Drug compounds

Abstract

Benzodiazepine derivatives of formula (I): wherein: R 1 and R 2 Each of R is independently H or halogen; 3 is H, C1-C6 alkyl or -NHR 8 ; (i) a, c, and e are all bonds, and b, d, and f are not present; or b, d, and f are all bonds, and a, c, and e are not present; R 4 is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic group, which group is unsubstituted or substituted; R 5 is H or halogen; R 6 Yes‑OR 8 , ‑NR 8 R 9 or ‑R 8 ; R 7 is H or halogen; R 8 and R 9 Each of which is independently H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclyl, which group is unsubstituted or substituted; n is 1 or 2; and one of V, W and X is N or CH, and the other two are CH; and pharmaceutically acceptable salts thereof are inhibitors of RSV and are therefore useful for treating or preventing RSV infection.

Description

Technical Field

[0001] The present invention relates to benzodiazepines Derivatives and their use in treating or preventing respiratory syncytial virus (RSV) infection. Background Art

[0002] RSV is a negative-sense single-stranded RNA virus of the family Paramyxoviridae. RSV is easily spread by the secretions of the infected person via surface or hand-to-hand transfer. Unlike influenza, it is not spread by small particle aerosols. After successful inoculation, the incubation period is 4 to 6 days, during which the virus spreads from the nasopharynx to the lower respiratory tract by fusion of infected cells with uninfected cells and shedding of necrotic epithelium. In infants, combined with increased mucus secretion and edema, this can lead to mucus blockage, causing overexpansion and collapse of distal lung tissue, indicating bronchiolitis. Common hypoxia, and usually impaired feeding ability due to respiratory distress. In RSV pneumonia, the inflammatory infiltration of the airways is composed of mononuclear cells and is more generalized to involve bronchioles, bronchi and alveoli. It has been found that the duration and degree of viral shedding are related to the clinical symptoms and severity of the disease.

[0003] RSV is the leading cause of severe respiratory infection in infants and young children worldwide. Morbidity and mortality are highest in premature infants and infants with chronic lung or heart disease, although many infants hospitalized with RSV infection are otherwise healthy. Severe RSV infection in infancy can lead to recurrent wheezing for years and is associated with the development of asthma later in life.

[0004] RSV is also a major cause of morbidity and mortality in elderly and immunocompromised children and adults, as well as patients with chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).

[0005] RSV has a seasonal onset; it is highly predictable and occurs in the winter in both hemispheres, from September to May in Europe and North America, peaking in December and January, and can occur year-round in tropical countries. It affects >90% of infants and young children < 2 years of age, and because natural immunity is short-lived; many will be reinfected each year. Like influenza, in the elderly, RSV causes about 10% of winter hospitalizations and has an associated mortality rate of 10%.

[0006] Current anti-RSV treatment includes the use of an anti-RSV monoclonal antibody, called palivizumab. This use of palivizumab is a preventive rather than therapeutic treatment of RSV. Although this antibody is generally effective, its use is limited to premature infants and high-risk infants. In fact, its limited availability means that it is unavailable for many people who need anti-RSV treatment. Therefore, there is an urgent need for an effective alternative to existing anti-RSV treatment.

[0007] Small molecules have also been proposed as inhibitors of RSV. These include benzimidazoles and benzodiazepines For example, RSV604, a benzodiazepine with submicromolar anti-RSV activity The discovery and initial development of the compound is described in Antimicrobial Agents and Chemotherapy, September 2007, 3346-3353 (Chapman et al). Benzodiazepines for RSV Inhibitors are also disclosed in publications including WO2004 / 026843 and WO2005 / 089770 (Arrow Therapeutics Limited); WO2016 / 166546 and WO2018 / 033714 (Durham University); and WO2017 / 015449, WO2018 / 129287 and WO2018 / 226801 (Enanta Pharmaceuticals, Inc.).

[0008] There is a need to identify further compounds having anti-RSV activity, particularly compounds having a combination of potent antiviral activity and favorable pharmacokinetic properties. Summary of the invention

[0009] A series of new benzodiazepines have been discovered The derivatives have effective anti-RSV activity as well as favorable pharmacokinetics and good physicochemical properties. Therefore, the present invention provides a compound, which is a benzodiazepine of formula (I) Pyrazole:

[0010]

[0011] in:

[0012] R 1 and R 2 Each of is independently H or halogen;

[0013] R 3 is H, C1-C6 alkyl or -NHR8 ;

[0014] (i) and are keys, and and does not exist; or and are keys, and and does not exist;

[0015] R 4 is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclyl, which group is unsubstituted or substituted;

[0016] R 5 It is a halogen;

[0017] R 6 It is H, -OR 8 、-NR 8 R 9 or -R 8 ;

[0018] R 7 is H or halogen;

[0019] R 8 and R 9 Each of the groups is independently H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclyl, which group is unsubstituted or substituted;

[0020] n is 1, 2, or 3;

[0021] One of V, W and X is N or CH, and the other two are CH;

[0022] or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0023] When any group, ring, substituent or moiety as defined herein is substituted, it is typically substituted by Q as defined below.

[0024] C 1-6 The alkyl group or moiety is straight chain or branched. 1-6 Alkyl groups are usually C 1-4 Alkyl or C 4-6 Alkyl. C 1-6Examples of alkyl and moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl (i.e. 3-methylbutan-1-yl), tert-pentyl (i.e. 2-methylbutan-2-yl), neopentyl (i.e. 2,2-dimethylpropan-1-yl), n-hexyl, isohexyl (i.e. 4-methylpentan-1-yl), tert-hexyl (i.e. 3-methylpentan-3-yl) and neopentyl (i.e. 3,3-dimethylbutan-1-yl). For the avoidance of doubt, when two alkyl moieties are present in a group, the alkyl moieties may be the same or different. C 1-6 Alkyl is unsubstituted or substituted - generally by one or more groups Q as defined below. For example, C 1-6 Alkyl is unsubstituted or substituted by 1, 2 or 3 groups Q as defined below.

[0025] Q is halogen, nitro, -CN, OH, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylthio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Haloalkoxy, -CO2R', -NR'2, -SR', -S(=O)R', -S(=O)2R', C3-C 10 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 12-membered aryl, or 5- to 10-membered heteroaryl, wherein each R' is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 5- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl. For the avoidance of doubt, the alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl portions of these definitions are themselves typically unsubstituted.

[0026] C 1-6 The alkoxy group is straight chain or branched. 1-4 Alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy. 1-6 Alkoxy is unsubstituted or substituted - typically by one or more groups Q as defined above.

[0027] C 1-6 The alkylthio group is straight chain or branched. 1-4 Alkylthio, for example methylthio, ethylthio, propylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio or tert-butylthio. 1-6 Alkylthio is unsubstituted or substituted - typically by one or more groups Q as defined above.

[0028] Halogen or halo group is F, Cl, Br or I. Typically, it is F or Cl. 1-6 Alkyl groups can be represented by "C 1-6 "Haloalkyl" means a C group as defined above in which one or more hydrogen atoms are replaced by halogen. 1-6 Similarly, halogen-substituted C 1-6 Alkoxy can be represented by "C 1-6 "Haloalkoxy" means a C as defined above in which one or more hydrogen atoms are replaced by halogen. 1-6 Alkoxy. Generally, C 1-6 Haloalkyl or C 1-6 The haloalkoxy group is substituted by 1, 2 or 3 of said halogen atoms. The haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups, such as -CX3 and -OCX3, wherein X is a halogen, such as -CF3, -CCl3, -OCF3 and -OCCl3.

[0029] C 1-6 Hydroxyalkyl is a C alkyl group as defined above substituted with one or more OH groups. 1-6 Alkyl. Typically, it is substituted with one, two or three OH groups. Preferably, it is substituted with a single OH group.

[0030] C6-C 10 Aryl is an aromatic carbocyclic group containing 6 to 10 carbon atoms. It is a monocyclic or fused bicyclic ring system in which an aromatic ring is fused to another aromatic carbocyclic ring. 10 Examples of aryl groups include phenyl and naphthyl. When substituted, aryl groups are generally substituted by a group Q as defined above, for example by 1, 2 or 3 groups selected from the group Q as defined above. More specifically, substituted aryl groups such as substituted phenyl groups are selected from C1-C6 alkyl, halogen, -OR 8 and -N(R 8 )2 is substituted with 1 or 2 groups, wherein R 8 is H or C1-C6 alkyl, when there are two, each R 8 Same or different.

[0031] C 3-10 Cycloalkyl is a saturated hydrocarbon ring having 3 to 10 carbon atoms. 3-10 Cycloalkyl can be, for example, a C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Typically, it is a C3-C6 cycloalkyl, or a C4-C6 cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, it is a cyclobutyl. 3-10 Cycloalkyl is unsubstituted or substituted - typically by one or more groups Q as defined above.

[0032] The 4- to 10-membered heteroaryl or moiety is a 4- to 10-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S. It is monocyclic or bicyclic. Typically, it contains 1 N atom and 0, 1, 2 or 3 additional heteroatoms selected from O, S and N. It can be, for example, a monocyclic 5- to 7-membered heteroaryl, such as a 5- or 6-membered N-containing heteroaryl. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, Oxazolyl, Azolyl, iso 1-10 yuan. Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, imidazolyl, pyrrolopyridinyl, pyrazolopyrimidinyl and pyrrolopyrimidinyl. When substituted, the heteroaryl (monocyclic or bicyclic) is generally replaced by one or more, for example 1, 2 or 3, selected from C 1-4 The alkyl group and the group Q are substituted with the groups defined above.

[0033] A 4- to 10-membered heterocyclyl is a monocyclic or bicyclic non-aromatic saturated or unsaturated ring system containing 5 to 10 carbon atoms and at least one atom or group selected from N, O, S, SO, SO2 and CO (more generally N or O). When the ring system is bicyclic, one ring may be saturated and one ring may be unsaturated. Generally, it is C 4-10 Ring system in which 1, 2 or 3 carbon atoms in the ring are substituted by atoms or groups selected from O, S, SO2, CO and NH. More generally, it is a monocyclic ring, preferably a monocyclic C4-C6 ring. Examples include piperidinyl, piperidine-2,6-dione, piperidine-2-one, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-one, pyrrolidin-2-one, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl moieties.

[0034] For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl refer to "N" atoms which may be present in the ring, it will be apparent to the skilled chemist that any such N atom will be protonated (or will carry a substituent as defined above) if it is attached to its adjacent ring atoms by a single bond. Such protonated forms are included within the present definitions of heteroaryl and heterocyclyl.

[0035] In one embodiment of formula (I) as defined above, R 2 Benzodiazepines A halogen substituent at the 9-position of the base ring system, specifically F. Examples of such compounds are those of the following formula (I'):

[0036]

[0037] Where R 1 is H or halogen, R 2 is H or halogen, and the remaining groups and variables are as defined above for formula (I). 1 is H or F, and R 2 is H or F. For example, R 1 is H or F, and R 2 It's F.

[0038] In one embodiment of formula (I), and are keys, and and This compound has the following formula (Ia):

[0039]

[0040] wherein all groups and variables are as defined above for formula (I) or (I').

[0041] In another embodiment of formula (I), and are keys, and and This compound has the following formula (Ib):

[0042]

[0043] wherein all groups and variables are as defined above for formula (I) or (I').

[0044] In one embodiment of the above formulae (I), (I'), (Ia) and (Ib), each of V and W is CH, and X is N. Examples of such structures include benzodiazepines of the following formulae (Ia') and (Ib'): Pyrazole:

[0045]

[0046] In the above formulae (Ia') and (Ib'), R 1 To R 7 Each of and n is as defined above for formula (I) or (I').

[0047] In another embodiment of the above formulae (I), (I'), (Ia) and (Ib), V, W and X are all CH. Examples of such structures include benzodiazepines of the following formulae (Ia") and (Ib") Pyrazole:

[0048]

[0049]

[0050] In formula (Ia") and (Ib"), R 1 To R 7 Each of and n is as defined above for formula (I) or (I').

[0051] In one aspect, the present invention provides a compound which is a benzodiazepine of formula (IIa): Pyrazole:

[0052]

[0053] wherein each of the groups and variables are as defined above for formula (I) or (I'), or a pharmaceutically acceptable salt thereof.

[0054] In another aspect, the present invention provides a compound which is a benzodiazepine of formula (IIb): Pyrazole:

[0055]

[0056] wherein each of the groups and variables are as defined above for formula (I) or (I′), and m is 0, 1 or 2.

[0057] In one embodiment of the compounds of the present invention having any of the structural formulas (I), (Ia), (Ib), (Ia'), (Ib'), (Ia", (Ib"), (IIa) or (IIb) as defined above, R 2 In benzodiazepines In this embodiment, typically, R 2 is a halogen substituent, specifically F. More generally, in this embodiment, R 1 is H or F, and R 2 is H or F. For example, R 1 is H or F, and R 2 It's F.

[0058] When R in formula (IIa) 1 and R 2 When the ring is located at the same position as shown in the above formula (I'), the resulting compound is a benzodiazepine of the following formula (IIa'): Pyrazole:

[0059]

[0060] Where R1 is H or halogen, R 2 is H or halogen, and the remaining groups and variables are as defined above for formula (IIa). 1 is H or F, and R 2 is H or F. For example, R 1 is H, and R 2 It's F.

[0061] Similarly, when R in formula (IIb) 1 R 2 When the ring is located at the same position as shown in the above formula (I'), the resulting compound is a benzodiazepine of the following formula (IIb'): Pyrazole:

[0062]

[0063] Where R 1 is H or halogen, R 2 is H or halogen, and the remaining groups and variables are as defined above for formula (IIb). 1 is H or F, and R 2 is H or F. For example, R 1 is H, and R 2 It's F.

[0064] In the compounds of the present invention having any of the structural formulas defined above, R 3 is selected from H, C1-C6 alkyl and -NR 8 R 9 A group in which R 8 and R 9 Each of R is independently H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic group, which group is unsubstituted or substituted. 8 is H, and R 9 is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic group, which group is unsubstituted or substituted. 8 is H, and R 9 It is H or C1-C6 alkyl.

[0065] In the compounds of the present invention having any of the structural formulas defined above, R 4 is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic group, which group is unsubstituted or substituted. 4 is a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic groups, which is unsubstituted or substituted.4 It is a group selected from C1-C6 alkyl (such as C1-C3 alkyl), C3-C6 cycloalkyl (such as cyclopropyl) and 4- to 10-membered heterocyclic groups (for example, O-containing heterocyclic groups such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl).

[0066] In the compounds of the present invention having any of the structural formulas defined above, R 5 is H or a halogen, specifically F.

[0067] In the compounds of the present invention having any of the structural formula (I), (I'), (Ia), (Ib), (Ia'), (Ib'), (Ia") or (Ib") defined above, one, two or three groups R may be present. 5 , when more than one is present, they may be identical or different. At least one radical R 5 Usually F. R 5 or each R 5 Bonded to any available ring carbon atom of the six-membered ring to which it is attached.

[0068] In one embodiment, R 6 is H, n is 2, one R 5 It's F, the other R 5 Is F or Cl. In another embodiment, R 6 is H, n is 3, two groups R 5 Each is F, and the other R 5 It is Cl.

[0069] In one embodiment, at least one R 5 bonded to the ortho position of the ring carbon that carries the bond connecting the six-membered ring to the adjacent O atom, i.e., one R 5 Bonded at ring position 2 or 6. For example, n is 1, and R 5 Bonded at ring position 2 or 6; or n is 2, and two groups R 5 Bonded at ring positions 2 and 4, or 2 and 6, or 4 and 6. In this embodiment, the ortho-bonded group R 5 or each ortho-bonded group R 5 Usually it is F.

[0070] In the compounds of the present invention having any of the structural formulas (I), (I'), (Ia), (Ib), (Ia'), (Ib'), (Ia", (Ib"), (IIb) or (IIb') as defined above, R 6 Bonding on the unbonded 5Any available ring carbon atom occupied by the six-membered ring can be bonded to any available ring carbon atom occupied by the six-membered ring. For example, it is bonded to the ring position 4 (i.e., the para position of the ring carbon that carries the bond connecting the six-membered ring to the adjacent O atom); or it is bonded to the ring position 3 or 5, i.e., the meta position of the ring carbon that carries the bond connecting the six-membered ring to the adjacent O atom.

[0071] In the compounds of the above formulae (I), (I'), (Ia), (Ib), (Ia'), (Ib'), (Ia") and (Ib"), the group R 5 and R 6 Examples of bonded six-membered rings include the following structures (i) to (v):

[0072]

[0073]

[0074] In the compounds of the present invention having any of the structural formulas defined above, R 6 Yes-OR 8 、-NR 8 R 9 or -R 8 , where R 8 and R 9 Each of R is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclic group, which group is unsubstituted or substituted. 6 H, C1-C6 alkyl, -OR 8 or -NR 8 R 9 , where R 8 is C1-C6 alkyl (such as C1-C3 alkyl), C3-C6 cycloalkyl (such as cyclopropyl or cyclobutyl), and R 9 is H or C1-C6 alkyl, the alkyl and cycloalkyl being unsubstituted or substituted. More generally, R 6 is C1-C6 alkyl, -OR 8 or -NR 8 R 9 , where R 8 is an unsubstituted C1-C6 alkyl group (such as methyl, ethyl or isopropyl) or a C3-C6 cycloalkyl group (such as cyclopropyl or cyclobutyl), the cycloalkyl group is unsubstituted or substituted by an unsubstituted C1-C3 alkyl group (such as methyl), and R 9 is C1-C6 alkyl or H.

[0075] In one embodiment, R 6 is a C1-C6 alkyl group or a group -NR 8 R 9 , where R 8 and R 9are the same or different and are each H or C1-C6 alkyl, n is 1 or 2, and each R 5 is F. C1-C6 in these embodiments is typically methyl or ethyl.

[0076] Specific compounds of the present invention include the following:

[0077] 5-(2,6-difluoro-4-methylphenoxy)-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]pyrazole-4-carboxamide;

[0078] 5-(2-Fluoro-4-methylphenoxy)-1-(oxacyclohexan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]pyrazole-4-carboxamide;

[0079] 5-(4-chloro-2-fluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide;

[0080] 5-(4-chloro-2-fluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxacyclohexan-4-yl)pyrazole-4-carboxamide;

[0081] 5-(4-chloro-2,6-difluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide;

[0082] 5-(4-chloro-2,6-difluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxacyclohexan-4-yl)pyrazole-4-carboxamide;

[0083] and pharmaceutically acceptable salts thereof.

[0084] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof such as racemic mixtures, form part of the present invention. Compounds of formula (I) containing one or more chiral centers may be used in enantiomerically or diastereomerically pure form or in the form of isomer mixtures.

[0085] The present invention includes all geometric and positional isomers of the compounds of the present invention as defined above. For example, if the compounds of the present invention contain double bonds or fused rings, cis- and trans-forms and mixtures thereof are all included within the scope of the present invention. Single positional isomers and positional isomer mixtures are also within the scope of the present invention.

[0086] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present invention embrace both solvated and unsolvated forms.

[0087] The compounds of the present invention may exist in different tautomeric forms, and all of these forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions through proton migration, such as keto-enol tautomerism. Valence tautomers include interconversions through the reorganization of some bonded electrons.

[0088] The compounds of the present invention can be prepared by the synthetic methods described in the examples below, or by analogy thereto using appropriate starting materials and methods well known to skilled chemists.

[0089] By conventional methods, the benzodiazepine of formula (I) The derivatives can be converted into their pharmaceutically acceptable salts, and the salts can be converted into free compounds. For example, the benzodiazepines of formula (I) The derivative can be contacted with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

[0090] Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, pyrophosphoric acid, hydrobromic acid or nitric acid; and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides; and organic bases such as alkylamines, arylalkylamines and heterocyclic amines.

[0091] Compounds of the present invention have been found to be inhibitors of respiratory syncytial virus (RSV) in biological tests. They have effective anti-RSV activity and a good bioavailability and a combination of good physicochemical properties. This combination of properties makes the compound useful in treatment and superior to many compounds disclosed in the prior art references discussed above as candidate drugs.

[0092] Therefore, the present invention further provides compounds which are benzodiazepines of formula (I) as defined above. A derivative or a pharmaceutically acceptable salt thereof for use in a method of treating the human or animal body by therapy.

[0093] The present invention also provides the compounds of this invention as defined above, for the treatment or prevention of RSV infection method. Still further, the present invention provides the compounds of this invention as defined above in the preparation of medicines for the treatment or prevention of RSV infection purposes. Therefore, the object that suffers from or is susceptible to RSV infection can be treated by including giving the compounds of this invention as defined above to it. The condition of the object can be improved or alleviated therefrom.

[0094] RSV infection is generally a respiratory tract infection. RSV infection can be the infection of children (e.g., children under ten years old or infants under two years old). In one embodiment, the invention provides compounds as defined above, for the treatment or prevention of RSV infection in pediatric patients. Alternatively, infection can be the infection of mature or elderly adults (e.g., adults over 60 years old, adults over 70 years old or adults over 80 years old). The invention further provides compounds, for the treatment or prevention of RSV infection in elderly patients.

[0095] The RSV infection can be an infection in an immunocompromised individual or an individual suffering from COPD or CHF. In another embodiment, the RSV infection is an infection in an uncompromised individual (eg, an otherwise healthy individual).

[0096] The compounds of the present invention can be administered in various dosage forms, for example, orally, such as in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions; or parenterally, such as intramuscularly, intravenously or subcutaneously. The compounds can therefore be administered by injection, infusion or by inhalation or atomization. The compounds are preferably administered by oral administration.

[0097] Dosage depends on various factors, including patient's age, body weight and condition and administration route. Daily dose can change within wide limits, and will be adjusted according to individual requirements in each specific case. However, generally, the dosage adopted by each administration route when compound is administered to adults alone is 0.0001 to 650mg / kg, most often in the range of 0.001 to 10mg / kg body weight, for example 0.01 to 1mg / kg. This dosage can be given, for example, 1 to 5 times a day. For intravenous injection, suitable daily dose is 0.0001 to 1mg / kg body weight, preferably 0.0001 to 0.1mg / kg body weight. Daily dose can be given as a single dose or according to a divided dose plan.

[0098] Unit dosage forms such as tablets or capsules will typically contain 1-250 mg of active ingredient. For example, a compound of formula (I) can be administered to a human patient at a dosage of 100-250 mg once a day, twice a day, or three times a day. For example, a compound of formula (I) can be administered to a human patient at a dosage of 100-250 mg once a day, twice a day, or three times a day.

[0099] The compound of formula (I) and its pharmaceutically acceptable salt can be used alone. Alternatively, it can be administered in the form of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, which includes a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. The conventional procedure for selecting and preparing appropriate pharmaceutical preparations is described in, for example, "Pharmaceuticals-The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0100] Depending on the mode of administration, the pharmaceutical composition will preferably comprise 0.05 to 99% w (weight percent), more preferably 0.05 to 80% w, still more preferably 0.10 to 70% w, even more preferably 0.10 to 50% w of active ingredient, all weight percentages being based on the total composition.

[0101] The present invention further provides a process for preparing a pharmaceutical composition of the present invention, which comprises mixing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0102] The compounds of the present invention can be given in various dosage forms. Therefore, it can be given orally, for example as tablets, lozenges, lozenges, aqueous or oily suspensions, solutions, dispersible powders or particles. The compounds of the present invention can also be given parenterally, no matter subcutaneously, intravenously, intramuscularly, intrasternal, transdermally, by infusion techniques or by inhalation or atomization. The compound can also be given as a suppository.

[0103] The solid oral form of the pharmaceutical composition of the present invention may contain (together with the active compound) a diluent such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; a lubricant such as silicon dioxide, talc, stearic acid, magnesium stearate or calcium stearate, and / or polyethylene glycol; a binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; a disaggregating agent such as starch, alginic acid, alginate or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; a wetting agent such as lecithin, polysorbate, lauryl sulfate (ester); and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. Such pharmaceutical preparations can be prepared in a known manner, for example, by mixing, granulating, tabletting, sugar coating or film coating processes.

[0104] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. Syrups may contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol, as a carrier.

[0105] Suspensions and emulsions can contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as carriers. Suspensions or solutions for intramuscular injection can contain (together with the active compound) a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride. Further carriers suitable for suspensions include sterile water, hydroxypropyl methylcellulose (HPMC), polysorbate 80, polyvinyl pyrrolidone (PVP), aerosol AOT (i.e., 1,2-bis(2-ethylhexyloxycarbonyl) ethanesulfonic acid sodium), pluronic F127 and / or captisol (i.e., sulfobutyl ether-β-cyclodextrin).

[0106] The compounds of the invention may, for example, be formulated as an aqueous suspension in a carrier selected from:

[0107] (i) 0.5% w / v hydroxypropyl methylcellulose (HPMC) / 0.1% w / v polysorbate 80;

[0108] (ii) 0.67% w / v polyvinylpyrrolidone (PVP) / 0.33% w / v aerosol AOT (sodium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulfonate);

[0109] (iii) 1% w / v pluronic F 127; and

[0110] (iv) 0.5% w / v Polysorbate 80.

[0111] The carrier can be prepared by standard procedures known to those skilled in the art. For example, each of carriers (i) to (iv) can be prepared by weighing the desired amount of excipient into a suitable container, adding about 80% of the final volume of water, and magnetic stirring until a solution is formed. The carrier is then made up to volume with water. An aqueous suspension of the compound of formula I can be prepared by weighing the desired amount of the compound of formula I into a suitable container, adding 100% of the desired volume of the carrier, and magnetic stirring.

[0112] Solutions for injection or infusion may contain, for example, sterile water as a carrier, or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0113] The compounds of the present invention can also be administered in combination with other compounds for the treatment of viral infections. Therefore, the present invention further relates to combination therapy, wherein the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions or preparations comprising the compounds of the present invention are administered synchronously or sequentially or as a combined preparation with one or more other therapeutic agents for the treatment or prevention of viral infections, specifically RSV infections.

[0114] In this document, where the term "combination" is used, it is understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In a further aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

[0115] Suitable therapeutic agents for combination therapy include

[0116] (i) RSV fusion inhibitors;

[0117] (ii) other RSV nucleocapsid (N) protein inhibitors;

[0118] (iii) other RSV protein inhibitors, such as those that inhibit the phosphoprotein (P) protein and the large (L) protein;

[0119] (iv) nucleoside or polymerase inhibitors that inhibit L protein;

[0120] (v) anti-RSV monoclonal antibodies, such as F protein antibodies;

[0121] (vi) immunomodulatory toll-like receptor compounds;

[0122] (vii) other respiratory virus antivirals, such as anti-influenza and anti-rhinovirus compounds; and / or

[0123] (viii) Anti-inflammatory compounds.

[0124] The RSV nucleocapsid (N) protein plays a key role in viral transcription and replication, mediating the interaction between genomic RNA and the virally encoded RNA-dependent RNA polymerase. The RSV P protein and L protein are components of the virally encoded RNA-dependent RNA polymerase of RSV.

[0125] According to a further aspect of the present invention, there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in combination with one or more of the therapeutic agents listed as (i) to (vi) above for use in treating RSV.

[0126] The following examples are used to further illustrate the present invention. The preparation examples relate to the preparation of starting materials and intermediates used to prepare the compounds of the examples. Neither the examples nor the preparation examples limit the present invention in any way.

[0127] Example

[0128] Reagents were obtained from commercial sources and used without further purification. All temperatures are in °C. TLC was performed on aluminum backed silica gel plates with a 254 nM fluorescent indicator (median pore size ). Unless otherwise stated, flash column chromatography was performed using a Biotage Isolera One system using KP-Sil or Ultra silica gel columns. NMR spectra were recorded on a 400 MHz spectrometer at ambient probe temperature (nominal 295 K). Chemical shifts (δ) are given in ppm and are calculated by using the residual peak of the solvent as an internal standard (CDCl3, δ H =7.26ppm, δ C =77.16ppm; DMSO-d6, δ H =2.50ppm, δ C =39.52 ppm) calibration. Coupling constants are given in Hertz (Hz). LRMS was performed using an Advion Plate Express expression L Compact mass spectrometer to record.

[0129] Preparation Example (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-ketone was prepared using the methods described in WO / 2004 / 026843, WO / 2005 / 090319 and WO / 2017 / 015449.

[0130] Abbreviations

[0131]

[0132] Preparation Example

[0133] 1A 5-amino-1-ethylpyrazole-4-carboxylic acid ethyl ester

[0134]

[0135] A suspension of ethyl (ethoxymethylene)cyanoacetate (10.50 g, 62.06 mmol) in anhydrous EtOH (120 mL) was prepared and ethyl hydrazine oxalate (9.32 g, 62.06 mmol) was added followed by NEt3 (17.3 mL, 124.1 mmol) via syringe over 15 min. The reaction was heated at 50 °C for 5 h and then stirred at rt for 16 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The crude product was washed with water (2 x 60 mL) and brine (60 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (30% EtOAc:heptane) to give a yellow solid (5.16 g, 45%). LRMS: 184.0 [M+H] + ; TLC (EtOAc) R f =0.63.

[0136] 2A 5-Chloro-1-ethylpyrazole-4-carboxylic acid ethyl ester

[0137]

[0138] Under nitrogen, tert-butyl nitrite (5.19 mL, 43.7 mmol) was added to a cold (0°C) solution of cuprous chloride (I) (3.24 g, 32.7 mmol) in MeCN (90 mL). Intermediate 1A (5.00 g, 27.3 mmol) was added portionwise over 30 min, the reaction was stirred at 0°C for 1 h, then heated at 65°C for 40 min. The reaction was cooled to rt and poured into 6M aqHCl (100 mL) and extracted with CH2Cl2 (100 mL, then 3×50 mL). The combined organic phases were dried (MgSO4), the solvent was removed under reduced pressure and the residue was purified by flash chromatography (0-10% EtOAc:heptane) to give a colorless oil (2.87 g, 52%). 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),4.23(q,J=7.1Hz,2H),4.19(q,J=7.3Hz,2H)1.33(t,J=7.2Hz,3H),1.27(t,J=7.1Hz,3H).LRMS:202.9[M+H] + .

[0139] 3A 5-bromo-1-(oxacyclohexan-4-yl)pyrazole-4-carboxylic acid ethyl ester

[0140] 4A 3-Bromo-1-(oxacyclohexane-4-yl)pyrazole-4-carboxylic acid ethyl ester

[0141]

[0142] 4-Methylbenzenesulfonic acid oxacyclohexane-4-ester (1.67 g, 6.53 mmol) was added to a solution of 3-bromo-1H-pyrazole-4-carboxylic acid ethyl ester (1.30 g, 5.93 mmol) and CsCO (2.63 g, 8.01 mmol) in DMF (10 mL) and heated at 80 ° C for 16 h. After cooling to rt, water (40 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with water and brine (20 mL each), dried (NaSO) and the solvent was removed under reduced pressure. Intermediate 3A was purified by flash chromatography (10-80% EtOAc: heptane) as a white solid (445 mg, 25%). 1H NMR(400MHz, DMSO-d6)δ8.05(s,1H),4.66(tt,J=11.3,4.3Hz,1H),4.24(q,J=7.1Hz,2H),4.01–3.91(m,2H) ,3.50(td,J=12.0,2.1Hz,2H),2.08–1.94(m,2H)1.83(ddd,J=12.6,4.4,2.0Hz,2H),1.27(t,J=7.1Hz,3H). LRMS:303.0 / 305.0[M+H] + Intermediate 4A (second eluting regioisomer) was obtained as a white solid (1.02 g, 57%). 1 H NMR(400MHz, DMSO-d6)δ8.43(s,1H),4.45(dd,J=10.5,5.0Hz,1H),4.22(q,J=7.1Hz, 2H), 4.00–3.88 (m, 2H), 3.48–3.36 (m, 2H), 2.04–1.83 (m, 4H), 1.27 (t, J = 7.1Hz, 3H). LRMS:303.4 / 305.4[M+H] + .

[0143] 5A 5-Bromo-1-(oxetan-3-yl)pyrazole-4-carboxylic acid ethyl ester

[0144] 6A 3-Bromo-1-(oxetan-3-yl)pyrazole-4-carboxylic acid ethyl ester

[0145]

[0146] Prepared by a procedure similar to that described for Intermediate 3A using ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.70 g, 7.76 mmol), 3-oxetanes-4-methylbenzenesulfonate (1.95 g, 8.50 mmol) and CsCO (3.43 g, 10.48 mmol) and heating at 90° C. for 22 h. Purification by flash chromatography (10-100% EtOAc:heptane) gave Intermediate 5A (first eluting regioisomer) as a white solid (640 mg, 30%). 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),5.75(tt,J=7.4,6.2Hz,1H),4.98–4.85(m,4H),4.24(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). LRMS:275.5 / 277.5[M+H] + Intermediate 6A: Second eluting regioisomer, white solid (1.06 g, 50%).1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),5.60(tt,J=7.5,6.1Hz,1H),4.94–4.77(m,4H),4.23(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H). LRMS:275.5 / 277.5[M+H] + .

[0147] 7A 5-(2-fluoro-4-methylphenoxy)-1-(oxacyclohexane-4-yl)pyrazole-4-carboxylic acid ethyl ester

[0148]

[0149] A solution of intermediate 3A (150 mg, 0.49 mmol), 2-fluoro-4-methylphenol (68.7 mg, 0.54 mmol) and CsCO (324 mg, 0.99 mmol) in 1-methyl-2-pyrrolidone (2 mL) was heated at 135 ° C for 21 h in a sealed vial. The reaction was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were washed with water (2×15 mL) and brine (15 mL), dried (NaSO), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc:heptane) to give a white solid (100 mg, 58%). 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.28–7.15(m,1H),6.98–6.86(m,1H),6.74(t,J=8.6Hz,1H),4.54–4.40(m,1H) ),4.04–3.86(m,4H),3.51–3.39(m,2H),2.27(s,3H),2.10–1.95(m,2H),1.84–1.72(m,2H),0.96(t,J=7.1Hz,3H). LRMS:349.1[M+H] + .

[0150] The following intermediate compounds were prepared by the same general procedure described for Intermediate 7A.

[0151]

[0152]

[0153] 13A 5-(4-chloro-2,6-difluorophenoxy)-1-(oxetan-3-yl)pyrazole-4-carboxylic acid ethyl ester

[0154]

[0155] Prepared by a similar procedure to Intermediate 2A using copper(II) chloride (25.0 mg, 0.19 mmol), tert-butyl nitrite (0.03 mL, 0.22 mmol), Intermediate 11A (63 mg, 0.15 mmol) in MeCN (8 mL) and stirring at 0 °C for 20 min, then at rt for 4 h. Yellow oil (20 mg, 38%). LRMS: 359.1 [M+H] + ; TLC (1:1 EtOAc:heptane) R f =0.65.

[0156] 14A 5-(4-chloro-2,6-difluorophenoxy)-1-(oxacyclohexane-4-yl)pyrazole-4-carboxylic acid ethyl ester

[0157]

[0158] Prepared by a similar procedure to Intermediate 2A using copper(II) chloride (76.4 mg, 0.57 mmol), tert-butyl nitrite (0.08 mL, 0.68 mmol) and Intermediate 12A (167 mg, 0.45 mmol) in MeCN (16 mL) and stirred at 0 °C for 30 min, then at rt for 3 h. White solid (27 mg, 15%). LRMS: 387.3 [M+H] + ; TLC (1:1 EtOAc:heptane) R f =0.83.

[0159] 15A 5-(2,6-difluoro-4-methylphenoxy)-1-ethylpyrazole-4-carboxylic acid

[0160]

[0161] A solution of intermediate 8A (70 mg, 0.230 mmol) and LiOH (1M aq; 1.8 mL, 1.8 mmol) in THF:MeOH (1:1; 6 mL) was heated at 55°C for 3 h. The volatiles were removed under reduced pressure, and the residue was acidified to pH≈2 with HCl (1M aq.) and then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water and brine (10 mL each), dried (MgSO4), and the solvent was removed under reduced pressure to give a white solid (58 mg, 91%). 1H NMR (400MHz, DMSO-d6) δ7.73 (s, 1H), 7.02 (d, J = 9.8Hz, 2H), 4.12 (q, J = 7.3Hz, 2H), 2.27 (s, 3H), 1.34 (t, J = 7.2Hz, 3H). LRMS:283.0[M+H] + .

[0162] The following intermediate compounds were prepared in a similar manner to Intermediate 15A.

[0163]

[0164]

[0165] Example

[0166] 1.5-(2,6-difluoro-4-methylphenoxy)-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]pyrazole-4-carboxamide

[0167]

[0168] NEt3 (0.04 mL, 0.32 mmol) and HATU (66.6 mg, 0.18 mmol) were added to Intermediate 15A (49.4 mg, 0.18 mmol) and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-ketone (40.0 mg, 0.16 mmol) in DMF (1 mL) was added and the reaction was stirred at rt for 2 hours and 45 minutes. Water (20 mL) was added to cause the formation of a precipitate, which was collected by filtration and washed with water (5 mL). The precipitate was dissolved in EtOAc (20 mL), dried (MgSO ), concentrated under reduced pressure and purified by flash chromatography (50-100% EtOAc: heptane) to give a white solid (66 mg, 80%). 1 H NMR(400MHz, DMSO-d6)δ10.85(s,1H),9.02(d,J=8.2Hz,1H),8.34(s,1H),7.65–7.59(m,1H),7.55–7.37(m,5H),7.31 –7.16(m,3H),6.93(d,J=9.8Hz,2H),5.23(d,J=8.2Hz,1H),4.12(q,J=7.2Hz,2H),2.21(s,3H),1.35(t,J=7.2Hz,3H). LRMS:516.5[M+H] + .

[0169] The compound of Example 1 was prepared by the procedure described for (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine. -2-one or (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-ketone to prepare the following compounds of the present invention.

[0170]

[0171]

[0172] Example 7: In vitro efficacy

[0173] Compounds were subjected to RSV plaque reduction assays according to the following protocol.

[0174] Plaque reduction assay:

[0175] Make Hep-G2 cell (ECACC, 85011430) go down to posterity in flask and be seeded in the DMEM containing antibiotic and supplementing 10%FBS in 24-well plates.During inoculation and subsequent cultivation, cell is cultivated in the DMEM containing 2%FBS.100 plaque forming units / wells of RSV (RSV A2 ECACC, 0709161v) are mixed with eight serial dilutions of compound.Subsequently, 100 μ L virus / compound mixtures are added in the Hep-G2 cell monolayer that converges.Cell and virus / compound mixture are cultivated 2h at 37 ℃ in humidifying 5%CO2 incubator, then remove inoculum and add the covering material (DMEM containing 2%FBS and 0.8%CMC) of 1mL containing compound dilution.Cell is cultivated 2 days at 37 ℃ in humidifying 5%CO2 incubator.

[0176] Cells were washed with PBS for 3 min before adding 75 / 25% v / v EtOH / MeOH. Fixative was removed and the plate was washed with PBS. The primary antibody titrated in advance was added to 200 μL PBS / 2% milk powder, and the plate was cultivated for 90 min at 37 ° C. The plate was washed 3 times with PBS / 0.05% Tween20, then rabbit anti-goat horseradish peroxidase was added in 200 μL PBS / 2% milk powder, and cultivated for 1 h at 37 ° C. After three washing steps using PBS / 0.05% Tween20, 200 μL of ready-to-use TrueBlue was added and the plate was cultivated for 10-15 min at rt, then washed with water. After removing the water, the plate was air-dried in the dark.

[0177] The plates were scanned and analyzed using an Immunospot S6 Macro analyzer equipped with BioSpot analysis software to count immunostained plaques (virospots). Plaque counts were used to calculate the infection % relative to the mean plaque counts in RSV virus control wells. EC was calculated at 50% signal reduction by interpolation of inhibition curves fitted by 4-parameter nonlinear regression with variable slope in Dotmatics. 50 Plaque EC 50 and cytotoxic CC 50 Values ​​are the means of at least two experiments, and numbers are rounded to whole units.

[0178] result

[0179]

[0180] Example 7: In vitro pharmacokinetics

[0181] Compounds were subjected to the following assays to investigate liver microsomal stability.

[0182] Microsome cultivation: experimental procedure

[0183] The pooled liver microsomes were purchased from a reputable commercial supplier and stored at -80°C before use. Microsomes (final protein concentration 0.5 mg / mL), 0.1 M phosphate buffer pH 7.4 and test compounds (final substrate concentration 1 μM; final DMSO concentration 0.25%) were pre-incubated at 37°C, and then NADPH (final concentration 1 mM) was added to start the reaction. The final incubation volume was 50 μL. Each compound tested included a control incubation in which 0.1 M phosphate buffer pH 7.4 was added instead of NADPH (NADPH-). Each species included two control compounds. All incubations were performed separately for each test compound. Each compound was incubated for 0, 5, 15, 30 and 45 min. The control (NADPH-) was incubated for only 45 min. The reaction was stopped by transferring the incubation to acetonitrile at a ratio of 1:3 at the appropriate time point. The termination plate was centrifuged at 3,000 rpm for 20 min at 4°C to precipitate protein. After protein precipitation, sample supernatants were combined in boxes of up to 4 compounds, internal standards were added, and samples were analyzed by LC-MS / MS. The gradient of the line was determined based on the plot of ln peak area ratio (compound peak area / internal standard peak area) vs. time. Subsequently, the half-life (t 1 / 2 ) and intrinsic clearance (CL int ).

[0184] result

[0185]

[0186] Example 8: Aqueous Formulation

[0187] The compound of Example 1 was formulated as a solution in 30% w / v captisol (ie, sulfobutyl ether-β-cyclodextrin) at pH 4 according to the following procedure.

[0188] The vehicle 30% w / v captisol (ie sulfobutyl ether-β-cyclodextrin) was prepared by weighing the required amount of captisol into a suitable container, adding approximately 80% of the final volume of water and stirring magnetically until a solution was formed. The vehicle was then made up to volume with water.

[0189] An aqueous solution of the compound of Example 1 was prepared by weighing 175 mg of the compound into a suitable container and adding approximately 80% of the required volume of carrier. The pH was adjusted to pH 2 using aqueous hydrochloric acid and the resulting mixture was stirred magnetically until a solution was formed. The formulation was then made up to volume with carrier and the pH was adjusted to pH 4 using aqueous sodium hydroxide.

[0190] Example 9: Tablet composition

[0191] Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention, are manufactured as follows:

[0192] Composition of 10,000 tablets

[0193] Compound of the present invention (250 g)

[0194] Lactose (800g)

[0195] Corn starch (415g)

[0196] Talc (30g)

[0197] Magnesium stearate (5g)

[0198] The compound of the present invention, lactose and half of corn starch are mixed. The mixture is then forced through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is suspended in warm water (90 mL). The resulting paste is used to granulate the powder. The particles are dried and broken into small pieces on a sieve with a mesh size of 1.4 mm. The remaining amount of starch, talc and magnesium are added, carefully mixed and processed into tablets.

[0199] Example 10: Injectable Formulations

[0200] 200 mg of the compound of the present invention

[0201] Hydrochloric acid solution 0.1M or

[0202] Sodium hydroxide solution 0.1M qs, to pH 4.0 to 7.0

[0203] Sterile water qs to 10mL

[0204] The compound of the invention was dissolved in mostly water (35°C-40°C) and the pH was adjusted to 4.0 to 7.0 with hydrochloric acid or sodium hydroxide as appropriate. The batch was then made up to volume with water and filtered through a sterile microporous filter into a sterile 10 mL amber glass vial (Type 1) and sealed with a sterile cap and seal.

[0205] Example 11: Intramuscular injection

[0206]

[0207]

[0208] The compound of the present invention was dissolved in glycofurol. Benzyl alcohol was then added and dissolved, and water was added to 3 mL. The mixture was then filtered through a sterile microporous filter and sealed in a sterile 3 mL glass vial (Type 1).

[0209] Example 12: Syrup Formulation

[0210]

[0211] The compound of the invention is dissolved in a mixture of glycerol and mostly purified water. Then the sodium benzoate aqueous solution is added to the solution, followed by the sorbitol solution and finally the flavoring. Make up to volume with purified water and mix thoroughly.

Claims

1. A compound which is a benzodiazepine of formula (I) Pyrazole: in: R 1 and R 2 Each of is independently H or halogen; R 3 It is H; (i) are keys, and does not exist; or are keys, and does not exist; R 4 is H or a 4- to 10-membered heterocyclic group; R 5 is H or halogen; R 6 is H or C1-C6 alkyl; R 7 is H or halogen; n is 1, 2, or 3; and Each of V, W, and X is CH; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 2 It is benzodiazepine A halogen substituent at the 9-position of the cyclopentyl ring system.

3. The compound according to claim 1 or 2, wherein are keys, and Does not exist.

4. The compound according to claim 1 or 2, wherein are keys, and Does not exist.

5. The compound according to claim 1, wherein R 2 It is benzodiazepine F at the 9-position of the base ring system.

6. The compound according to claim 1, wherein n is 1, R 5 In R 5 and R 6 The six-membered ring to which the bond is attached is at position 2, and R 6 In R 6 and R 5 The ring position of the six-membered ring to which it is bonded is 4.

7. The compound according to claim 1, which is selected from: 5-(2,6-difluoro-4-methylphenoxy)-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]pyrazole-4-carboxamide; 5-(2-Fluoro-4-methylphenoxy)-1-(oxacyclohexan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]pyrazole-4-carboxamide; 5-(4-chloro-2-fluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 5-(4-chloro-2-fluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxacyclohexan-4-yl)pyrazole-4-carboxamide; 5-(4-chloro-2,6-difluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 5-(4-chloro-2,6-difluorophenoxy)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine -3-yl]-1-(oxacyclohexan-4-yl)pyrazole-4-carboxamide; and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.

9. Use of a compound as defined in any one of claims 1 to 7 in the preparation of a medicament for the treatment or prevention of RSV infection.

10. A process for producing a pharmaceutically acceptable salt as defined in claim 1, said process comprising treating a benzodiazepine of formula (I) as defined in claim 1 with a suitable acid in a suitable solvent. derivative.

11. The method of claim 10, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid.

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