KR20070017357A - Benzodiazepines for treating or preventing rsv infection - Google Patents

Abstract

The present invention provides the use of a compound which is (a) a benzodiazepine derivative of formula (I) or an N-oxide thereof or (b) a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating or preventing RSV infection.

<Formula I>

In the above formula,

- R ¹ is C _{1 -6} alkyl, aryl or heteroaryl;

- R ² represents hydrogen or C _{1 -6} alkyl;

- each R ³ are the same or different, halogen, hydroxy, C _{1 -6} alkyl, C _{1 -6} alkoxy, C _{1 -6} alkylthio, C _{1 -6} haloalkyl, C _{1 -6} haloalkoxy, amino , Mono (C _1-6 alkyl) amino, di (C _1-6 alkyl) amino, nitro, cyano, -CO ₂ R ', -CONR'R ", -NH-CO-R', -S (O ) R ', -S (O) ₂ R', -NH-S (O) ₂ R ', -S (O) NR'R "or -S (O) ₂ NR'R", wherein R 'and R "are the same or different and represents hydrogen or C _{1 -6} alkyl;

n is from 0 to 3;

- R ⁴ represents hydrogen or C _{1 -6} alkyl;

-X represents -CO-, -CO-NR'-, -S (O)-or -S (O) _2- , wherein R 'is hydrogen or a C ₁ -C ₆ alkyl group;

R ⁵ represents an aryl, heteroaryl or heterocyclyl group, which is a C ₁ -C ₆ hydroxyalkyl group or-(C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X ₂ Substituted with a-(C ₁ -C ₄ alkyl) group, wherein X ₁ represents —O—, —S— or —NR′—, wherein R ′ represents H or a C ₁ -C ₄ alkyl group, X ₂ Represents -CO-, -SO- or -SO _2- , or R ⁵ represents -A ₁ -YA ₂ , wherein:

A ₁ represents an aryl, heteroaryl, carbocyclyl or heterocyclyl group;

Y represents a direct bond or a C ₁ -C ₄ alkylene, —SO ₂ —, —CO—, —O—, —S— or —NR′- moiety, wherein R ′ is a C ₁ -C ₆ alkyl group ego;

A ₂ is an aryl, heteroaryl, carbocyclyl or heterocyclyl group.

Benzodiazepines derivatives, JR infection, human metapneumovirus, measles

Description

BENZODIAZEPINES FOR TREATING OR PREVENTING RSV INFECTION}

The present invention relates to a series of benzodiazepine derivatives active against respiratory syncytial virus (RSV).

RSV is a major cause of respiratory illness in patients of all ages. In adults, they tend to cause mild cold symptoms. In school-age children, it can cause colds and bronchial cough. In infants, it may cause bronchiolitis (inflammation of the small airways of the lungs) or pneumonia. It has also been found that in preschool children, it is a frequent cause of middle ear infections (otitis media). The first RSV infection in life is also involved in the development of asthma during childhood.

Current anti-RSV therapies include the use of monoclonal antibodies against RSV, the so-called palivizumab. The use of palivizumab is a prophylactic rather than a therapeutic treatment of RSV. However, these antibodies are often expensive but expensive. In fact, the cost means that it is not available to many people in need of anti-RSV therapy. Thus, there is an urgent need for effective alternatives to existing anti-RSV therapies.

It has surprisingly been found that certain benzodiazepine derivatives of the general formula (I) are active against RSV.

Thus, in the first embodiment,

Provided is the use of a compound which is (a) a benzodiazepine derivative of formula (I) or an N-oxide thereof or (b) a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating or preventing RSV infection.

In the above formula,

R ¹ represents C _1-6 alkyl, aryl or heteroaryl;

R ² represents hydrogen or C _1-6 alkyl;

Each R ³ is the same or different and is halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, amino , Mono (C _1-6 alkyl) amino, di (C _1-6 alkyl) amino, nitro, cyano, -CO ₂ R ', -CONR'R ", -NH-CO-R', -S (O ) R ', -S (O) ₂ R', -NH-S (O) ₂ R ', -S (O) NR'R "or -S (O) ₂ NR'R", wherein R 'and R "are the same or different and represent hydrogen or C _1-6 alkyl;

n is from 0 to 3;

R ⁴ represents hydrogen or C _1-6 alkyl;

-X represents -CO-, -CO-NR'-, -S (O)-or -S (O) _2- , wherein R 'is hydrogen or a C ₁ -C ₆ alkyl group;

R ⁵ represents an aryl, heteroaryl or heterocyclyl group, which is a C ₁ -C ₆ hydroxyalkyl group or-(C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X ₂ Substituted with a-(C ₁ -C ₄ alkyl) group, wherein X ₁ represents —O—, —S— or —NR′—, wherein R ′ represents H or a C ₁ -C ₄ alkyl group, X ₂ Represents -CO-, -SO- or -SO _2- , or R ⁵ represents -A ₁ -YA ₂ , wherein:

A ₁ represents an aryl, heteroaryl, carbocyclyl or heterocyclyl group;

Y represents a direct bond or a C ₁ -C ₄ alkylene, —SO ₂ —, —CO—, —O—, —S— or —NR′- moiety, wherein R ′ is a C ₁ -C ₆ alkyl group ego;

A ₂ is an aryl, heteroaryl, carbocyclyl or heterocyclyl group.

As used herein, a C _1-6 alkyl group or moiety is a linear or branched alkyl group or moiety containing 1 to 6 carbon atoms, such as a C _1-4 alkyl group or moiety. Examples of C _1-4 alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. To avoid uncertainty, when two alkyl residues are present in a group, the alkyl residues may be the same or different.

As used herein, a hydroxyalkyl group is typically said alkyl group substituted with one or more hydroxy groups. Typically, it is substituted with 1, 2 or 3 hydroxy groups. Preferably, it is substituted with a single hydroxy group. Preferred hydroxyalkyl groups are -CH ₂ -OH.

As used herein, an acyl group is a C _2-7 acyl group, such as a group CO-R, where R is said C _1-6 alkyl group.

As used herein, aryl groups are typically C _6-10 aryl groups, such as phenyl or naphthyl. Phenyl is preferred. Aryl groups may be unsubstituted or substituted at any position. Typically it has 0, 1, 2 or 3 substituents.

Suitable substituents on the aryl group are halogen, C _1-6 alkyl, C _2-7 acyl, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, Nitro, cyano, carbamoyl, mono (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) carbamoyl, amino, mono (C _1-6 alkyl) amino, di (C _{1 -6} alkyl) amino, -CO ₂ R ', -CONR'R ", -S (O) R', -S (O) ₂ R'R", -S (O) NR'R ", -S ( O) ₂ NR'R ", --NH-S (O) ₂ R 'or -NH-CO-R', wherein each R 'and R" are the same or different and are hydrogen or C _{1- 6} alkyl.

Preferred substituents on the aryl group are halogen, C _1-6 alkyl, C _2-7 acyl, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, Amino, mono (C _1-6 alkyl) amino, di ( _1-6 alkyl) amino, nitro, cyano, -CO ₂ R ', -S (O) R', -S (O) ₂ R 'and- S (O) ₂ NR′R ″, wherein each R ′ and R ″ are the same or different and represent hydrogen or C _1-4 alkyl.

Particularly preferred substituents are fluorine, chlorine, bromine, iodine, cyano, C _1-4 alkyl, C _2-4 acyl, hydroxy, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 haloalkyl, C _1-4 haloalkoxy, amino, mono (C _1-4 alkyl) amino, di (C _1-4 alkyl) amino, nitro, —CO ₂ R ′, —S (O) ₂ R ′ and —S (O ) ₂ NH ₂ , wherein R ′ represents C _1-2 alkyl. Most preferred substituents are chlorine, fluorine, cyano, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl substituents.

As used herein, reference to an aryl group refers to an aryl group fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group, or a fused group that is a monocyclic carbocyclyl, heterocyclyl or heteroaryl group fused to a phenyl ring. Fused ring systems. Typically, the fused ring system is a system in which an aryl group is fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group.

Preferred such fused ring systems are those in which the aryl group is fused to a monocyclic heterocyclyl or heteroaryl group or a monocyclic carbocyclic group fused with a phenyl ring, in particular an aryl group is fused to a heterocyclyl or heteroaryl group. It is a ring system. Examples of such fused ring systems are groups in which the phenyl ring in the group is fused to a thienyl group or tetrahydrofuranyl group to form a benzothienyl or dihydrobenzofuranyl group. Further examples of such fused rings are phenyldioxynyl, indolyl or 9H-fluorene- in which the phenyl ring in the group is fused to a dioxanyl group, a pyrrolyl group or a 2,3-dihydroinden-1-one group. Groups to form 9- warm groups. However, most preferably the aryl group as used herein is not fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group or the fusion group.

Carbocyclyl groups as used herein are typically nonaromatic saturated or unsaturated monocyclic hydrocarbon rings having 3 to 6 carbon atoms. Preferably, it is a saturated hydrocarbon ring (ie cycloalkyl group) having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably cyclopropyl, cyclopentyl or cyclohexyl, most preferably cyclopropyl. Cycloalkyl groups may be unsubstituted or substituted at any position. Typically it has 0, 1, 2 or 3 substituents.

Suitable substituents on the carbocyclyl group are halogen, C _1-6 alkyl, C _2-7 acyl, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 halo Alkoxy, nitro, cyano, carbamoyl, mono (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) carbamoyl, amino, mono (C _1-6 alkyl) amino, di (C _1-6 alkyl) amino, oxo, -CO ₂ R ', -CONR'R ", -S (O) R', -S (O) ₂ R ', -S (O) NR'R", -S (O) ₂ NR'R ", -NH-S (O) ₂ R 'or -NH-CO-R', wherein each R 'and R" are the same or different and are hydrogen or C _{1- 6} alkyl.

Preferred substituents on carbocyclyl groups are halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono (C _1-6 alkyl ) Amino, di (C _1-6 alkyl) amino, nitro, cyano and oxo. Particularly preferred substituents include fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, nitro and oxo. Most preferably, the carbocyclyl group is unsubstituted.

Heterocyclyl groups as used herein are typically nonaromatic saturated or unsaturated carbocyclic rings having 5 to 10 carbon atoms, and at least one of these, for example 1, 2 or 3 carbon atoms. Is substituted with a heteroatom 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. Further examples include dithiolanyl, oxazolidinyl, tetrahydrothiopyranyl and dithianil. Preference is given to piperazinyl, piperidinyl, thiomorpholinyl, imidazolidinyl and morpholinyl groups.

Reference to heterocyclyl group as used herein includes fused ring systems in which the heterocyclyl group is fused to a phenyl group. Preferred such fused ring systems are ring systems wherein 5- to 6-membered heterocyclyl groups are fused to phenyl groups. Examples of such fused ring systems include a 1H-imidazole-2 (3H) -onyl group or an imidazolidine-2-onyl group fused to a phenyl ring or a pyridine ring, for example 1H-benzo [d] imidazole- Group forming a 2 (3H) -onyl group or a 1H-imidazo [4,5-b] pyridin-2 (3H) -one group. However, most preferably, the heterocyclyl group is monocyclic.

Heterocyclic groups may be unsubstituted or substituted at any position. Typically, it has 0, 1 or 2 substituents.

Suitable substituents on heterocyclyl groups are halogen, C _1-6 alkyl, C _2-7 acyl, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 halo Alkoxy, Nitro, Cyano, Carbamoyl, Mono (C _1-6 Alkyl) carbamoyl, Di (C _1-6 Alkyl) Carbomil, Amino, Mono (C _1-6 Alkyl) amino, Di (C _{1 -6} alkyl) amino, oxo, -CO ₂ R ', -CONR'R ", -S (O) R', -S (O) ₂ R ', -S (O) NR'R", -S ( O) ₂ NR′R ″, —NH—S (O) ₂ R ′ or —NH—CO—R ′, wherein each R ′ and R ″ is the same or different and is hydrogen or C _1-6 Alkyl.

Preferred substituents on heterocyclyl groups are halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono (C _1-6 alkyl ) Amino, di (C _1-6 alkyl) amino, nitro, cyano and oxo. Particularly preferred substituents include fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, nitro and oxo. Most preferably, the heterocyclyl group is unsubstituted or substituted with 1 or 2 C _1-2 alkyl or oxo groups. An example of a substituted heterocyclic group is S, S-dioxothiomorpholino.

Halogen as used herein is typically chlorine, fluorine, bromine or iodine. Preferably chlorine, fluorine or bromine. More preferably chlorine or fluorine.

Alkoxy groups, as used herein, are typically such alkyl groups attached with an oxygen atom. Alkylthio groups are typically said alkyl groups attached with thio groups. Haloalkyl or haloalkoxy groups are typically said alkyl or alkoxy groups substituted with one or two said halogen atoms. Typically, it is substituted with one, two or three such halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups, such as -CX ₃ and -OCX ₃ , wherein X is the halogen atom, for example chlorine or fluorine. Particularly preferred haloalkyl groups are -CF ₃ and -CCl ₃ . Particularly preferred haloalkoxy groups are -OCF ₃ and -OCCl ₃ .

Heteroaryl groups as used herein are typically 5- to 10-membered aromatic rings, such as 5- or containing one or more heteroatoms selected from O, S and N, for example 1, 2 or 3 heteroatoms. 6-membered ring. Examples are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadizolyl, isoxazolyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl Contains groups. Further examples include oxazolyl and isothiazolyl. Preferred heteroaryl groups are pyridyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, furanyl and pyrazolyl.

Reference to a heteroaryl group as used herein includes fused ring systems in which the heteroaryl group is fused to a phenyl group or a monocyclic heterocyclyl group. Preferred such fused ring systems are those in which 5- to 6-membered heteroaryl groups are fused to phenyl groups or 5- to 6-membered heterocyclyl groups. Examples of such fused ring systems are benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, quinazolinyl, isoquinolinyl and 1H-imidazo [4,5-b ] Pyridin-2 (3H) -one residue. Most preferably, the fused ring system is a 1H-imidazo [4,5-b] pyridin-2 (3H) -one moiety.

Heteroaryl groups may be unsubstituted or substituted at any position. Typically it has 0, 1, 2 or 3 substituents.

Suitable substituents on heteroaryl groups are halogen, C _1-6 alkyl, C _2-7 acyl, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy , Nitro, cyano, carbamoyl, mono (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) carbamoyl, amino, mono (C _1-6 alkyl) amino, di (C _{1 -6} alkyl) amino, -CO ₂ R ', -CONR'R ", -S (O) R', -S (O) ₂ R ', -S (O) NR'R", -S (O) ₂ NR′R ″, —NH—S (O) ₂ R ′ or —NH—CO—R ′, wherein each R ′ and R ″ are the same or different and represent hydrogen or C _1-6 alkyl Indicates.

Preferred substituents on heteroaryl groups are halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono (C _1-6 alkyl) Amino, di (C _1-6 alkyl) amino, nitro and cyano. Particularly preferred substituents include fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl and nitro. Most preferred substituents include fluorine, chlorine, bromine, C _1-2 alkyl and C _1-2 haloalkyl substituents.

When R ¹ is an aryl or heteroaryl group, it is typically unsaturated, or from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl or C _1-6 haloalkoxy Substituted with 1, 2 or 3 substituents selected. Preferably it is not saturated or is selected from fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 haloalkyl or C _1-4 haloalkoxy Substituted with one or two substituents. More preferably, it is unsaturated or substituted with a single fluorine, chlorine, C _1-2 alkyl, C _1-2 alkoxy, C _1-2 alkylthio, C _1-2 haloalkyl or C _1-2 haloalkoxy substituents. .

Typically, R ¹ is C _{1 -6} alkyl or aryl. Preferably, R ¹ is a C _{1 -2} alkyl, or aryl. More preferably, R ¹ is C _1-2 alkyl or phenyl. More preferably, R ¹ is an unsubstituted phenyl group.

Typically, R ² is hydrogen or C _{1 -4} alkyl. Preferably, R ² is hydrogen.

Typically, R ³ is halogen, hydroxy, C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} alkylthio, C _1-4 haloalkyl, C _1-4 haloalkoxy, amino, mono (C _1-4 alkyl) amino or di (C _1-4 alkyl) amino. Preferably, R ³ is fluorine, chlorine, bromine, C _1-2 alkyl, C _1-2 alkoxy, C _1-2 alkylthio, C _1-2 haloalkyl, C _1-2 haloalkoxy, amino, mono ( C _1-2 alkyl) amino or di (C _1-2 alkyl) amino. More preferably, R ³ is methyl, trifluoromethyl, fluorine, chlorine or bromine. Most preferably, R ³ is methyl or chlorine.

Typically, n is 0, 1 or 2. Preferably, n is 0 or 1. Most preferably, n is zero.

Typically, R ⁴ is hydrogen or C _{1 -4} alkyl. Preferably, R ⁴ is hydrogen or C _1-2 alkyl. More preferably, R ⁴ is hydrogen or methyl. Most preferably, R ⁴ is hydrogen.

Typically, X is —CO—, —S (O) ₂ — or —CO—NR′—, wherein R ′ represents hydrogen or a C ₁ -C ₂ alkyl group. Preferably, X is -CO- or -CO-NR'-.

R ⁵ is a heterocyclyl or C ₁ -C ₆ hydroxyalkyl group or-(C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X _2- (C ₁ -C ₄ alkyl) When a heterocyclyl group is substituted with a group, the heterocyclyl or heteroaryl group is typically a 5- or 6-membered ring. Preferably, it is a 5- or 6-membered heteroaryl group, for example furanyl group.

Typically, C ₁ -C ₆ hydroxyalkyl groups are —CH ₂ —OH groups. Typically, X is -NR'- where R 'is hydrogen or C ₁ -C ₂ alkyl. Typically, X ₂ is -S (O) _2- .

Typically, A ₁ is an aryl or heteroaryl group. Preferably, A ₁ is a monocyclic aryl or heteroaryl group, a naphthyl group or heteroaryl group fused to a monocyclic oxo substituted heterocyclyl group. More preferably, A ₁ is a phenyl group, a monocyclic 5- or 6-membered heteroaryl group or a monocyclic oxo substituted 5- to 6-membered heterocyclyl group (eg, oxo substituted imida) 5- to 6-membered heteroaryl group fused to a zolidine group). Most preferably, A ₁ is a phenyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thienyl or 1H-imidazo [4,5-b] pyridin-2- (3H) -one moiety to be.

Typically, A ₁ is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ alkoxy substituents. do. Preferably, the substituents are selected from halogen, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ alkoxy substituents.

Typically, Y represents a direct bond, a C ₁ -C ₂ alkylene group, —SO ₂ — or —O—.

Typically, A ₂ is a phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or C ₃ -C ₆ cycloalkyl group. Preferably, A ₂ is a piperazinyl, pyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl or phenyl group.

Typically, when A ₂ is a heterocyclyl group, it is attached to residue Y via the N atom.

Typically, residue A ₂ is unsubstituted, or if A ₂ is a heteroaryl or aryl group, one or two substituents selected from C ₁ -C ₄ alkyl and halogen substituents and A ₂ is carbocyclic or heterocyclyl Group is substituted with one or two substituents selected from C ₁ -C ₄ alkyl, halogen and oxo substituents.

Most preferably, A ₂ is a piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thiomorpholino group, these The group is unsubstituted or substituted with a C ₁ -C ₂ alkyl group.

Preferred compounds of the invention

R ¹ is C _1-6 alkyl or aryl;

R ² is hydrogen or C _1-4 alkyl;

R ³ is halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 haloalkyl, C _1-4 haloalkoxy, amino, mono (C _1-4 Alkyl) amino or di (C _1-4 alkyl) amino, or preferably, R ³ is fluorine, chlorine, bromine, C _1-2 alkyl, C _1-2 alkoxy, C _1-2 alkylthio, C _{1- 2} haloalkyl, C _1-2 haloalkoxy, amino, mono (C _1-2 alkyl) amino or di (C _1-2 alkyl) amino;

n is 0, 1 or 2;

R ⁴ is hydrogen or C _1-4 alkyl;

X is —CO—, —CO—NR ′ or —S (O) ₂ —, wherein R ′ is hydrogen or a C ₁ -C ₂ alkyl group;

R ⁵ is a C ₁ -C ₆ hydroxyalkyl group or a-(C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X _2- (C ₁ -C ₄ alkyl) group where , X ₁ and X ₂ are as defined above, or a 5- or 6-membered heterocyclyl or heteroaryl ring, or R ⁵ represents -A ₁ -YA ₂ , wherein:

A ₁ is an aryl or heteroaryl group;

Y is a direct bond, a C ₁ -C ₂ alkylene group, —SO ₂ — or —O—;

A ₂ is an aryl, heteroaryl, heterocyclyl or carbocyclyl group,

Wherein the aryl moiety in the R ¹ group is unsubstituted or halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ Substituted with 1, 2 or 3 substituents selected from haloalkoxy groups,

The A ₁ residue is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ alkoxy substituents;

A ₂ is a residue is optionally substituted, A ₂ is a heteroaryl or aryl group case, C ₁ -C ₄ alkyl and the substituents are selected from halogen, A ₂ is carbocyclic or if heterocyclyl group include C ₁ -C ₄ alkyl , Substituted with one or two substituents selected from halogen and oxo substitutions.

Further preferred compounds of the invention are

R ¹ is C _1-2 alkyl or phenyl;

R ² is hydrogen or C _1-4 alkyl;

R ³ is methyl, trifluoromethyl, fluorine, chlorine or bromine;

n is 0 or 1;

R ⁴ is hydrogen or C _1-2 alkyl;

X is —CO—, —CO—NR′— or —S (O) ₂ , wherein R ′ is hydrogen or a C ₁ -C ₂ alkyl group;

R ⁵ is substituted with a C ₁ -C ₆ hydroxyalkyl group or a-(C ₁ -C ₄ alkyl) -NR ′-(C ₁ -C ₄ alkyl) -SO _2- (C ₁ -C ₄ alkyl) group A 5- or 6-membered heterocyclyl or heteroaryl group, wherein R ′ is hydrogen or C ₁ -C ₂ alkyl, or R ⁵ represents —A ₁ -YA ₂ , wherein:

A ₁ is a 5- or 6-membered heteroaryl group fused to a phenyl group, a monocyclic 5- or 6-membered heteroaryl group or a monocyclic oxo-substituted 5- to 6-membered heterocyclyl group;

Y represents a direct bond, a C ₁ -C ₂ alkylene moiety, —SO ₂ — or —O—;

A ₂ is a phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or a C ₃ -C ₆ cycloalkyl group,

The phenyl moiety in the R ¹ group is unsubstituted or from fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 haloalkyl or C _1-4 haloalkoxy Substituted with one or two substituents selected,

The A ₁ residue is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl and C _1-4 alkoxy substituents;

A ₂ is a residue is optionally substituted, if A ₂ is a heterocyclyl or cycloalkyl group when C ₁ -C ₄ alkyl and is selected from halogen and oxo substituents, A ₂ is phenyl or heteroaryl group is C ₁ -C ₄ Compound substituted with one or two substituents selected from alkyl and halogen substituents.

Particularly preferred compounds of the present invention are compounds of formula la and pharmaceutically acceptable salts thereof.

In the above formula,

-X is -CO- or -CO-NH-;

R ⁵ is a 5- to 6-membered heteroaryl group, for example furanyl group, which is —CH ₂ —OH or — (C ₁ -C ₄ alkyl) -N (CH ₃ )-(C ₁ -C ₄ alkyl) -SO ₂ - (C ₁ -C ₄ substituted by alkyl), or or R ⁵ represents an -A ₁ -YA _2, wherein:

A ₁ is a phenyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thienyl or 1H-imidazo [4,5-b] pyridin-2- (3H) -one moiety, which is substituted Or substituted with 1 or 2 substituents selected from halogen, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ alkoxy substituents;

Y is a direct bond, a C ₁ -C ₂ alkylene group, —SO ₂ — or —O—;

A ₂ is piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thiomorpholino group, which is unsubstituted, Substituted with a C ₁ -C ₂ alkyl group.

In compounds of formula (Ia), typically n is 0 and R ₄ is hydrogen.

Compounds of formula (I) having one or more chiral centers can be used in enantiomeric or diastereomerically pure forms or in the form of mixtures of isomers. For the avoidance of doubt, the chemical structures shown herein are intended to include all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and / or diastereomers.

Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) having one chiral center contain R enantiomers in substantially pure form, S enantiomers in substantially pure form and excess R enantiomers or excess S enantiomers Enantiomeric mixtures. To avoid uncertainty, the compounds of formula (I) may optionally be used in the form of solvates.

As used herein, pharmaceutically acceptable salts are salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid or organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethane Both sulfonic acid, benzenesulfonic acid or p-toloenesulfonic acid. Pharmaceutically acceptable bases include alkaline bases (eg sodium or potassium) and alkaline earth metals (eg calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. .

Particularly preferred compounds of the invention are

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- [1,2 '] bipyridinyl-5'-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e ] [1,4] diazepin-3-yl) -amide;

(S) -2- (1,1-dioxo-1λ6-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] diazepine-3 -Yl) -benzamide;

(S) -2- (1,1-dioxo-1λ6-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-1λ6-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-1λ6-thiomorpholin-4-yl) -5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H- Benzo [e] [1,4] diazepin-3-yl) -benzamide;

(S) -5- (4-Methyl-piperazin-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-pyrrolidin-1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia Zepin-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] dia Zepin-3-yl) -amide;

(S) -5-dimethylaminomethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 Hbenzo [e] [1, 4] diazepin-3-yl) -amides;

(S) -4-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperi Din-1-yl-benzamide;

(S) -4-fluoro-2-morpholino-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine 3-yl) -benzamide;

(S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrroli Din-1-yl-benzamide;

(S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-piperidine- 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-1 H-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-1λ6-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-1λ6-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-1λ6-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-1λ6-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-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide;

(S) -3-cyclopropyl-2-oxo-2,3-dihydro-imidazo [4,5-b] pyridine-1-carboxylic acid (2-oxo-5-phenyl-2,3-di Hydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide;

(S) -3- (4-methyl-piperazin-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia Zepin-3-yl) -benzamide;

(S) -4- (4-methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepine 3-yl) -benzamide;

(S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (piperidine-1- Sulfonyl) -benzamide;

(S) -3- (morpholine-4-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3- Yl) -benzamide;

(S) -5-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine -3-yl) -amide;

(S) -5-hydroxymethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl )-amides;

(S) -5- (1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H -Benzo [e] [1,4] diazepin-3-yl) -amide;

(S) -2-chloro-4- (1,1-dioxo-1λ6-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-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide;

(S) -5-{[(2-Methanesulfonyl-ethyl) -methyl-amino] -methyl} -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -Benzo [e] [1,4] diazepin-3-yl) -amide;

(S) -2-pyridin-3-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1 H-benzo [e] [1, 4] diazepine- 3-yl) -amide;

(S) -2-pyridin-4-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine -3-yl) -amide;

(S) -4-methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4 ] Diazepin-3-yl) -amide;

(S) -2-morpholin-4-ylmethyl-furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepine -3-yl) -amide;

(S) -3-morpholin-4-ylmethyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) Benzamide;

(S) -5-morpholin-4-ylmethyl-isoxazole-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] dia Zepin-3-yl) -amide;

(S) -3-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepine -3-yl) -amide;

(S) -5-pyridin-2-yl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine- 3-yl) -amide;

(S) -2-methyl-4- (morpholine-4-sulfonyl) -furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [ 1,4] diazepin-3-yl) -amide;

(S) -6-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl)- Nicotinamide;

(S) -3-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide;

(S) -5-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia Zepin-3-yl) -amide;

2-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-benzamide;

(S) -5-phenyl-oxazole-4-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl) -amides;

1- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-phenoxy-phenyl) -urea;

N-oxides of any of the above compounds; And pharmaceutically acceptable salts thereof.

The main part of formula (II) is protected by reacting a compound of formula (I) with glyoxylic acid (HCO-CO ₂ H), benzotriazole and appropriate benzyl carbamate at reflux in toluene under Dean-Stark conditions. Amino acids can be obtained and prepared.

The amino acid of formula (II) thus obtained can then be reacted with a suitable chlorinating agent such as oxalyl chloride and then reacted with 2-aminobenzophenone of formula (III) to give an intermediate amide of formula (IV) which requires no characterization. .

The ammonolysis of the compound of formula IV may then be followed by ring closure in acetic acid containing ammonium acetate to afford the protected benzodiazepines of formula V below.

The compound of formula V can then be deprotected with hydrogen bromide in acetic acid to produce a protected amine of formula VI.

The compound of formula (I), wherein X is -CO- or -CO-NR ', reacts the compound of formula (VI) as defined above with acid anhydride at ambient temperature in a suitable solvent, preferably pyridine, or preferably in the presence of a base. Can be prepared by reaction with acid chloride in the presence of triethylamine at ambient temperature in THF. Alternatively, the compound may react the compound of formula VI with triethylamine and O-benzotriazol-1-yl-N, N, N 'at ambient temperature in a suitable solvent in the presence of a base and a coupling agent, preferably in THF. It can be prepared by reacting with acid in the presence of, N'-tetramethyluronium hexafluorophosphate (HBTU).

If the acid chloride used is amino carbonyl chloride, the compound of formula I is urea. When R 'in the X residue is hydrogen, the compound may be prepared by reacting a compound of formula VI with an isocyanate. This reaction is preferably carried out at ambient temperature in THF. Alternatively, isocyanates can be prepared in situ from the relevant amines and phosgene in THF, in the presence of a base, usually triethylamine. Compounds in which R 'is not hydrogen, as well as corresponding compounds in which R' is hydrogen, can be prepared by reaction with a suitable alkylating agent, for example L- (C ₁ -C ₆ alkyl), in which L is a leaving group, for example chlorine have.

Compounds of formula I, wherein X is -S (O) _2- , can be prepared by reacting a compound of formula VI with a suitable sulfonyl chloride. Similarly, compounds of formula I, wherein X is -S (O)-, can be prepared by reacting compounds of formula VI with a suitable sulfinyl chloride.

In the preparation of the benzodiazepine skeleton, commercially available aminobenzophenone compounds of the general formula (III) can be used where possible. Non-commercial compounds of formula III can be prepared by known methods, for example by reaction of the group R ¹ -Li or Grinard reagents such as R ′ ^' -MgBr with a Weinreb type amide of formula VII It can manufacture.

Preferably, this reaction is carried out in THF at -100 ° C.

Compounds of formula (VII) are known compounds or can be similarly prepared using known methods. For example, they can be prepared from the reaction of N, O-dimethyl hydroxylamine with isatophosphoric anhydride of formula VIII under standard conditions.

Starting materials of the formulas (II), (III), (VII) and (VIII) are known compounds or can be similarly prepared using known methods.

Further synthetic manipulations of the compounds of formula (I) thus obtained may be carried out in a conventional manner to achieve further compounds of formula (I). For example, the benzodiazepines of formula (I) can be chlorided by treatment with a suitable acid or base.

Although the above described route to the claimed compounds provides adequate synthesis for laboratory scale preparation, it is believed that alternative routes are likely as preparation routes. Starting material (2-amino-benzophenone) (1) is used in both routes, but in alternative routes it is initially reacted with bromoacetyl bromide (or an equivalent reagent thereof), followed by ring closure with ammonia. Form a benzodiazepine ring system. These reactions are carried out in a suitable solvent such as dichloromethane at a suitable temperature such as in the range of -20 to 150 ° C. To protect the NH functionality, unsubstituted benzodiazepines are reacted with base and alkylating agent in this step. For example, the addition of sodium hydride in DMF followed by 4-methoxy-benzyl chloride produces the intermediate 2 as shown below. The material is further reacted with a base (eg potassium tert-butoxylate) in a suitable solvent (eg THF or DMF) and then quenched with isoamyl nitrite (or alternative analogous reagent). An oxime intermediate (3) is obtained, which can be converted to a racemic primary amine via a process involving the use of hydrogen and a suitable catalyst. This amine is then treated with a Dynamic Kinetic Resolution (DKR) procedure where the racemic amine causes precipitation in the presence of a suitable optically active acid and a suitable aldehyde to treat the desired (S) -amine (4) salt. Good yields and very high enantiomeric purity are obtained. Suitable acids for this conversion can be, for example, camposulfonic acid, Boc-phenyl alanine, and the like, and suitable aldehydes can be benzaldehydes such as 3,5-dichlorosalicylaldehyde.

The optical amine thus formed can then be converted to the desired derivative, such as an amide or urea. Amide formation can be carried out using suitable carboxylic acids and coupling agents, or carbonyl chlorides or other suitable reagents, and urea can be prepared by using a suitable isocyanate or alternatively by reacting with a phosgene followed by a suitable amine. Can be.

The derivatives thus formed can then be removed with protecting groups. This reaction can be carried out in the presence of Lewis acids such as aluminum chloride, boron trifluoride, titanium tetrachloride and the like. This reaction is carried out in a suitable inert solvent such as dichloromethane. The reaction temperature may range from -20 to 150 ° C., but is typically performed at temperatures below room temperature.

As described above, the compounds of the present invention are active against RSV. Accordingly, the present invention provides a method of treating a patient comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient suffering from or susceptible to RSV infection.

RSV is easily transmitted to children under 2 years old, asthma, adults with chronic obstructive respiratory disorder (COPD), or immunodeficiency. This is especially dangerous for children with chronic lung disease. Thus, the compositions or medicaments are typically for use in treating children under 2 years of age, adults and elderly people suffering from asthma, COPD or immunodeficiency, and patients living in long-term care facilities. Typically, the child suffers from chronic lung disease.

In addition, anti-RSV prophylaxis is recommended for infants, the elderly, people with immunodeficiency, and residents of long-term care facilities up to 32 weeks of gestation or up to 6 months of gestation. Accordingly, the composition or medicament is for use in preventing RSV infection in infants under 6 years old, elderly, immunocompromised and residents of long-term care facilities born at 32 weeks of gestation or earlier.

RSV infection is known to be accompanied by an inflammatory response (Noah et al, Clinical Immunology 2000, Vol 97, 43-49). The invention also relates to the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an anti-inflammatory compound and the use of said medicament in the treatment of RSV. Typically, the anti-inflammatory compounds are steroids such as budesonide or fluticasone, non-steroids such as leukotriene antagonists, phosphodiesterase 4 inhibitors or TNF alpha inhibitors or interleukin 8 or interleukin 9 inhibitors.

Thus, in one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a steroidal anti-inflammatory compound, for example butesonide or fluticasone. In a preferred embodiment, the steroid is administered at a low dose to minimize the immunosuppressive effect. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a nonsteroidal anti-inflammatory compound, eg, a leukotriene antagonist such as Mercer or Astra Zeneca, phosphodiesterase 4 inhibitor Such as Loflumilast (Altana), TNF alpha inhibitors such as Ambrel, Remicade, Centocor, Abbott or CDP870 (Celltech) or NSAIDS. In a further embodiment, the compound of formula (I) is combined with an interleukin 8 or interleukin 9 inhibitor. Accordingly, the present invention also relates to a product containing a compound of formula (I) or a pharmaceutically acceptable salt and anti-inflammatory compound thereof for use in the treatment of RSV simultaneously, separately or sequentially.

The invention also relates to the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an antiinfluenza compound and the use of such a combination in the treatment of concomitant RSV and influenza infections. Accordingly, the invention also relates to a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-influenza compound thereof for use simultaneously, separately or sequentially for the treatment of companion RSV and influenza infections. It is about.

It is a further surprising finding of the present invention that the compounds of the present invention are active against human metapneumovirus, measles, parainfluenza virus, paramyxovirus and mumps. Accordingly, the present invention provides a use in the manufacture of a medicament for use in the treatment of human metapneumovirus, measles, parainfluenza virus, paramyxovirus and mumps of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be administered in a variety of dosage forms. Thus, they can be administered orally, eg as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the present invention may also be administered parenterally, whether subcutaneous, intravenous, intramuscular, intrasternal, transdermal or infusion techniques. The compounds may also be administered as suppositories.

In a preferred embodiment, the compounds of the present invention are administered intranasally or bronchically. The invention also provides an inhaler or nebulizer containing a medicament comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and (b) a pharmaceutically acceptable carrier or diluent as defined above. .

The present invention also provides a pharmaceutical composition comprising a benzodiazepine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

Such pharmaceutical compositions typically contain up to 85% by weight of the compound of the present invention. More typically, it contains up to 50% by weight of the compound of the present invention. Preferred pharmaceutical compositions are sterile and pyrogen-free. In addition, pharmaceutical compositions provided by the present invention typically contain a compound of the present invention that is a substantially pure optical isomer.

Typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms can be used with active compounds in combination with diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; Lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; Binders; For example starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; Disintegrants such as starch, alginic acid, alginate or sodium starch glycolate; Foamy mixtures; dyes; Sweeteners; Wetting agents such as lecithin, polysorbates, laurylsulfate; And generally non-toxic pharmacologically inactive substances used in pharmaceutical compositions. Such pharmaceutical formulations can be prepared by known methods, such as mixing, granulating, tableting, sugar coating or film coating processes.

Liquid dispersants for oral administration include syrups, emulsions and suspensions. Syrups may contain, for example, saccharose or saccharose and glycerin and / or mannitol and / or sorbitol as carriers.

Suspensions and emulsions may contain, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as carriers. Suspensions or solutions for intramuscular injection may contain pharmaceutically acceptable carriers such as sterile water, olive oil, ethyloleate, glycols such as propylene glycol and optionally suitable amounts of lidocaine hydrochloride together with the active compound. have.

Liquid solutions for injection or infusion may, for example, contain a sterile water as a carrier, or preferably in the form of a sterile isotonic saline solution.

A therapeutically effective amount of a compound of the present invention is administered to a patient. Typical dosages are from about 0.001 to 50 mg of active ingredient per kg of body weight, depending on the activity of the specific composition, the age, weight and condition of the subject treated, the type and severity of the disease and the frequency and route of administration. Preferably, the daily dosage level is 5 mg to 2 g of active ingredient.

Certain benzodiazepine derivatives of formula (I) are novel in themselves. The present invention includes these novel compounds and their pharmaceutically acceptable salts. Accordingly, the present invention also provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof.

In the above formula, R ₁ , R ₃ , n, R ₄ , X and R ₅ are as defined above.

Typically, R ₁ in formula (Ib) is an unsubstituted phenyl group.

Typically, A ₁ in formula (Ib) is a heteroaryl group, which is not a 5-methyl-isoxazolyl moiety.

Typically, A ₁ in formula (Ib) is an aryl or heteroaryl moiety.

Typically, X in formula (Ib) is -CO- or -CO-NR'-, wherein R 'is as defined above, provided that when X is -CO-NR'-, the residue -A ₁ -YA ₂ Is -phenyl-O-phenyl.

Typically, A ₂ in formula (Ib) is not a 4- to 10-membered saturated cycloalkyl ring in which one of the carbon atoms is replaced by an N atom. In particular, A ₂ is typically not a substituted or unsubstituted moiety of the formula:

Wherein n and m are the same or different and each represents an integer of 1 to 4

Typically, A ₂ in Formula Ib is piperazinyl, pyridyl, pyrrolidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thio unsubstituted or substituted with a C ₁ -C ₂ alkyl group Morpholino group.

A novel compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating a human or animal body. The invention also relates to pharmaceutical compositions comprising the novel compounds as defined above and pharmaceutically acceptable diluents or carriers. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the novel compound as defined above. Pharmaceutically acceptable salts are defined as above. The novel compounds of the present invention are administered in the above defined manner and the compounds are typically formulated for administration in the above defined manner.

Preferably, the pharmaceutical composition comprises optically active isomers of the novel compounds of the present invention. Thus, for example, preferred compounds of the present invention having only one chiral center can be used to form R enantiomers in substantially pure form, S enantiomers in substantially pure form and excess R enantiomers or excess S enantiomers. Enantiomeric mixtures containing. It contains in particular the compounds of the invention which are substantially pure optical isomers. To avoid uncertainty, the novel compounds of the present invention may optionally be used in the form of solvates.

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 characterization used in the Examples section is only for showing antiviral activity. There are a number of assays that can determine the activity of the compounds presented for RSV, so the negative results in any one characterization are not definitive.

Intermediate 1

2-Chloro-4- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid

A mixture of 4-amino-2-chlorobenzoic acid (172 mg) and ethenesulfonyl-ethene (0.15 ml) in water (3 ml) containing sodium carbonate (212 mg) was heated to 100 ° C. for 18 hours. The mixture was cooled and acidified with 2N HCl. An off-white precipitate was collected and dried (263 mg).

LC / MS RT = 4.09 min, ES-288,290

Intermediate 2

2-Chloro-5- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid

A mixture of 5-amino-2-chlorobenzoic acid (172 mg) and ethenesulfonyl-ethene (0.15 ml) in water (3 ml) was heated to 100 ° C. for 18 hours. The mixture was cooled down and extracted with dichloromethane. The dried extract was evaporated to give a light brown solid (265 mg).

LC / MS RT = 4.13 min, ES-288,290

Intermediate 3

2- (1,1-Dioxo-1λ6-thiomorpholine-4-el) -nicotinic acid

This material was prepared as described for Intermediate 1, except using 2-amino-nicotinic acid (138 mg). The title compound was isolated as an off-white solid (93 mg).

Intermediate 4

2- (1,1-Dioxo-1λ6-thiomorpholin-4-yl) -3-methyl-benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-3-methyl-benzoic acid (302 mg). The title compound was isolated as a light brown solid (486 mg).

Intermediate 5

2- (1,1-Dioxo-1λ6-thiomorpholin-4-yl) -4-methyl-benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-4-methyl-benzoic acid (302 mg). The title compound was isolated as a brown solid (430 mg).

Intermediate 6

2- (1,1-Dioxo-1λ6-thiomorpholin-4-yl) 6-methyl-benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-6-methyl-benzoic acid (302 mg). The title compound was isolated as a brown solid (490 mg).

Intermediate 7

3- (4-Methyl-piperazine-1-sulfonyl) -benzoic acid

A solution of 3-chlorosulfonyl-benzoic acid (89 mg), 4-dimethylamino-pyridine (catalyst amount) and N-methylpiperazine (0.045 ml) in dichloromethane (10 ml) was heated at reflux for 2 hours. The solvent was then removed and the crude used in the next synthetic step without purification or characterization.

Intermediate 8

3-piperidine-1-sulfonyl-benzoic acid

This material was prepared as described for intermediate 7 except using piperidine as the nucleophile. As for intermediate 7, this material was used as crude.

Intermediate 9

3- (Morpholine-4-sulfonyl) -benzoic acid

This material was prepared as described for Intermediate 7, except for using morpholine as nucleophile. As for intermediate 7, this material was used as crude.

Intermediate 10

2-Chloro-6- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-6-chloro-benzoic acid (343 mg). The title compound was isolated as a pale yellow solid (405 mg).

Intermediate 11

5-Chloro-2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-5-chloro-benzoic acid (200 mg). The title compound was isolated as a white solid (233 mg).

Intermediate 12

2- (1,1-Dioxo-1λ6-thiomorpholin-4-yl) -5-fluoro-benzoic acid

This material was prepared as described for Intermediate 2, except using 2-amino-5-fluoro-benzoic acid (200 mg). The title compound was isolated as a white solid (310 mg).

Intermediate 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 minutes. . The residue was then partitioned between water and dichloromethane. The dried organic layer was evaporated and then purified on silica gel SPE cartridge. Dichloromethane was then eluted with a gradient of 800: 8: 1 to 200: 8: 1 of dichloromethane: ethanol: 0.880 ammonia to give the title material as a white solid (292 mg).

Intermediate 14

2- (1,1-Dioxo-4-oxy-1λ 6-thiomorpholin-4-yl) -4-fluoro-benzoic acid

Intermediate 11 (262 mg) and potassium peroxymonosulfate (1.34 g) in methanol (5 ml) and water (2.5 ml) were stirred at room temperature for 6 hours. The precipitate formed was collected by filtration and then dissolved in aqueous sodium bicarbonate. Acidify to pH 3 with 1M HCl to form a white precipitate which was collected and dried (194 mg).

Intermediate 15

6-Chloro-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-nicotinamide

Racemic 3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (1 g), O-benzotriazole- in anhydrous DMF (20 ml) A mixture of 1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (1.51 g), triethylamine (0.83 ml) and 6-chloro-nicotinic acid (0.63 g) was added at room temperature. Stir for hours. Water (200 ml) was then added and the mixture was vigorously stirred for 10 minutes. The colorless precipitate was collected by filtration and dried (1.1 g).

Intermediate 16

Thiomorpholine-1,1-dioxide

9.98 g of thiomorpholine and 14.8 g of trif anhydride were stirred together in DCM for 2 h. The reaction was then partitioned between 1 MK ₂ CO _{3 (aq)} and DCM. The organic layer was separated, passed through hydrophobic frit, dried and concentrated in vacuo. 13.82 g of the resulting oil was stirred for 18 h at room temperature with 50 mL of methanol and 85.2 g of oxone in 50 mL of water. The reaction was then filtered, washed with methanol and the filtrate was concentrated. It was then partitioned between water and EtOAc and the aqueous layer washed three times with EtOAc. The combined organic extracts were then dried (MgSO ₄ ) and concentrated to give a white solid. Then it was stirred for 18 h with 40 g of K ₂ CO ₃ in 80 mL of methanol at room temperature. Methanol was then removed under vacuum and the residue was partitioned between DCM and saturated K ₂ CO _{3 (aq)} . The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo to yield 3.51 g of the title compound.

Intermediate 17

5-{[(2-methanesulfonyl-ethyl) -methyl-amino] -methyl} -furan-2-carboxylic acid ethyl ester

0.5 g of 5-chloromethyl-furan-2-carboxylic acid ethyl ester in THF and 20 ml of 2 M methylamine solution were stirred at room temperature under nitrogen for 5 days. The solution was then concentrated and purified by SPE. The resulting oil was heated to 200 ° C. in microwave for 1 hour with 0.2 mL of methanesulfonyl-ethene in 3 mL of acetonitrile. The solution was concentrated and purified by chromatography to give the title compound as a colorless oil.

Intermediate 18

5-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 for 30 minutes at room temperature under a nitrogen atmosphere. Then a solution of 5-chloromethyl-furan-2-carboxylic acid ethyl ester in 2 mL of DMF was added dropwise over 30 minutes. The reaction was then stirred for 2 days. The solvent was then removed in vacuo and 5 mL of EtOH and 0.35 ml of 2 M NaOH were added and stirred at 80 ° C. for 40 minutes. Upon recovery, the reaction was acidified to pH 5.0 or below and the solvent removed in vacuo to afford the title compound which was hydrolyzed and used as crude in the next step.

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

Intermediate 19

5-Morpholin-4-ylmethyl-furan-2-carboxylic acid

Intermediate 20

5- (1,1-dioxo-1λ ⁶ -Thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid

Intermediate 21

5- (4-Methyl-piperazin-1-ylmethyl) -furan-2-carboxylic acid

Intermediate 22

5- (Piperidin-1-ylmethyl) -furan-2-carboxylic acid

Intermediate 23

5- (Pyrrolidin-1-ylmethyl) -furan-2-carboxylic acid

Intermediate 24

3-cyclopropyl-1,3-dihydro [4,5-b] pyridin-2-one

A mixture of 2-chloro-3-nitro-pyridine (2 g), cyclopropylamine (1.13 ml) and potassium carbonate (3.48 g) in acetonitrile (30 ml) was stirred at room temperature for 18 hours. The mixture was then partitioned between water and ethyl acetate. The dried extract was evaporated to give a light yellow solid (2.1 g).

This material was then hydrogenated at atmospheric pressure in ethanol (150 ml) on a palladium catalyst on carbon (10%, 100 mg). When hydrogen absorption ceased, the mixture was filtered through celite and evaporated to give a dark gum (1.7 g). This material was then dissolved in anhydrous THF (40 ml) and treated with carbonyl diimidazole (2.2 g) for 2.5 hours at reflux. The mixture was then partitioned between water and ethyl acetate. The dried organic extract was evaporated to leave a dark gum which was crystallized from ethyl acetate / gasoline to give a colorless solid (1.2 g).

Intermediate 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) was stirred at room temperature for 2 hours. The mixture was then partitioned between dichloromethane and aqueous sodium bicarbonate solution. The dried organic layer was evaporated to give a yellow oil (75 mg).

Intermediate 26

3-Morpholin-4-ylmethyl-benzoic acid methyl ester

This material was prepared as for intermediate 25. The product was a colorless oil (210 mg).

Intermediate 27

5-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) in anhydrous chloroform (4 ml) are stirred, 5 Heat at 85 ° C. for hours. This solution was cooled to room temperature and treated with morpholine (0.27 ml). Stirring continued for 20 hours, then the mixture was partitioned between water and dichloromethane. The dried organic extract was evaporated and the residue was purified on silica gel SPE cartridge. Dichloromethane, followed by dichloromethane: ethanol: 0.880 ammonia; Elution at 200: 8: 1 gave a colorless oil (50 mg).

Intermediates 28-30 were prepared in a similar manner to intermediate 25.

Intermediate 28

3-Morpholin-4-ylmethyl-furan-2-carboxylic acid methyl ester

This compound was isolated as a yellow oil (189 mg).

Intermediate 29

3-Morpholin-4-ylmethyl-thiophene-2-carboxylic acid methyl ester

This compound was isolated as a yellow oil (197 mg).

Intermediate 30

5-Morpholin-4-ylmethyl-thiophene-2-carboxylic acid methyl ester

This compound was isolated as a yellow oil (214 mg).

Intermediates 25-30 were hydrolyzed with the corresponding carboxylic acid prior to use in the final coupling step of the synthesis sequence.

Intermediate 31

4-Fluoro-2-morpholin-4-yl-benzoic acid

2,4-Difluoro-benzoic acid (50 mg) and morpholine (0.03 ml) in acetonitrile (0.5 ml) were heated in microwave at 200 ° C. for 15 minutes. The solvent was evaporated to leave a dark gum which was used without purification in the next synthetic step.

Intermediate 32

4-Fluoro-2-piperidin-1-yl-benzoic acid

It was prepared by a procedure similar to intermediate 31.

Intermediates 33-35 were prepared in a similar procedure to Intermediate 31 except using 2-fluoro-4-trifluoromethyl-benzoic acid.

Intermediate 33

2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid

Intermediate 34

2-Piperidin-1-yl-4-trifluoromethyl-benzoic acid

Intermediate 35

2-Morpholin-4-yl-4-trifluoromethyl-benzoic acid

Intermediates 36 and 37 were prepared in a similar procedure to Intermediate 31 except using 2-fluoro-5-trifluoromethyl-benzoic acid.

Intermediate 36

2-Pyrrolidin-1-yl-5-trifluoromethyl-benzoic acid

Intermediate 37

2-Morpholin-4-yl-5-trifluoromethyl-benzoic acid

Intermediates 38 and 39 were prepared in a similar procedure to Intermediate 31 except using 4-cyano-2-fluoro-benzoic acid.

Intermediate 38

4-Cyano-2-pyrrolidin-1-yl-benzoic acid

Intermediate 39

4-Cyano-2-piperidin-1-yl-benzoic acid

Example 1

6- (4-methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl ) -Nicotinamide

Intermediate 15 (50 mg) and N-methylpiperazine (0.022 ml) in acetonitrile (1 ml) containing triethylamine (0.027 ml) were heated in microwave to 200 ° C. for 10 minutes. The mixture was then partitioned between water and dichloromethane. The dried organic layer was evaporated and the residue was purified on silica gel SPE cartridge. Gradient eluting with 5 to 10% methanol in dichloromethane gave a colorless solid (10 mg).

Example 2

3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1H-benzo [e ] [1,4] diazepin-3-yl) -amide

This material was prepared as described for intermediate 7 except using piperidine as the nucleophile. The product was a colorless solid (15 mg).

Example 3

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [ 1,4] diazepin-3-yl-benzamide

(S) -3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (100 mg) in anhydrous DMF (1 ml), O-benzotria Zol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (150 mg), 2- (1,1-dioxo-1λ6-thiomorpholin-4-yl)- Benzoic acid (102 mg) and triethylamine (0.083 ml) were stirred at rt for 1 h. Water (10 ml) was then added and stirring continued for 10 minutes. 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 silica gel SPE cartridge. Elution with ethyl acetate: gasoline 1: 1 afforded the title compound as a colorless solid (140 mg).

Example 4

(S) -2-chloro-4-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3 -Yl) -benzamide

This material was prepared as in Example 3, except using 2-chloro-4-morpholin-4-yl-benzoic acid (86 mg). The title compound was a colorless solid (112 mg).

Example 5

(S) -2- (1,1-dioxo-4-oxy-1λ6-thiomorpholin-4-yl) -4-fluoro- (2-oxo-5-phenyl-2,3-dihydro- 1H-benzo [e] [1,4] diazepin-3-yl-benzamide

This material was prepared as in Example 3, except that 2- (1,1-dioxo-4-oxy-1λ6-thiomorpholin-4-yl) -benzoic acid (intermediate 14, 30 mg) was used. It was. The title compound was a colorless solid (29 mg).

Example 6

(S) -5-Chloro-2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 5-chloro-2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid (intermediate 11, 58 mg) was used. It was. The title compound was a colorless solid (70 mg).

Example 7

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H- Benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was used as in Example 3, except that 5-fluoro-2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid (intermediate 12, 54 mg) was used. Prepared. The title compound was a colorless solid (70 mg).

Example 8

(S) -5- (4-Methyl-piperazin-1-ylmethyl) -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [ 1,4] diazepin-3-yl) -amide

This material was prepared as in Example 3, except that 5- (4-methyl-piperazin-1-ylmethyl) -furan-2-carboxylic acid (Intermediate 21) was used. The title compound was a colorless solid (15 mg).

Example 9

(S) -5-pyrrolidin-1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide

This material was prepared as in 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).

Example 10

(S) -5-piperidin-1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide

This material was prepared as in Example 3, except that 5- (piperidin-1-ylmethyl) -furan-2-carboxylic acid (intermediate 22) was used. The title compound was a colorless solid (21 mg).

Example 11

(S) -5-dimethylaminomethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl )-amides

This material was prepared as in Example 3, except that 5-dimethylaminomethyl-furan-2-carboxylic acid (Intermediate 18) was used. The title compound was a colorless solid (5 mg).

Example 12

(S) -4-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperi Din-1-yl-benzamide

This material was prepared as in Example 3, except 4-fluoro-2-piperidin-1-yl-benzoic acid (Intermediate 32) was used. The title compound was a colorless solid (58 mg).

Example 13

(S) -4-fluoro-2-morpholino-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine -3-yl) -benzamide

This material was prepared as in Example 3 except using 4-fluoro-2-morpholin-4-yl-benzoic acid (Intermediate 31). The title compound was a colorless solid (19 mg).

Example 14

(S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrroli Din-1-yl-benzamide

This material was prepared as in Example 3, except using 4-cyano-2-pyrrolidin-1-yl-benzoic acid (Intermediate 38). The title compound was a colorless solid (13 mg).

Example 15

(S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-piperidine- 1-yl-benzamide

This material was prepared as in 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).

Example 16

(S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl 4-trifluoromethyl-benzamide

This material was prepared as in Example 3, except using 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid (Intermediate 33). The title compound was a colorless solid (5 mg).

Example 17

(S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperidin-1-yl -4trifluoromethyl-benzamide

This material was prepared as in Example 3 except using 2-piperidin-1-yl-4-trifluoromethyl-benzoic acid (Intermediate 34). The title compound was a colorless solid (14 mg).

Example 18

(S) -2-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl)- 4-trifluoromethyl-benzamide

This material was prepared as in Example 3, except using 2-morpholin-4-yl-4-trifluoromethyl-benzoic acid (Intermediate 35). The title compound was a colorless solid (14 mg).

Example 19

(S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrrolidin-1-yl -5-trifluoromethyl-benzamide

This material was prepared as in Example 3, except that 2-pyrrolidin-1-yl-5-trifluoromethyl-benzoic acid (Intermediate 36) was used. The title compound was a colorless solid (8 mg).

Example 20

(S) -2-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl)- 5-trifluoromethyl-benzamide

This material was prepared as in Example 3, except using 2-morpholin-4-yl-5-trifluoromethyl-benzoic acid (Intermediate 37). The title compound was a colorless solid (19 mg).

Example 21

(S) -2-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [3] [1,4] diazepin-3-yl)- Nicotinamide

This material was prepared as in Example 3, except for using 2-morpholin-4-yl-nicotinic acid. The title compound was a colorless solid (45 mg).

Example 22

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [ 1,4] diazepin-3-yl) -nicotinamide

This material was prepared as in Example 3, except that 2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -nicotinic acid (intermediate 3) was used. The title compound was a colorless solid (10 mg).

Example 23

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -3-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -3-methyl-benzoic acid (Intermediate 4) was used. The title compound was a colorless solid (65 mg).

Example 24

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -4-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [3] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -4-methyl-benzoic acid (Intermediate 5) was used. The title compound was a colorless solid (72 mg).

Example 25

(S) -2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -6-methyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -6-methyl-benzoic acid (Intermediate 6) was used. The title compound was a colorless solid (32 mg).

Example 26

(S) -2-chloro-6- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2-chloro-6- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid (Intermediate 10) was used. The title compound was a colorless solid (51 mg).

Example 27

(S) -3-cyclopropyl-2-oxo-2,3-dihydro-imidazo [4,5-b] pyridine-1-carboxylic acid (2-oxo-5-phenyl-2,3-di Hydro-1H-benzo [el [1,4] diazepin-3-yl) -amide

3-cyclopropyl-1,3-dihydro [4,5-b] pyridin-2-one (intermediate 24, 35 mg), triethylamine (0.028 ml) and triphosgen (20 mg) were converted to dichloromethane (3 ml) for 1 hour at room temperature. Then (S) -3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (50 mg) was added and stirring continued for 18 hours. . Solvent was evaporated and the residue was purified on silica gel SPE cartridge. Dichloromethane: ethanol: 0.880 ammonia; Elution at 200: 8: 1 gave a colorless solid (3 mg).

Example 28

(S) -3- (4-methyl-piperazine-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] 1 Diazepin-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 colorless solid (23 mg).

Example 29

(S) -4- (4-methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine -3-yl) -benzamide

This material was prepared as in Example 3, except that 4- (4-methyl-piperazin-1-yl) -benzoic acid was used. The title compound was a colorless solid (46 mg).

Example 30

(S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (piperidine-1- Sulfonyl) -benzamide

This material was prepared as in Example 3, except 3-piperidine-1-sulfonyl-benzoic acid (Intermediate 8) was used. The title compound was a colorless solid (35 mg).

Example 31

(S) -3- (morpholine-4-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3- Sun) -benzamide

This material was prepared as in Example 3, except that 3- (morpholine-4-sulfonyl) -benzoic acid (Intermediate 9) was used. The title compound was a colorless solid (29 mg).

Example 32

(S) -5-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine -3-yl) -amide

This material was prepared as in 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).

Example 33

(S) -5-hydroxymethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl )-amides

This material was prepared as in 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).

Example 34

(S) -5- (1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H -Benzo [e] [1,4] diazepin-3-yl) -amide

This material was prepared as in Example 3, except that 5- (1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid (intermediate 20) was used. It was. The title compound was a colorless solid (192 mg).

Example 35

(S) -2-chloro-4- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2-chloro-4- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid (Intermediate 1) was used. The title compound was a colorless solid (41 mg).

Example 36

(S) -2-chloro-5- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide

This material was prepared as in Example 3, except that 2-chloro-5- (1,1-dioxo-1λ6-thiomorpholin-4-yl) -benzoic acid (Intermediate 2) was used. The title compound was a colorless solid (69 mg).

Example 37

(S) -5-{[(2-Methanesulfonyl-ethyl) -methyl-amino] -methyl} -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -Benzo [e] [1,4] diazepin-3-yl) -amide

This material was prepared as in Example 3, except that 5-([(2-methanesulfonyl-ethyl) -methyl-amino] -methyl} -furan-2-carboxylic acid ethyl ester (Intermediate 17) was used. Prepared as: The title compound was a colorless solid (87 mg).

Example 38

(S) -2-pyridin-3-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1 H-benzo [e] [1, 4] diazepine- 3-yl) -amide

This material was prepared as in Example 3, except for using 2-pyridin-3-yl-thiazole-4-carboxylic acid. The title compound was a colorless solid (55 mg).

Example 39

(S) -2-pyridin-4-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1 H-benzo [e] [1, 4] diazepine- 3-yl) -amide

This material was prepared as in Example 3, except using 2-pyridin-4-yl-thiazole-4-carboxylic acid. The title compound was a colorless solid (54 mg).

Example 40

(S) -4-methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4 ] Diazepin-3-yl) -amide

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).

Example 41

(S) -2-morpholin-4-ylmethyl-furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1, 4] diazepine -3-yl) -amide

This material was prepared as in Example 3, except using 2-morpholin-4-ylmethyl-furan-3-carboxylic acid (intermediate 25). The title compound was a colorless solid (24 mg).

Example 42

(S) -3-morpholin-4-ylmethyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -Benzamide

This material was prepared as in Example 3, except using 3-morpholin-4-ylmethyl-benzoic acid (Intermediate 26). The title compound was a colorless solid (24 mg).

Example 43

(S) -5-morpholin-4-ylmethyl-isoxazole-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] dia Zepin-3-yl) -amide

This material was prepared as in 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).

Example 44

(S) -3-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepine -3-yl) -amide

This material was prepared as in Example 3, except using 3-morpholin-4-ylmethyl-furan-2-carboxylic acid (intermediate 28). The title compound was a colorless solid (20 mg).

Example 45

(S) -5-pyridin-2-yl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine- 3-yl) -amide

This material was prepared as in Example 3, except that 5-pyridin-2-yl-thiophene-2-carboxylic acid was used. The title compound was a colorless solid (32 mg).

Example 46

(S) -2-methyl-4- (morpholine-4-sulfonyl) -furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [ 1,4] diazepin-3-yl) -amide

This material was prepared as in Example 3, except that 2-methyl-4- (morpholine-4-sulfonyl) furan-3-carboxylic acid was used. The title compound was a colorless solid (75 mg).

Example 47

(S) -6-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) nicotine amides

This material was prepared as in Example 3 except 6-morpholin-4-nicotinic acid was used. The title compound was a colorless solid (28 mg).

Example 48

(S) -3-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide

This material was prepared as in Example 3, except using 3-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (intermediate 29). The title compound was a colorless solid (34 mg).

Example 49

(S) -5-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide

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).

Example 50

2-Morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-benzamide

This material was prepared as in Example 3, except using 2-morpholin-4-yl-benzoic acid (49 mg). The title compound was a colorless solid (33 mg).

Example 51

(S) -5-phenyl-oxazole-4-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl) -Benzamide

(S) -3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (60 mg) in THF (3 ml), triethylamine (0.037 ml) and 5-phenyl-oxazole-4-carbonyl chloride (50 mg) were stirred for 2 hours at room temperature. The mixture was then partitioned between water and dichloromethane. The dried organic phase was evaporated and the residue was purified on silica gel SPE cartridge. Dichloromethane: ethanol: 0.880 ammonia; Elution at 400: 8: 1 gave the title compound as a colorless solid (42 mg).

Example 52

1- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-phenoxy-phenyl) -urea

Racemic 3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diazepin-2-one (30 mg) and 1-isocyanato in dry THF (4 ml) 4-phenoxy-benzene (0.022 ml) was stirred at rt for 18 h. The mixture was then partitioned between water and dichloromethane. The dried organic layer was evaporated and the residue triturated from dichloromethane / diethyl ether to afford the title compound as a white solid (25 mg).

activation Example  One

Using mouse monoclonal antibodies against rabbit protein (P), nucleocapsid (N) & fusion (F) proteins of RSV and rabbit anti-mouse-horseradish peroxidase (HRP) conjugated secondary antibodies A reduction in RSV antigen was demonstrated through conversion of the o-phenylene diamine dihydrochloride (OPD) substrate to the colored product. This was quantified by optical density (OD) measurement.

This assay was prepared using all 96 wells of a flat-bottom 96-well plate. The outer wells were performed to allow for greater evaporation than the inner wells during the three day analysis period (ie, no "edge effect" was seen).

Plates were prepared one day before the addition of virus and compound. The assay was then performed for 3 days to perform ELISA development on day 4.

Day 0

Preparation of Assay Plates

All 96 wells of the microtiter plates were filled with Dulbecco containing Glutamax-1, sodium pyruvate, 1000 mg / l glucose and pyridoxine (Invitrogen, catalog # 21885-025). Seed at a density of 5 × 10 ³ Hep-2 cells / well in 100 μl / well of growth medium (GM) consisting of MEM (DMEM) and supplemented with 10% FBS (see plate 1).

In tissue culture, cells were attached to tissue culture flasks and grown at 37 ° C., 5% CO ₂ until 90% confluent.

The monolayer was washed with 20 ml of sterile PBS to remove serum and the cells were detached from the flask by treatment with 1 ml of trypsin.

Cells were suspended in a known small volume of growth medium and counted using a hemocytometer. Cell suspensions were prepared at the desired concentrations in growth medium and added to the wells by multichannel pipettes. Briefly, moderate shaking allowed the cells to be more evenly distributed across the wells.

Plate 1

Plates were maintained at 37 ° C. in a 5% CO ₂ atmosphere for 24 hours during which cells were seated to form a uniform cell monolayer.

Day 1

Addition of virus

Frozen vial stock solution of RSV (RSS species provided by Virogen Ltd) is removed from the -80 freezer or liquid nitrogen reservoir and subjected to known Multiplicity of Infection (moi) in growth medium. Diluted.

As virus feed required to achieve a window of 0.8 OD or more between infected wells and uninfected control wells m.o.i. was calculated by pre-titration of virus stocks (ELISA assay).

50 μl of diluted virus was added to the infected “virus +” wells with a multichannel pipette; 50 μl of growth medium was added to the uninfected cell control wells (CC) by multichannel pipette (see plate 2).

Plate 2

The side of the plate was marked with a strip to distinguish the plate when the lid was removed.

Plates were incubated at 37 ° C. for 1 hour to allow virus adsorption.

Compound dilution

Compounds were prepared at 4 × concentration in GM containing 2% DMSO (final DMSO concentration in 0.5% analyte).

Six compounds were tested on each assay plate as shown below (plate 3). Compounds were tested via a 7-point dilution series (50 μM to 0.78 μM) in double wells in the presence of virus.

Virus infected untreated wells serve as virus control (VC); Uninfected untreated wells served as cell control (CC). The absorbance difference between CC and VC constitutes the analysis window.

Plate 3

Dilution Plate Preparation

Compounds were serially diluted in individual microtiter plates as follows. (See plate 4)

200 μl of GM containing 2% DMSO was added to all wells except '50 μM 'or the first column to add 392 μl of GM. 8 μl of each test compound was carefully selected from frozen Arrow screening plates and transferred to appropriate wells on a '50 μM 'column. Compound stock was set at 100 mM DMSO 10 mM, which was maintained at 2% DMSO at the highest compound concentration.

200 μl was transferred from a 50 μM column to 25 μM using a multichannel pipette and then traversed a dilution plate to form a series 2-fold dilution with a 12.5 μM column or the like. Compounds were mixed upon transfer and tips were exchanged between transfers so that no compound was transferred to the last column of the compound-free well (0 μM).

Plate 4

BL = blank / empty well

Addition of compounds

The dilution plate was rotated vertically and 50 μl of compound was easily transferred from the dilution plate to the assay plate by multichannel pipette from column to column. Thus, there is an excess of 100 μl remaining in the dilution plate.

Plates were incubated at 37 ° C., 5% CO ₂ for 3 days.

ELISA Steps

Day four

The medium was drained directly from the wells into Virkon (1% solution in water) and the plates were washed by dipping into plastic boxes containing PBS. 50 μl / well of 75% / 25% vol / vol acetone / methanol fixative was added with a multichannel pipette and allowed to stand for 3 minutes.

Acetone / methanol was removed from El with beacon and the wells were washed with PBS as above.

Some 200 μl of blocking solution (2% Marvel in PBS containing 0.05% Tween) was added per well with a multichannel pipette. Plates were incubated for 60 minutes in a shake incubator at 37 ° C.

The blocking solution was discarded in the sink and the diluted primary antibody was added directly to the wells (ie no washing was required).

RSV mouse monoclonal antibody NCL-RSV3 (Novocastra) was diluted 1/400 in PBS / 2% Marvel / 0.05% Tween and 50 μl was added per well. Plates were incubated for 90 minutes in a shake incubator at 37 ° C.

Antibodies were discarded in sinks and plates were washed four times by immersing in PBS / 0.05% Tween.

DAKo rabbit anti-mouse HRP conjugate (DAKO catalog # P0260) was diluted to 1/1000 in PBS / 2% Marvel / 0.05% Tween and 50 μl was added per well. Plates were incubated for 60 minutes in a shake incubator at 37 ° C.

The antibody was discarded in a sink and the plate was washed six times by immersing in PBS / 0.05% Tween.

Substrate (SigmaFast OPD) was prepared in advance by dissolving one urea tablet in 20 mL of water. One OPD tablet was added to the urea solution immediately before use (NB. OPD is photosensitive), vortexed and mixed. 50 μl of substrate was added per well.

When sufficient color was expressed, while the cell control background was still low (about 5 minutes), the reaction was stopped by adding 25 μl of 20% sulfuric acid per well.

Plates were read on a SpectraMax (Molecular Devices) meter at wavelength 490 nm.

The wells were emptied, washed with tap water, and the monolayer was stained with 50 μl of 2% crystal violet in 20% methanol / water per well for at least 1 hour. Wells were then washed, air dried and monolayers evaluated microscopically for indicators of cytotoxicity.

result

The Softmax data file was exported to Excel. The data task used a graphically plotted dose response curve and used the template described in Excel's own to calculate IC50 values from the resulting curve.

All replicate wells were averaged. Assay windows were calculated by subtracting the averaged cell control (CC) from the averaged viral control (VC). For each compound, the averaged CC was subtracted from the averaged value for each concentration point. Control (%) was then calculated for each concentration point as a percentage of the window.

Control (%) was plotted against compound concentration. A straight line was fitted to the curve and the IC50 was calculated using the slope and intercept functions.

A <5 μM

B = 5 to 10 μM

C> 10 μM

Claims (46)

Use of a compound which is (a) a benzodiazepine derivative of formula (I) or an N-oxide thereof or (b) a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating or preventing RSV infection. <Formula I>

In the above formula, - R ¹ is C _{1 -6} alkyl, aryl or heteroaryl; - R ² represents hydrogen or C _{1 -6} alkyl; - each R ³ are the same or different, halogen, hydroxy, C _{1 -6} alkyl, C _{1 -6} alkoxy, C _{1 -6} alkylthio, C _{1 -6} haloalkyl, C _{1 -6} haloalkoxy, amino , Mono (C _1-6 alkyl) amino, di (C _1-6 alkyl) amino, nitro, cyano, -CO ₂ R ', -CONR'R ", -NH-CO-R', -S (O ) R ', -S (O) ₂ R', -NH-S (O) ₂ R ', -S (O) NR'R "or -S (O) ₂ NR'R", wherein R 'and R "are the same or different and represents hydrogen or C _{1 -6} alkyl; n is from 0 to 3; - R ⁴ represents hydrogen or C _{1 -6} alkyl; -X represents -CO-, -CO-NR'-, -S (O)-or -S (O) _2- , wherein R 'is hydrogen or a C ₁ -C ₆ alkyl group; R ⁵ represents an aryl, heteroaryl or heterocyclyl group, which is a C ₁ -C ₆ hydroxyalkyl group or-(C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X ₂ Substituted with a-(C ₁ -C ₄ alkyl) group, wherein X ₁ represents —O—, —S— or —NR′—, wherein R ′ represents H or a C ₁ -C ₄ alkyl group, X ₂ Represents -CO-, -SO- or -SO _2- , or R ⁵ represents -A ₁ -YA ₂ , wherein: A ₁ represents an aryl, heteroaryl, carbocyclyl or heterocyclyl group; Y represents a direct bond or a C ₁ -C ₄ alkylene, —SO ₂ —, —CO—, —O—, —S— or —NR′- moiety, wherein R ′ is a C ₁ -C ₆ alkyl group ego; A ₂ is an aryl, heteroaryl, carbocyclyl or heterocyclyl group. According to claim 1, wherein R ¹ is C _{1 -2} purpose alkyl or phenyl. The use according to claim 1 or 1, wherein R ¹ is hydrogen. The method according to any one of claims 1 to 3, R ³ is halogen, hydroxy, C _{1 -4} alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 haloalkyl, C _{1 -4} haloalkoxy, amino, mono (C _1-4 alkyl) amino or di (C _{1 -4} alkyl) amino purposes. 5. The method of claim 4, R ³ is fluorine, chlorine, bromine, C _{1 -2} alkyl, C _{1 -2} alkyl, C _{1 -2} alkyl thio, C _1-2 haloalkyl, C _1-2 haloalkoxy, amino, Use is mono (C _1-2 alkyl) amino or di (C _1-2 alkyl) amino. Any one of claims 1 to A method according to any one of claim 5, wherein, R ⁴ is the use of hydrogen or C _{1 -2} alkyl. 7. The use according to claim 1, wherein X is —CO— or —CO—NR′—, wherein R ′ represents hydrogen or a C ₁ -C ₂ alkyl group. 8. The compound of claim 1, wherein R ⁵ is a C ₁ -C ₆ hydroxyalkyl group or — (C ₁ -C ₄ alkyl) -X _1- (C ₁ -C ₄ alkyl) -X _Use is a 5- or 6-membered heterocyclyl group, aryl or heteroaryl ring substituted with a 2-(C ₁ -C ₄ alkyl) group wherein X ₁ and X ₂ are as defined in claim 1. The compound of claim 8, wherein R ⁵ is —CH ₂ —OH or — (C ₁ -C ₄ alkyl) -NR ′-(C ₁ -C ₄ alkyl) -S (O) _2- (C ₁ -C ₄ alkyl ) A 5- or 6-membered heteroaryl group substituted with a substituent wherein R 'is hydrogen or C ₁ -C ₂ alkyl. The use according to any one of claims 1 to 9, wherein A ₁ is an aryl or heteroaryl group. The 5- or 6-membered hetero group of claim 10, wherein A ₁ is fused to a phenyl group, a monocyclic 5- or 6-membered heteroaryl group or a monocyclic oxo substituted 5- to 6-membered heterocyclyl group Use for aryl groups. The method according to any one of claims 11, wherein, A ₁ is unsubstituted or substituted, halogen, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ alkoxy substituents And substituted with one or two substituents selected from. The use according to any one of claims 1 to 12, wherein Y represents a direct bond, a C ₁ -C ₂ alkylene group, -SO ₂ -or -O-. The use according to any one of claims 1 to 13, wherein A ₂ is a phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or C ₃ -C ₆ cycloalkyl group. The use according to any one of claims 1 to 14, wherein when A ₂ is a heterocyclyl group, it is attached to residue Y via an N atom. The substituent according to any one of claims 1 to 15, wherein A ₂ is unsubstituted or when A ₂ is a heteroaryl or aryl group, 1 or 2 substituents selected from C ₁ -C ₄ alkyl and halogen substituents. _{And when the divalent} carbocyclic or heterocyclyl group is substituted with one or two substituents selected from C ₁ -C ₄ alkyl, halogen and oxo substituents. The compound according to any one of claims 1 to 16, wherein A ₂ is piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo -Thiomorpholino groups, wherein these groups are unsubstituted or substituted with C ₁ -C ₂ alkyl groups. 18. The use according to any one of claims 1 to 17, wherein the benzodiazepine derivative of formula (I) is a compound of formula (Ia). <Formula Ia>

In the above formula, -X is -CO- or -CO-NH-; R ⁵ is a 5- to 6-membered heteroaryl group, for example furanyl group, which is —CH ₂ —OH or — (C ₁ -C ₄ alkyl) -N (CH ₃ )-(C ₁ -C ₄ alkyl) -SO ₂ - (C ₁ -C ₄ substituted by alkyl), or or R ⁵ represents an -A ₁ -YA _2, wherein: A ₁ is a phenyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thienyl or 1H-imidazo [4,5-b] pyridin-2- (3H) -one moiety, which is substituted Or substituted with 1 or 2 substituents selected from halogen, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ alkoxy substituents; Y is a direct bond, a C ₁ -C ₂ alkylene group, —SO ₂ — or —O—; A ₂ is piperazinyl, pyridyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrazinyl, cyclopropyl, phenyl or S, S-dioxo-thiomorpholino group, which is unsubstituted, Substituted with a C ₁ -C ₂ alkyl group. 19. The method of any one of claims 1 to 18, wherein the medicament is for treating a child under 2 years of age, an adult, elderly or long-term care facility resident with asthma, chronic obstructive respiratory disorder (COPD) or immunodeficiency. Use for use. The use of claim 19, wherein the child suffers from chronic lung disease. The use according to any one of claims 1 to 18, wherein the medicament is for use in preventing RSV infection in infants under 6 years of age born at 32 weeks of gestation or earlier. Use according to any one of claims 1 to 21, wherein the medicament is suitable for intranasal or intrabronchial administration. The use according to any one of claims 1 to 22, wherein the medicament further comprises an anti-inflammatory compound or an anti-influenza compound. Use according to claim 23, wherein the anti-inflammatory compound is budesonide or fluticasone. Use according to claim 23, wherein the anti-inflammatory compound is a leukotriene antagonist, a phosphodiesterase 4 inhibitor or a TNF alpha inhibitor. Use according to claim 23, wherein the anti-inflammatory compound is an interleukin 8 or interleukin 9 inhibitor. The use according to any one of claims 1 to 22, wherein the medicament is coadministered with an anti-inflammatory compound or an anti-influenza compound as defined in any of claims 24 to 26. A method of treating a patient, comprising administering an effective amount of a compound as defined in any one of claims 1 to 18 to a patient suffering from or susceptible to RSV infection. The method of claim 28, wherein the patient is a patient as defined in any one of claims 19-21. The method of claim 28 or 29, wherein said compound is administered intranasally or bronchically. (a) a compound as defined in any one of claims 1 to 18 and (b) a pharmaceutically acceptable carrier or diluent Inhaler or nebulizer containing a medicament comprising a. A product comprising a compound as defined in any one of claims 1 to 18 and an anti-inflammatory or anti-influenza compound as defined in any one of claims 24 to 26. Use of a product according to claim 32 in the manufacture of a medicament for use in the treatment of companion RSV and influenza infection. The method according to any one of claims 1 to 18 in the manufacture of a medicament for use in the treatment of human metapneumovirus, measles, parainfluenza virus, mumps, yellow fever virus (B5 strain), dengue 2 virus or West Nile virus. Use of a compound as defined. (a) a benzodiazepine derivative of formula (Ib) or an N-oxide thereof or (b) a pharmaceutically acceptable salt thereof. <Formula Ib>

In said formula, R <_1> , R <_3> , n, R <_4> , X and R <_5> are as defined in any one of Claims 1-18. 36. The compound of claim 35, wherein R ₁ is an unsubstituted phenyl group. 37. The compound of claim 35 or 36, wherein A ₁ is a heteroaryl group, which is not a 5-methyl-isoxazolyl residue. 38. The compound of any one of claims 35-37, wherein A ₁ is an aryl or heteroaryl moiety. 39. The compound of any one of claims 35-38, wherein X is -CO- or -CO-NR'-, wherein R 'is as defined in any one of claims 1-18, When X is -CO-NR'-, the residue -A ₁ -YA ₂ is -phenyl-O-phenyl. 40. The compound of any one of claims 35-39, wherein A ₂ is not a 4- to 10-membered saturated cycloalkyl ring wherein one of the carbon atoms is substituted with an N atom. 41. The piperazinyl, pyridyl, pyrrolidinyl, pyrazinyl, cyclopropyl, phenyl or S of any one of claims 35 to 40 wherein A ₂ is unsubstituted or substituted with a C ₁ -C ₂ alkyl group. Compound of the S-dioxo-thiomorpholino group. The method of claim 1 wherein the benzodiazepine derivative of formula (Ib) is 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- [1,2 '] bipyridinyl-5'-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e ] [1,4] diazepin-3-yl) -amide; (S) -2- (1,1-dioxo-1λ6-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] diazepine-3 -Yl) -benzamide; (S) -2- (1,1-dioxo-1λ6-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-1λ6-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-1λ6-thiomorpholin-4-yl) -5-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H- Benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -5- (4-Methyl-piperazin-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-pyrrolidin-1-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-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] dia Zepin-3-yl) -amide; (S) -5-dimethylaminomethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 Hbenzo [e] [1, 4] diazepin-3-yl) -amides; (S) -4-fluoro-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-piperi Din-1-yl-benzamide; (S) -4-fluoro-2-morpholino-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine 3-yl) -benzamide; (S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -2-pyrroli Din-1-yl-benzamide; (S) -4-cyano-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-piperidine- 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-1λ6-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-1λ6-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-1λ6-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-1λ6-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-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -3-cyclopropyl-2-oxo-2,3-dihydro-imidazo [4,5-b] pyridine-1-carboxylic acid (2-oxo-5-phenyl-2,3-di Hydro-1H-benzo [e] [1,4] diazepin-3-yl) -amide; (S) -3- (4-methyl-piperazin-1-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] dia Zepin-3-yl) -benzamide; (S) -4- (4-methyl-piperazin-1-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine 3-yl) -benzamide; (S) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (piperidine-1- Sulfonyl) -benzamide; (S) -3- (morpholine-4-sulfonyl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3- Yl) -benzamide; (S) -5-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine -3-yl) -amide; (S) -5-hydroxymethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl )-amides; (S) -5- (1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl) -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H -Benzo [e] [1,4] diazepin-3-yl) -amide; (S) -2-chloro-4- (1,1-dioxo-1λ6-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-1λ6-thiomorpholin-4-yl) -N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -benzamide; (S) -5-{[(2-Methanesulfonyl-ethyl) -methyl-amino] -methyl} -furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H -Benzo [e] [1,4] diazepin-3-yl) -amide; (S) -2-pyridin-3-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1 H-benzo [e] [1, 4] diazepine- 3-yl) -amide; (S) -2-pyridin-4-yl-thiazole-4-carboxylic acid (2-oxo-5-phenyl-2, 3-dihydro-1 H-benzo [e] [1, 4] diazepine- 3-yl) -amide; (S) -4-methyl-2-pyrazin-2-yl-thiazole-5-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4 ] Diazepin-3-yl) -amide; (S) -2-morpholin-4-ylmethyl-furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepine -3-yl) -amide; (S) -3-morpholin-4-ylmethyl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) Benzamide; (S) -5-morpholin-4-ylmethyl-isoxazole-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] dia Zepin-3-yl) -amide; (S) -3-morpholin-4-ylmethyl-furan-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepine -3-yl) -amide; (S) -5-pyridin-2-yl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] diazepine- 3-yl) -amide; (S) -2-methyl-4- (morpholine-4-sulfonyl) -furan-3-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [ 1,4] diazepin-3-yl) -amide; (S) -6-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl)- Nicotinamide; (S) -3-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] dia Zepin-3-yl) -amide; (S) -5-morpholin-4-ylmethyl-thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1,4] dia Zepin-3-yl) -amide; 2-morpholin-4-yl-N- (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl)-benzamide; (S) -5-phenyl-oxazole-4-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1 H-benzo [e] [1, 4] diazepin-3-yl) -amides; or 1- (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -3- (4-phenoxy-phenyl) -ureaine compound. 43. A compound according to any one of claims 35 to 42 for use in a method of treating a human or animal body. 44. A pharmaceutical composition comprising a compound according to any one of claims 35 to 43 and a pharmaceutically acceptable diluent or carrier. 45. The composition of claim 44 comprising the optically active isomer of the compound according to any one of claims 35-42. 46. A composition according to claim 44 or 45 in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.