartridge Elution with dichloromethane: ethanol : 0.880 ammonia; 400: 8: 1 gave the title compound as a colorless solid (42 mg) .1H NMR (DMSO, d) 5.40 (d, 1H) 7.27-7.70 (m, 12H) 8.22-8.26 (m, 2H) 8.72 (s, 1H) 8.88 (d, 1H) 11.14 (s, 1H) RT = 5.22, ES + 423.49 Example 52 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzoflu-1,41-diazepin-3-yl) -3- (4-phenoxy-phenyl-urea) 3-amino-5-phenyl- was stirred Racemic 1,3-dihydro-benzo [e] [1,4] diazepin-2-one (30 mg) and 1-isocyanato-4-phenoxy-benzene (0.022 ml) in Dry THF (4 mL) at room temperature for 18 h. The mixture was then partitioned between water and dichloromethane. The dried organic layer was evaporated and the residue was titrated from dichloromethane / ether diethyl g4 to give the title compound as a white solid (25 mg) 1H NMR (DMSO, d) 5.23 (d, 1H) 6.g8-7.03 (m, 3H) 7.11 (t, 1H) 7.33-7.58 (m, 131-1) 7.71 (dt, 1H) 9.18 (s, 1H) 11.03 (brs, 1H) RT = 5.57, ES + 463.45 Example 53 Dimethylamide of 3- [1- (3-methyl-butyl) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydrobenzoimidazole-1-sulphonic acid, 1-methanesulfonyl-3- [1- (3-methyl-butyl) -1H-benzozidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 3- [1- (3-methyl-butyl) -benzylamide 1 H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid, 5-. { 3- [1 - (3-Methansulfo ni l-propi l) -1 H -benzo imidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazol-1-yl} -pentan-nitrile, 7- [2- (3-Isopropenyl-2-oxo-2,3-dihydrobenzoimidazoI-1-ylmethyl) -benzoimidazo I-1-yl] -heptanenitrile, 1-Ethyl-3- [ 1- (4-hydroxy-butyl) -1 H -benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 1-Ethyl-3- [1- (2-hydroxy-2-f in i-eti I) - 1 H-benzo imidazo l-2-ymethyl I] -1,3-dihydro-benzoimidazol-2-one, 1-lsop ropenil-3- [1 - (3-oxo b uti I) - 1 H -benzoimidazol-2-ylmethyl] -1, 3-dihydro-benzoimidazol-2-one, 1- (4-hydroxy-benzyl) -3- [1- (3-methyl-butyl) -1H-benzoimidazole -2-ylmethyl] -1,3-dihydro-benzoimidazol-2-one, 1-lsopropenyl-3- [1- (3-methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydrobenzoimidazole- 2-one, 1-Cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-imidazo [4,5-c] pyridin-2-one and 1-Isopropenyl-3- (1-propyl-1H-benzoimidazol-2-ylmethyl) -1,3-dihydro- imidazo [4,5-c] pyridin-2-one were prepared as described in WO00195gi0.

Example 54 f2-r2- (1,2-Dihydro-benzotriazol-1-ylmethyl-benzoimidazole-1-imetiP-diethylamine is prepared as described in WO00004900.

Example 55 . { 2-r2- (3-Vodo-2,3-dihydro-indazol-1-ylmethyl-benzimidazole-1-in-ethyl > -dimethyl-amine is prepared as described in WO03053344.

Example 56 Bis (5-amidino-2-benzimidazol-P-methane is prepared as described in US4.3247g4.

Example 57 2- 2- [1-f1. { (2-ami no-etiP-piperid i n-4-ylamino] -4-methyl-benzoimidazol-1-ylmethyl> -6-methyl-pyridin-3-ol is prepared as described in WO0100612. g6 Example of Activity 1 Determination of RSV Fusion Inhibitor Activity RSV enters the host cell through binding to and fusion with the membrane of the host cell. The effect of an inhibitor on the virus-cell-specific fusion event can be qualitatively determined using a fluorescence de-extinction system. The design of this assay takes advantage of the fact that RSV binds to cells at 4 ° C and at 37 ° C, but that fusion only occurs at concentrations above 18 ° C. The RSV labeled with octadecyl-rhodamine dye (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 before being 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 phorophores that are in close proximity. After the fusion of the labeled virus with the cell membrane, the distance between the fluorophores increased due to the expansion of the dye and there was a reduction in the extinction. This was observed as an increase in the fluorescence intensity of g7 R18. Therefore, inhibition of fusion could lead to a reduction in fluorescence of R18 compared to the untreated control. When the fluorescent performance of R18 in the presence of the inhibitor was comparable with the untreated control, this suggested that the inhibitor did not exert its effects on the fusion protein.

Activity Example 2 Determination of RSV replication inhibitory activity The 60 internal cavities of 96-well tissue culture plates were seeded with Hep-2 cells at 4x104 cells / well for studies of compound activity and toxicity at 100μ! of medium and incubated at 37 ° C overnight or until confluence. The cells were infected with 25 μl RSV, for example the RSS strain, previously ground to give 80% cell annihilation. To each well, 25μM of the test compound was added. The final DMSO concentration. it 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 warm XTT / PMS solution was added to each well and incubated for 1 hour at 37 ° C. The maximum reading of OD450nm (untreated, uninfected control cells) corresponds to 100% inhibition. Readings minimum OD450nm (infected control cells) correspond to 0% inhibition. The concentration of Log10 was plotted against OD450nm and the IC50 values were calculated from the reading with a value of 50% of the graph or using regression analysis.

Example of Activity 3 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 2-chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro, 1H-benzo [e] [1,4] diazepin-3-ii) -benzamide or (2-oxo-5-phenyl-2,3-dihydro- 1 H-Benzo [e] [1,4] diazepin-3-yl) -amide of 5- (1,1-dioxo-1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid amide ( compound A) with an RSV fusion inhibitor selected from 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazoi-2-ylmethyl] -1,3-dihydro-imidazo [4,5- c] pyridin-2-one (compound B) or 1-isopropenyl-3- (1-propyl-1 H -benzoimidazo! -2-ylmethyl) -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. 9g (HRP) of rabbit anti-mouse to demonstrate a reduction in RSV antigen through the conversion of o-phenylene diamine dihydrochloride substrate (OPD) to a colored product. This was quantified through an optical density (OD) measurement.

Method This test was performed using 6 cavities of g6 round bottom cavities. The external cavities were not subjected to any greater amount of evaporation than the internal cavities during day 3 of the trial 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 gd cavities of a microtiter plate were seeded at a density of 5x103 Hep-2 cells / well? in 10Oμl / cavity 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% C02 until having a confluence of g?%. The monolayers were washed with 20 ml of sterile PBS to remove the serum and treated with 1 ml of trypsin to separate the cells from the flask. The cells were suspended in a small known volume of growth medium and counted using a hemocytometer. The cell suspension was developed to 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% C02 atmosphere for 24 hours, during which time the cells were pelleted 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 titration of the virus material (through the ELISA assay method) since virus entry was required to achieve a window of at least 0.8 OD units between infected and uninfected control cells.

Multiplicity of Infection = plaque forming units per cavity (pfucavity) cell numbers per cavity 550 μl of diluted virus was added to infected cavities through a multichannel pipette; 50 I of Growth Medium was added to uninfected cell control cavities through a multichannel pipette. The sides of the plates were marked with stripes to identify the plates in case the covers were separated. Plates were incubated at 37 ° C for 1 hour to allow virus uptake.

Dilutions of the Compound Compound "A" was titled horizontally through the plate and Compound "B" was titled vertically down the plate, creating a checker board. The 2 compounds were titrated to V-log or double dilutions either through (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 1C50 of the compound below the IC50 of the compound and OM control was included for each compound. The compounds were formed in a separate microtiter plate at a resistance of 8x in GM containing 2% DMSO (a final concentration of DMSO in the 0.5% assay). Then 25μl of the dilution series of Compound "A" and 25μl of the "B" dilution series were transferred to the appropriate wells of the assay plate through a multichannel pipette, according to what is marked on the checker board. 25μl of GM (containing 2% DMSO) was added to the cavities receiving 0 / M Compound "A" or 0 / M Compound "B". 50μl of GM (containing 2% DMSO) was added to cavities containing no compound. The untreated cavities, infected with viruses, served as virus control (VC); Untreated, uninfected cavities served as cell control (CC). The difference in absorbance between the CC and VC cavities constitutes the window of test. Plates were incubated at 37 ° C, 5% C02 for 3 days.

ELISA stage Day 4 The media were placed in the cavities capped directly in Virkon (1% solution in water) and the plates were washed by immersing in a plastic box containing PBS. 50μl / 75% / 25% vol / vol cavity of fixed acetone / methanol was added through a multichannel pipette and left for 3 minutes. Acetone / methanol was discarded from the cavities to Virkon and the wells 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 diluted primary antibody was added directly to the wells (ie, without a required wash). RSV mouse monoclonal antibody NCL-RSV3 (Novocastra) was diluted 1/400 in PBS / 2% Marvel / 0.05% Tween and 50μl per cavity was added. Plates were incubated at 37 ° C in a shaking incubator for or minutes. The antibody was discarded from the collector and the plates washed. times through immersion in PBS / 0.05% Tween. The HRP conjugate of rabbit anti-mouse DAKo was diluted (DAKO catalog number P0260) 1/1000 in PBS / 2% Marvel / 0.05% Tween and 50 μl were added per cavity. The plates were incubated at 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 (SigmaFast OPD) was prepared above by dissolving 1 tablet of urea in 20mL of water. One OPD tablet was added to the urea solution just before use (slightly sensitive NB, OPD) and swirled to mix. They added 50μl of the substrate per cavity. The reaction was stopped by the addition of 25μl / cavity of % sulfuric acid, once enough color developed but while the antecedent of cell control remained low (~ 5 minutes). The plates were read in a SpectraMax spectrophotometer (Molecular Devices) at a wavelength of 490nm and used the software package SOFTmax Pro. The cavities were emptied, washed with running water and the monolayers were stained with 50μl / 2% crystal violet cavity 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. The data management used Excel templates written at home to graph dose-response curves graphically and calculate IC50 values 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 control was plotted against the concentration of compounds. A straight line was fixed to the curve and the slope and intersection functions were used to calculate the IC50. The IC50 for Compound "A" was calculated for each previous concentration of! Compound "B". Similarly, 1C50 for Compound "B" was calculated for each prior concentration of Compound "A".

Example 3a 2-Chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [eU1,4l diazepin-3-yl) -benzamide (Compound A) in combination with 1-cyclopropyl-3-y1- (4-hydroxy-butyl) -1H-benzoimidazol-2-methylmethyl-1-, 3-dihydro-imidazof4,5-clpiridin-2-one (Compound B) Compound A has an ELISA IC50 of 1.6μM against the RSS strain of RSV. Compound B has an ELISA IC50 of 0.015μM against the RSV RSS strain. In combination, at concentrations of Compound A below its IC50, the IC50 of Compound B was reduced from 0.15μM to at least 0.003 // M (5-fold reduction). At concentrations of Compound B below its IC 50, the IC 50 of Compound A was reduced from 1.6 μM to at least 1 μM (1.6 fold reduction).

Example 3b (2-0X0-5-phenyl-2,3-dihydro-1 H-benzo [[1,4-diazepin-3-yl] -amide of 5- (1, dioxo-1? 6-thiomorph! in-4-ylmethyl) -furan-2-carboxylic acid (Compound A) in combination with 1-cyclopropyl-3-f1- (4-hydroxy-butyl) -1H-benzoimidazole-2-methyl-1,1-dihydro-imidazo [4,5-c1pyridin-2- ona (Compound B) Compound A has a 1C50 ELISA of 3.5μM against the RSV RSS strain. Compound B has an ELISA IC50 of O.OdμM against the RSV RSS strain. In combination, concentrations of Compound A below its IC50, 1C50 of Compound B was reduced from 0.06μM to at least 0. 006μM (10 times reduction). At concentrations of the Compound B below its IC50, the IC50 of Compound A was reduced from 3.5μM to at least 0.312μM (11.2 fold reduction).

The formula presented below can be used to identify a synergistic interaction.

FIC = Inhibitory Concentration Fracciona! Compare the activity of a compound in combination (Compound A + Compound B) with the activity of the compound alone (Compound A or Compound B). c Fw1C - = l IoCe5n0 ™ mAas *. l ba-io- Co "m ™" p A? CO MBIN ACIÓN +. ? InC5cn0"ma • s _ ba": i "o / C- • or ~ ~ m. "P or B COMBINATION IC50 Cpd A ONLY 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 2-chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-e-il) - 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-one : 0.3 FIC for 5- (1,1-dioxo- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide. 1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid (Compound A) in combination with 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzo-midazol-2-ylmethyl ] -1, 3-dihydro-imidazo [4,5-c] pyridin-2-one: 0.14

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 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 from 1 to 6 carbon atoms, amino, mono- (alkyl of 1 to 6 carbon atoms) amino, di- (alkyl of 1 to 6 carbon atoms) carbon) amino, nitro, cyano, -C02R ', -CONR'R ", -NH-CO-R',

-S (0) R ', -S (0) 2R', -NH-S (0) 2R ', -S (0) NR'R "or -S (0) 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 represents hydrogen or alkyl of 1 to 6 carbon atoms, - X represents -CO -, -CO-NR'-, -S (O) - or -S (0) 2-, wherein R 'is hydrogen or an alkyl group of 1 to 6 carbon atoms, and - R 5 represents an aryl group, heteroaryl or heterocyclyl, which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (C? -C4 alkyl) -X? - (C1-C4 alkyl) -X2- (C1-C alkyl), wherein Xi represents -O-, -S- or -NR ', wherein R' represents H or an alkyl group of 1 to 4 carbon atoms, and X2 represents -CO-, -SO- or -S02-, or R5 represents -A? -Y-A2, wherein: - Ai is an aryl, heteroaryl, carbocyclyl or heterocyclyl group;

Y represents a direct bond or an alkylene portion of 1 to 4 carbon atoms, -S02-, -CO-, -O-, -S- or -NR'- wherein R 'is an alkyl group of 1 to 6 carbon atoms; and - A2 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group. 3. A composition according to claim 2, wherein R1 is alkyl of 1 to 2 carbon atoms or phenyl. 4. A composition according to claim 2 or

Claim 3, wherein R2 is hydrogen.

5. A composition according to any of claims 2 to 4, 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, haloalkoxy of 1 to 4 carbon atoms, amino, mono (alkyl of 1 to 4 carbon atoms) amino or di (alkyl of 1 to 4 carbon atoms) amino.

6. A composition according to claim 5, wherein 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 or di (alkyl of 1 to 2 carbon atoms) amino.

7. A composition according to any of claims 2-6, wherein R4 is hydrogen or alkyl of 1 to 2 carbon atoms.

8. A composition according to any of claims 2-7, wherein X is -CO- or -CO-NR'-, wherein R 'represents hydrogen or an alkyl group of 1 to 2 carbon atoms.

9. A composition according to any of claims 2-8, wherein R5 is a 5- or 6-membered heterocyclyl, aryl or heteroaryl ring, which is substituted by a hydroxyalkyl group of 1 to 6 carbon atoms or a group - (Ci-C4 alkyl) -X? - (C1-C4 alkyl) -X2- (C1-C4 alkyl), wherein Xi and X2 are as were defined in claim 2.

10. A composition according to claim 9, wherein R5 is a 5- or 6-membered heteroaryl group, which is substituted by a substituent -CH2OH or - (C-, -C- alkyl) -NR '- (C 1 -C 4 alkyl) -S (0) 2- (C 1 -C 4 alkyl), where R' is hydrogen or alkyl of 1 to 2 carbon atoms.

11. A composition according to claims 2-10, wherein Ai is an aryl or heteroaryl group.

12. A composition according to claim 1, wherein Ai is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group or a 5-6 membered heteroaryl group fused to a 5-6 membered heterocyclyl group substituted with oxo monocyclic

13. A composition according to claims 2-12, wherein Ai is unsubstituted or substituted by 1 or 2 substituents selected from the substituents halogen, cyano, nitro, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms.

14. A composition according to claims 2-13, wherein Y represents a direct bond, an alkylene group of 1 to 2 carbon atoms, -S02- or -O-.

15. A composition according to claims 2-14, wherein A2 is a phenyl, heteroaryl group of 5 to 6 members, heterocyclyl of 5 to 6 members or cycloalkyl of 3 to 6 carbon atoms.

16. A composition according to claims 2-15, wherein when A2 is a heterocyclyl group, it is attached to the Y portion through an N.

17. A composition according to claims 2-16, wherein A2 is unsubstituted or substituted by 1 or 2 substituents which are selected from alkyl substituents of 1 to 4 carbon atoms when A2 is a heteroaryl or aryl group and which are selected from the alkyl substituents of 1 to 4 carbon atoms, halogen and oxo, when A2 is a carbocyclic or heterocyclyl group.

18. A composition according to claims 2-17, wherein A2 is a piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thiomorpholino group, which is unsubstituted or substituted by an alkyl group of 1 to 2 carbon atoms.

19. A "composition according to any of claims 2-18, wherein the benzodiazepine derivative of the formula (V) is a benzodiazepine derivative of the formula (Va): wherein: X is -CO- or -CO-NH-; Y R5 is a 5-6 membered heteroaryl group, for example, a furanyl group, which is substituted by -CH2-OH or - (C1-C4 alkyl) -N (CH3) - (C1-C4 alkyl) -S02- (C? -C4 alkyl) or R5 represents -A? -Y-A2, wherein: - Ai is a phenyl portion, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolllo, thienyl or 1 H-imidazo [4,5-b] pyridin-2- (3H) -one, which is unsubstituted or substituted by 1 or 2 substituents selected from the halogen substituents , cyano, alkyl of 1 to 2 carbon atoms, haloalkyl of 1 to 2 carbon atoms and alkoxy of 1 to 2 carbon atoms; Y is a direct bond, an alkylene group of 1 to 2 carbon atoms, -S02- or -O-; and A2 is a piperazinyl, pyridyl, morpholinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo, thiomorpholino group, which is unsubstituted or substituted by an alkyl group of 1 to 2 carbon atoms.

20. A composition according to claim 1, wherein the benzodiazepine derivative of the formula (V) is: 6- (4-Methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl- 2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide 3,4,5,6-tetrahydro-2H- [1] , 2 '] bipyridinyl-5'-carboxylic acid; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepin-3-yl-benzamide; (S) -2-Chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H- benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1, 1-Dioxo-1? 6-thiomorpholin-4-yl) -4-fluoro- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [ 1,4] diazepin-3-yl-benzamide; (S) -5-Chloro-2- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl) -2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thomorpholin-4-yl); i) -5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-oxo- 5-Phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5- (4-methyl-piperazin-1-ylmethyl) - furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-Pyrrolidin- 1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide (S) -5-Piperidin-1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-Dimethylaminomethyl-furan-2-carboxylic acid; (S) -4-Fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepin-3-yl) -2-piperidin-1-yl-benzamide; (S) -4-Fluoro-2-morpholino -4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzofe] [1,4] diazepin-3-yl) -benzamide; (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl -benzamide; (S) -4-Cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -piperidin-1-yl-benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrroli in-1-yl-4- trifluoromethyl-benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperidin-1-yl-4-trifluoromethyl -benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -4-trifluoromethyl -benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaze? In-3-yl) -2-pyrrolidin-1-yl-5 -trifluoromethyl-benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -5-trifluoromethyl -benzamide; (S) -2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nicotinamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepin-3-yl) -nicotinamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -2-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-Dioxo-1? 6-thiomorpholin-4-yl) -4-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2- (1,1-D -oxo-1? 6-thiomorphol-4-yl) -6-methyl-N- (2-oxo-5-phenyi-2,3-dihydro-1H-benzo [ e] [1,4] diazepin-3-yl) -benzamide; (S) -2-Chloro-6- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -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 (S) -3-Cyclopropyl-2-oxo-2, 3-dihydro-imidazo [4,5-b] pyridine-1-carboxylic acid; (S) -3- (4-Methyl-piperazin-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3- dihydro-1 H- benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -4- (4-Methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3- il) -benzamide; (S) -N- (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazep in-3-yl) -3- (piperidin-1-sulfonyl) -benzamide; (S) -3- (Morpholin-4-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzophe] [1,4] diazepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-morpholin-4-ylmethyl-furan -2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-hydroxymethyl-furan-2-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5- (1,1-dioxo- 1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid; (S) -2-Chloro-4- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (S) -2-Chloro-5- (1,1-dioxo-1? 6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -benzamide; (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl-amide of (S) -5-. {[[(2-methanesulfonyl)] ethyl) -methyl-amino] -methyl.}. -furan-2-carboxylic acid; (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3- il) - (S) -2-pyridin-3-yl-thiazole-4-carboxylic acid amide: (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1, 4] ] diazepin-3-yl) - amide of (S) -2-pyridin-4-yl-thiazole-4-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -4-methyl-2-pyrazin-2 -amide il-thiazole-5-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -2-morpholin-4-iimethyl-furan- 3-carboxylic; (S) -3-Morpholin-4-ylmethyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-morpholin-4-ylmethyl-isoxazole -3-carboxylic acid; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] d.azepin-3-yl) -amide of (S) -3-morpholin-4-ylmethyl- furan-2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-pyridin-2-yl-thiophene 2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -2-methyl-4- (morpholine- 4-sulfonyl) -furan-3-carboxylic acid; (S) -6-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -nlcotinamide; (2-Oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -amide of (S) -3-morpholin-4-ylmethyl-thiophene -2-carboxylic; (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide of (S) -5-morpholin-4-ylmethyl-thiophene 2-carboxylic; 2-Morpholin-4-yl-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 (S) -5-phenyl-oxazole-4 carboxylic; 1- (2-Oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-phenoxy-phenyl) -urea; or a pharmaceutically acceptable salt thereof.

21. A composition according to claim 1, wherein the benzodiazepine derivative of the formula (V) is (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4]. diazepin-3-yl) (S) -5- (1,1-dioxo-1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid amide or (S) -2-chloro- 4- Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H -benzo [e] [1,4] diazepin-3-yl) -benzamide or a pharmaceutically acceptable salt thereof .

22. A composition according to claim 21, wherein the benzodiazepine derivative of the formula (V) is (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4]. diazepin-3-yl) (S) -5- (1,1-dioxo-1? 6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid amide, or a pharmaceutically acceptable salt thereof.

23. A composition according to any of the preceding claims, wherein component (a) is a compound of formula (I), or a pharmaceutically acceptable salt thereof, nde: - X is H or alkyl of 1 to 6 carbon atoms; the alkyl of 1 to 6 carbon atoms being optionally substituted by halogen, OCOR4 or S (0) 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 CONR R5, C02R4 or alkyl of 1 to 6 carbon atoms, the alkyl of 1 to 6 carbon atoms may be optionally substituted with OR or NR8Rg; - R8 and R9 are each independently H, alkyl of 1 to 6 carbon atoms, S02R5, C02R4 or COR4; - R2 is selected from the group consisting of NH2, CONR6R ', heteroaryl, alkenyl of 2 to 6 carbon atoms, C02R4, 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, NR10R11, OS02R4 and OR4; - R10 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, C02R4, COR4 and S02R4; R3 is selected from the group consisting of (1) C02Rg; (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, alkenyl of 2 to 6 carbon atoms, cyano-alkyl of 1 to 6 carbon atoms, C02R4, aryl, benzoaminocarbonyl, hydroxybenzyl, S02NR4R5 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, N02, CN, halogen, COR4, COOR4, CONHR4C (= NH) NH2 or C (= NOH) NH2.

24. A composition according to claim 23, wherein the component (a) is a compound of the general formula (I), as defined above, or a pharmaceutically salt acceptable of it, where at least two of R1? R2 and R3 are hydrogen, and the other is hydrogen or -C (NH) -NH2 and / or -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 ', -S02R' or phenyl, wherein R 'and R" are the same or different and represent 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-, 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, -S02- (alkyl of 1 to 6 carbon atoms ), -S02-N (alkyl of 1 to 6 carbon atoms) 2 or - (CO-NH) a- (alkyl of 1 to 4 carbon atoms) -phenyl, where a is 0 or 1, said group is unsubstituted or substituted with a hydroxy or cyano substituent.

25. A composition according to claims 1 to 22, wherein component (a) is a compound of formula (II), or a pharmaceutically acceptable salt thereof, nde: - 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 (= 0) -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; Y - m = 1-6.

26. A composition according to any one of claims 1 to 22, wherein component (a) is: 1-Cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzo imidazo l-2- ilmeti I] -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-lsopropenyl-3- [1- (3-methyl-butyl) -1 H -benzoimidazoi-2-ylmethyl]] - 1,3-dihydro-benzoimidazol-2-one 1- (4-Hydroxy-benzyl) - 3- [1- (3-methyl-butyl) -1H-benzoimidazol-2-ylmethyl] -1,3-dihydro-benzoimidazo-l-2-one 1-lsopropenyl-3- [1- (3-oxo- butyl) -1 H -benzoimidazol-2-ylmethyl] -1,3-dihydrobenzoimidazol-2-one 1-Ethyl-3- [1- (2-hydroxy-2-phenyl-ethyl) -1H-benzoimidazol-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-lsopropenyl-2-oxo-2,3-dihydrobenzoimidazol-1-ylmethyl) -benzoimidazol-1-yl] -heptan-nitrile 5-. { 3- [1- (3-Methanesulfonyl-propyl) -1H-benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazol-1-yl} -pentan-nitrile benzyl amide of 3- [1- (3-methyl-butyl) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydrobenzoimidazole-1-carboxylic acid 1-Methanesulfonyl-3- [1- (3-methyl-butyl) -1 H -benzoimidazo l-2-ylmethyl] - 1,3-dihydro-benzoimidazol-2-one dimethylamide of 3- [1-] (3-Methyl-butyl) -1 H -benzoimidazol-2-ylmethyl] -2-oxo-2,3-dihydro-benzoimidazole-1-sulfonic acid 1-lso.propenyl-3- (1-propyl-1H-benzoimidazole-2-yl) ilmethyl) -1,3-dihydro-imidazo [4,5-c] pyridin-2-one Bis (5-amidino-2-benzimidazolyl) -methane 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.

27. A composition according to any of claims 1 to 22, wherein component (a) is 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-yl ethyl] -1, 3-dihydro-imidazo [4,5-c] pyridin-2-one,. { 2- [2- (1, 2-dihydro-benzotriaol-1-ylmethyl) -benzoimidazol-1-yl]] ethyl} -diethylamine,. { 2- [2- (3-iodo-2,3-dihydro-indazol-1-ylmethyl) -benzimidazol-1-y!] - ethyl} dimethylamine or a pharmaceutically acceptable salt thereof.

28. A composition according to any of claims 1 to 22, wherein component (a) is 1-cyclopropyl-3- [1- (4-hydroxy-butyl) -1H-benzoimidazol-2-ylmethyl] -1 , 3-dihydro-imidazo [4,5-c] pyridin-2-one or 1-isopropenyl-3- (1-propyl-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 component (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 23 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 32, wherein the medicament is a composition as defined in claim 20 or 30.

34. A product comprising: (a) an RSV fusion protein inhibitor as defined in any of claims 1 and 23 to 28; and (b) a benzodiazepine derivative defined in any of claims 1 to 22, for separate, simultaneous or sequential use in the treatment of 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 an RSV infection.

36. A method for the treatment or prevention of an RSV infection in a patient, said method comprising administering to said patient, of: (a) an RSV fusion protein inhibitor as defined in any one of claims 1 and 23 to 28; and (b) a benzodiazepine derivative defined in any of claims 1 to 22.

37. The use of an RSV fusion protein inhibitor according to any of claims 1 and 23 to 28, in the manufacture of a medicament for used in the treatment or revention of an SVR infection, through co-administration with a benzodiazepine derivative as defined in any of claims 1 to 22.

38. The use of a benzodiazepine derivative according to 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 the subdivisions 1 and 23 to 28.