Benzodiazepine derivatives for the treatment of respiratory syncytial virus (RSV) infections

Abstract

Formula (I): (in the formula: R 1 and R 2 each independently is H or halo; R 3 is H, C1-C6 alkyl, -NHR 8 or -OR'; (i) either a, c, and e are all bonds and b, d, and f are absent; or b, d, and f are all bonds and a, c, and e are absent; 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; R 5 is H or halo; R 6 -OR 8 , -NR 8 R 9 or -R 8 and;R 7 is H or halo; R 8 and R 9 wherein each is independently H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclyl, which groups are unsubstituted or substituted; R' is H or C1-C6 alkyl; and one of V and W is CH, and the other is N or CH; and pharmaceutically acceptable salts thereof, are inhibitors of RSV and can therefore be used to treat or prevent RSV infection.

Description

[Technical field]

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

[0002] 2. Background of the Invention RSV is a negative single-stranded RNA virus of the Paramyxoviridae family. RSV is easily transmitted by secretions from infected individuals via surfaces or hand-to-hand transfer. Unlike influenza, it is not transmitted by small particle aerosols. After successful inoculation, the incubation period is between 4 and 6 days, during which time the virus spreads from the nasopharynx to the lower respiratory tract by fusion of infected cells with uninfected cells and by sloughing of necrotic epithelium. In young children, this, coupled with increased mucus secretion and edema, can lead to mucosal plugging, causing hyperinflation and collapse of distal lung tissue indicative of bronchiolitis. Hypoxia is common and supply capacity is often impaired due to respiratory distress. In RSV pneumonia, inflammatory infiltration of the airways is composed of mononuclear cells and is more generalized to include bronchioles, bronchi, and alveoli. The duration and extent of viral shedding have been found to correlate with clinical signs and disease severity.

[0003] RSV is the leading cause of severe respiratory tract infections in infants and children worldwide. Although many infants hospitalized for RSV infection are otherwise healthy, the highest morbidity and mortality occurs in those born prematurely and those with chronic lung or heart disease. Severe RSV infection in childhood can lead to recurrent wheezing for several years and is associated with the later development of asthma.

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

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

[0006] Current anti-RSV treatments include the use of a monoclonal antibody against RSV called palivizumab. Such use of palivizumab is a preventative rather than a curative treatment for RSV. Although this antibody is often effective, its use is restricted to premature and high-risk infants. In fact, its limited availability means that anti-RSV treatments are unavailable to many people who need them. Thus, there is an urgent need for effective alternatives to existing anti-RSV treatments.

[0007] Small molecules have also been proposed as inhibitors of RSV. These include benzimidazoles and benzodiazepines. For example, the discovery and early development of RSV604, a benzodiazepine compound with submicromolar anti-RSV activity, is described in Antimicrobial Agents and Chemotherapy, Sept. 2007, 3346-3353 (Chapman et al). Benzodiazepine inhibitors of RSV have also been 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 additional compounds with anti-RSV activity, particularly compounds that have a combination of potent antiviral activity and favorable pharmacokinetic properties. Summary of the Invention

[0009] It has now been found that a novel series of benzodiazepine derivatives have potent anti-RSV activity combined with favorable pharmacokinetics and good solubility. Thus, the present invention provides compounds of formula (I):

[0010] [ka]

[0011] (In the formula: R 1 and R 2 each is independently H or halo; R 3 is H, C1-C6 alkyl, -NHR 8 or-OR'; (i)

[0012] [ka]

[0013] [ka]

[0014] [ka]

[0015] are all bonds,

[0016] [ka]

[0017] [ka]

[0018] [ka]

[0019] is absent; or

[0020] [ka]

[0021] [ka]

[0022] [ka]

[0023] are all bonds,

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027] is either absent; 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; R 5 is H or halo; R6 -OR 8 , -NR 8 R 9 or -R 8 and; R 7 is H or halo; R 8 and R 9 each is independently H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclyl, which groups are unsubstituted or substituted; R' is H or C1-C6 alkyl; One of V and W is CH, and the other is N or CH. or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description of the Invention When any group, ring, substituent or moiety defined herein is substituted, it is typically substituted by Q, as defined below.

[0029] C 1-6 The alkyl group or moiety may be linear or branched. 1-6 The alkyl group is typically 1-4 Alkyl group, or C 4-6 It is an alkyl group. 1-6Examples of alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl (i.e. 3-methylbut-1-yl), t-pentyl (i.e. 2-methylbut-2-yl), neopentyl (i.e. 2,2-dimethylpropan-1-yl), n-hexyl, i-hexyl (i.e. 4-methylpentan-1-yl), t-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 groups are unsubstituted or typically substituted by one or more groups Q as defined below. For example, C 1-6 The alkyl group is unsubstituted or substituted by one, two or three groups Q as defined below.

[0030] Q is halo, 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 12-membered heteroaryl, where each R' is independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 and 5-10 membered heteroaryl. For the avoidance of doubt, the alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl moieties in these definitions are themselves typically unsubstituted.

[0031] C 1-6 The alkoxy group may be linear or branched. It is typically1-4 Alkoxy groups, for example methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy groups. 1-6 Alkoxy groups are unsubstituted or typically substituted by one or more groups Q as defined above.

[0032] C 1-6 The alkylthio group may be linear or branched. It is typically 1-4 An alkylthio group, for example a methylthio, ethylthio, propylthio, i-propylthio, n-propylthio, n-butylthio, sec-butylthio or tert-butylthio group. 1-6 Alkylthio groups are unsubstituted or typically substituted by one or more groups Q as defined above.

[0033] The halogen or halo group is F, Cl, Br or I. Typically it is F or Cl. C substituted by halogen 1-6 The alkyl group is "C 1-6 "haloalkyl" refers to the C defined above in which one or more hydrogens are replaced by halo. 1-6 Similarly, C substituted with halogen 1-6 The alkoxy group is "C 1-6 "haloalkoxy" refers to the C defined above in which one or more hydrogens are replaced by halo. 1-6 It means an alkoxy group. Typically, C 1-6 Haloalkyl or C 1-6 Haloalkoxy is substituted with one, two or three of said halogen atoms. Haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX3 and -OCX3 (wherein X is a halogen), e.g., -CF3-CCl3-OCF3 and -OCCl3.

[0034] C 1-6 Hydroxyalkyl groups are C as defined above substituted with one or more OH groups.1-6 It is an alkyl group. Typically, it is substituted by one, two or three OH groups. Preferably, it is substituted by a single OH group.

[0035] C6-C 10 An aryl group is an aromatic carbocyclic group containing from 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. C6-C 10 Examples of aryl groups include phenyl and naphthyl. When substituted, the aryl group is typically substituted by a group Q as defined above, for example by one, two or three groups selected from the groups Q as defined above. More specifically, substituted aryl groups, such as substituted phenyl groups, include C1-C6 alkyl, halo, -OR 8 and -N(R 8 )2, wherein R 8 is H or C1-C6 alkyl, and when there are two, each R 8 are the same or different.

[0036] C 3-10 A cycloalkyl group is a saturated hydrocarbon ring having from 3 to 10 carbon atoms. 3-10 The cycloalkyl group may 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 cyclobutyl. 3-10 Cycloalkyl groups are unsubstituted or substituted, typically by one or more groups Q as defined above. A 4-10 membered heteroaryl group or moiety is a 4-10 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 one N atom and 0, 1, 2 or 3 additional heteroatoms selected from O, S and N. It can be, for example, a monocyclic 5-7 membered heteroaryl group, such as a 5 or 6 membered N-containing heteroaryl group. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl and pyrazolyl groups. Furanyl, thienyl, imidazolyl, pyridyl and pyrimidinyl groups are preferred. It can alternatively be a bicyclic heteroaryl group, such as an 8-10 membered bicyclic heteroaryl group. Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, imidazopyridazinyl, pyrrolopyridinyl, pyrazolopyrimidinyl and pyrrolopyrimidinyl. When substituted, heteroaryl groups (monocyclic or bicyclic) are typically 1-4 It is substituted by one or more, such as one, two or three, groups selected from alkyl groups and groups Q as defined above.

[0037] A 4- to 10-membered heterocyclyl group is a monocyclic or bicyclic non-aromatic saturated or unsaturated ring system containing from 5 to 10 carbon atoms and at least one atom or group selected from N, O, S, SO, SO2 and CO, more typically N or O. When the ring system is bicyclic, one ring may be saturated and one ring may be unsaturated. Typically, it is a C ring system in which one, two or three of the carbon atoms in the ring are replaced by an atom or group selected from O, S, SO2, CO and NH. 4-10It is a ring system. More typically, it is a monocyclic ring, preferably a monocyclic C4-C6 ring. Examples include piperidyl, piperidine-2,6-dionyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl moieties.

[0038] For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl groups refer to "N" atoms that may be present in the ring, it will be apparent to the skilled chemist that any such N atom, when attached to each of its adjacent ring atoms via a single bond, will be protonated (or will bear a substituent as defined above). Such protonated forms are encompassed within the present definitions of heteroaryl and heterocyclyl groups.

[0039] In one embodiment of formula (I) defined above, R 2 is a halo substituent at the 9-position of the benzodiazepinyl ring system, particularly F. Examples of such compounds are represented by the following formula (I'):

[0040] [ka]

[0041] (In the formula, R 1 is H or halo, R 2 is H or halo, and the remaining groups and variables are as defined above for formula (I). Typically, R 1 is H or F, and R 2 is H or F. For example, R 1 is H or F, and R 2 is F.

[0042] In one embodiment of formula (I),

[0043] [ka]

[0044] [ka]

[0045] [ka]

[0046] are all bonds,

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] Such compounds have the following formula (Ia):

[0051] [ka]

[0052] wherein all groups and variables are as defined above for formula (I) or (I').

[0053] In another embodiment of formula (I),

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] are all bonds,

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] Such compounds have the following formula (Ib):

[0062] [ka]

[0063] wherein all groups and variables are as defined above for formula (I) or (I').

[0064] In one embodiment of formulae (I), (I'), (Ia) and (Ib) above, V is N and W is CH. Examples of such structures are shown below in formulae (Ia') and (Ib'):

[0065] [ka]

[0066] Contains benzodiazepinylpyrazoles.

[0067] In formulae (Ia') and (Ib'), R 1 From R 7 Each of is as defined above for formula (I) or (I').

[0068] In another embodiment of formulae (I), (I'), (Ia) and (Ib) above, V is CH and W is N. Examples of such structures are shown below in formulae (Ia'') and (Ib''):

[0069] [ka]

[0070] Contains benzodiazepinylpyrazoles.

[0071] In formulae (Ia'') and (Ib''), R 1 From R 7 Each of is as defined above for formula (I) or (I').

[0072] In further embodiments of formulae (I), (I'), (Ia) and (Ib) above, V is CH and W is CH. Examples of such structures are shown below in formulae (Ia'') and (Ib''):

[0073] [ka]

[0074] Contains benzodiazepinylpyrazoles.

[0075] In formulae (Ia''') and (Ib''), R 1 From R 7 Each of is as defined above for formula (I) or (I').

[0076] In the compounds of the invention having any of the structural formulae defined above, R 5 may be attached at any available ring position of the six-membered ring to which it is attached. In one embodiment, it is attached at ring position 2, i.e., ortho to the bond connecting the six-membered ring to the adjacent pyrazole ring. Typically, R 5 is F at the 2-position, i.e., a 2-fluoro group.

[0077] In the compounds of the invention having any of the structural formulae defined above, R 6 may be attached at any available ring position of the six-membered ring to which it is attached. In one embodiment, it is attached at ring position 4, i.e., para to the bond connecting the six-membered ring to the adjacent pyrazole ring.

[0078] In one aspect, the present invention provides a compound of formula (I″):

[0079] [ka]

[0080] The present invention provides a compound which is a benzodiazepinyl pyrazole of the formula: wherein each of the groups and variables is as defined above for formula (I), or a pharma- ceutically acceptable salt thereof.

[0081] R in formula (I″) 1 and R 2 When takes the same ring position as shown in formula (I') above, the resulting compound has the following formula (I'''):

[0082] [ka]

[0083] (In the formula, R 1 is H or halo, R 2is H or halo, and the remaining groups and variables are as defined above for formula (I). Typically, R 1 is H or F, and R 2 is H or F. For example, R 1 is H and R 2 is F.

[0084] In one embodiment of the compounds of the invention having any of structural formula (I″), (Ia), (Ib), (Ia′), (Ib′), (Ia″), (Ib″), (Ia′″) or (Ib′″), R 2 is at the 9-position of the benzodiazepinyl ring system. In this embodiment, typically R 2 is a halo substituent, particularly F. More typically 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 is F.

[0085] In the compounds of the invention having any of the structural formulae defined above, R 3 is H, C1-C6 alkyl, -NR 8 R 9 and -OR', where R' is H or C1-C6 alkyl, e.g., methyl or ethyl, and 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 heterocyclyl, which groups are unsubstituted or substituted. In one embodiment of the formula defined above, R 3 is H, C1-C6 alkyl and -NR 8 R 9 Typically, R 8 is H and R 9is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclyl, which groups are unsubstituted or substituted. In one embodiment, R 8 is H and R 9 is H or C1-C6 alkyl.

[0086] In the compounds of the invention having any of the structural formulae defined above, R 4 is H or a group selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclyl, which groups are unsubstituted or substituted. In one embodiment, R 4 is a group selected from C1-C6 alkyl, C3-C6 cycloalkyl and 4- to 10-membered heterocyclyl, which group is unsubstituted or substituted. Typically R 4 is a group selected from C1-C6 alkyl (such as C1-C3 alkyl), C3-C6 cycloalkyl (such as cyclopropyl) and 4-10 membered heterocyclyl (e.g. an O-containing heterocyclyl group such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl).

[0087] In the compounds of the invention having any of the structural formulae defined above, R 5 is H or halo, especially F.

[0088] In the compounds of the invention having any of the structural formulae defined above, R 6 -OR 8 , -NR 8 R 9 or -R 8 (In the formula, 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 heterocyclyl, which groups are unsubstituted or substituted. Typically, R 6 -OR 8 , -NR 8 R 9and R 8 (In the formula, R 8 is C1-C6 alkyl (such as C1-C3 alkyl), C3-C6 cycloalkyl (such as cyclopropyl or cyclobutyl), R 9 is H or C1-C6 alkyl, the alkyl and cycloalkyl groups being unsubstituted or substituted. More typically, R 6 -OR 8 , -NR 8 R 9 or R 8 , e.g. -OR 8 or -NR 8 R 9 (In the formula, R 8 is an unsubstituted C1-C6 alkyl (such as methyl, ethyl, or i-propyl) or a C3-C6 cycloalkyl (such as cyclopropyl or cyclobutyl), the cycloalkyl group being unsubstituted or substituted with an unsubstituted C1-C3 alkyl (such as methyl); R 9 is C1-C6 alkyl or H).

[0089] Particular compounds of the present invention are 1-Ethyl-5-[2-fluoro-6-(methylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[2-fluoro-6-(cyclopropylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclobutylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[2-fluoro-6-[(1-methylcyclopropyl)amino]pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[5-(cyclopropylamino)-3-fluoropyridin-2-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[3-fluoro-5-(propan-2-ylamino)pyridin-2-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[2-fluoro-4-(propan-2-ylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-3-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[5-(cyclopropylamino)-3-fluoropyridin-2-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-5-[5-(ethylamino)-3-fluoropyridin-2-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Cyclopropyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Cyclopropyl-5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-propan-2-ylpyrazole-4-carboxamide; 1-Ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[3-fluoro-5-(propan-2-ylamino)pyridin-2-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide;

[0090] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-3-[2-fluoro-6-(propylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-Ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-[2-fluoro-6-(propylamino)pyridin-3-yl]pyrazole-4-carboxamide; 1-tert-Butyl-3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-tert-Butyl-3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)-1H-pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; (3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(4,4-difluorocyclohexyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(4,4-difluorocyclohexyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; -Ethyl-5-(3-fluoro-5-(methylamino)pyridin-2-yl)-N-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-1H-pyrazole-4-carboxamide; 1-Ethyl-5-(5-(ethylamino)-3-fluoropyridin-2-yl)-N-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-1H-pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide;

[0091] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-cyclopropyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-cyclopropyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(2-fluoro-4-propan-2-ylphenyl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(6-cyclopropyl-2-fluoropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(6-ethyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(6-ethyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-Ethoxy-1-ethyl-5-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-Ethoxy-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-(2-fluorophenyl)pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)pyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide; 1-(oxan-4-yl)-5-[6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(1-methylpiperidin-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; and pharma-ceutically acceptable salts thereof.

[0092] The compounds of the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of the present invention form part of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures.The compounds of formula (I) that contain one or more chiral centers may be used in enantiomerically or diastereoisomeric pure form, or in the form of mixtures of isomers.

[0093] The present invention encompasses all geometric and positional isomers of the compounds of the present invention as defined above.For example, if the compounds of the present invention incorporate a double bond or a fused ring, both cis- and trans-forms, as well as mixtures thereof, are encompassed within the scope of the present invention.Both single positional isomers and mixtures of positional isomers are also within the scope of the present invention.

[0094] The compounds of the present invention can exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the present invention is meant to encompass both the solvated and unsolvated forms.

[0095] The compounds of the present invention may exist in different tautomeric forms, and all such 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 via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol tautomerism. Valence tautomers include interconversions via some rearrangement of bond electrons.

[0096] The compounds of the invention may be prepared by the synthetic methods described in the Examples which follow, or by methods analogous to such methods using appropriate starting materials and methodology familiar to the skilled chemist.

[0097] By conventional methods, the benzodiazepine derivative of formula (I) can be converted into its pharmaceutically acceptable salt, and the salt can be converted into the free compound.For example, the benzodiazepine derivative of formula (I) can be contacted with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt.The pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

[0098] Pharmaceutically acceptable acids include both inorganic acids, such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid, and organic acids, such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic 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, as well as organic bases, such as alkyl amines, aralkyl amines and heterocyclic amines.

[0099] The compounds of the present invention have been found to be inhibitors of respiratory syncytial virus (RSV) in biological tests.They have a combination of strong anti-RSV activity, good bioavailability and good solubility properties.This combination of properties makes the compounds therapeutically useful and better drug candidates than many of the compounds disclosed in the prior art references discussed above.

[0100] Thus, the present invention further provides a compound which is a benzodiazepine derivative of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0101] The present invention also provides the compound of the present invention as defined above for use in a method for treating or preventing RSV infection.Furthermore, the present invention provides the use of the compound of the present invention as defined above in the manufacture of a medicament for use in treating or preventing RSV infection.Subjects suffering from or susceptible to RSV infection can be treated by a method comprising administering the compound of the present invention as defined above to said subject.The condition of the subject can be improved or ameliorated thereby.

[0102] RSV infection is typically a respiratory tract infection.RSV infection can be an infection in children, such as children under 10 years old or infants under 2 years old.In one embodiment, the present invention provides the compound as defined above for use in treating or preventing RSV infection in pediatric patients.Alternatively, infection can be an infection in mature or elderly adults, such as adults over 60 years old, adults over 70 years old, or adults over 80 years old.The present invention further provides a compound for use in treating or preventing RSV infection in elderly patients.

[0103] The RSV infection can be an infection in an immunocompromised individual or an individual suffering from COPD or CHF, hi another embodiment, the RSV infection is an infection in an individual who is not immunocompromised, such as an individual who is otherwise healthy.

[0104] 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- or film-coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. The compounds can thus be administered by injection, infusion, or by inhalation or spray. The compounds are preferably administered by oral administration.

[0105] The dosage depends on various factors, including the age, weight and condition of the patient and the route of administration. The daily dosage can vary within wide limits and will be adjusted to the individual requirements in each case. Typically, however, the dosage adopted for each route of administration when the compound is administered alone to an adult human is in the range of 0.0001 to 650 mg / kg, most commonly 0.001 to 10 mg / kg, body weight, for example 0.01 to 1 mg / kg. Such dosages can be given, for example, 1 to 5 times a day. For intravenous infusion, a suitable daily dose is 0.0001 to 1 mg / kg body weight, preferably 0.0001 to 0.1 mg / kg body weight. The daily dosage can be administered as a single dose or according to a divided dose schedule.

[0106] A unit dosage form such as a tablet or capsule will usually contain 1-250 mg of active ingredient. For example, a compound of formula (I) may be administered to a human patient at a dose between 100-250 mg either once a day, twice or three times a day. For example, a compound of formula (I) may be administered to a human patient at a dose between 100-250 mg either once a day, twice or three times a day.

[0107] The compound of formula (I) and its pharmaceutically acceptable salts can be used as they are. Alternatively, they can be administered in the form of pharmaceutical compositions. Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0108] Depending on the mode of administration, the pharmaceutical composition preferably contains from 0.05 to 99% w (weight percent), more preferably from 0.05 to 80% w, even more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all weight percentages being based on the total composition.

[0109] The present invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) as hereinbefore defined or a pharma- ceutically acceptable salt thereof with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0110] The compounds of the present invention can be administered in various dosage forms.That is, they can be administered orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, solutions, dispersible powders or granules.The compounds of the present invention can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, by infusion techniques, or by inhalation or aerosol.The compounds can also be administered as suppositories.

[0111] The solid oral form of pharmaceutical composition of the present invention can contain, together with active compound, diluent such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricant such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agent such as starch, alginic acid, alginate or sodium starch glycolate; foaming mixture; dye; sweetener; wetting agent such as lecithin, polysorbate, lauryl sulfate; and non-toxic pharmacologically inactive substances generally used in pharmaceutical preparations.Such pharmaceutical preparations can be produced by known methods, for example, by mixing, granulating, tableting, sugar coating or film coating process.

[0112] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and / or mannitol and / or sorbitol.

[0113] Suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma- ceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. Further suitable carriers for suspensions include sterile water, hydroxypropylmethylcellulose (HPMC), polysorbate 80, polyvinylpyrrolidone (PVP), aerosol AOT (i.e., sodium l,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate), pluronic F127, and / or captisol (i.e., sulfobutylether-beta-cyclodextrin).

[0114] The compounds of the present invention may be, for example: (i) 0.5% w / v hydroxypropyl methylcellulose (HPMC) / 0.1% w / v polysorbate 80; (ii) 0.67% w / v polyvinylpyrrolidone (PVP) / 0.33% w / v aerosol AOT (sodium l,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate); (iii) 1% w / v pluronic F 127; and (iv) 0.5% w / v polysorbate 80 The composition may be formulated as an aqueous suspension in a carrier selected from:

[0115] 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 required amount of excipient into a suitable container, adding about 80% of the final volume of water, and magnetically stirring until a solution is formed.The carrier is then made up to volume with water.The aqueous suspension of the compound of formula I can be prepared by weighing the required amount of the compound of formula I into a suitable container, adding 100% of the required volume of carrier, and magnetically stirring.

[0116] Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0117] The compounds of the present invention may also be administered in combination with other compounds used for the treatment of viral infections.That is, the present invention further relates to combination therapy in which the compounds of the present invention, or their pharma- ceutical acceptable salts, or pharmaceutical compositions or preparations containing the compounds of the present invention are administered simultaneously or sequentially or as a combined preparation with other therapeutic agent(s) for the treatment or prevention of viral infections, particularly infections caused by RSV.

[0118] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration.In one aspect of the present invention, "combination" refers to simultaneous administration.In another aspect of the present invention, "combination" refers to separate administration.In a further aspect of the present invention, "combination" refers to sequential administration.When administration is sequential or separate, the delay in administering the second component should not be such that it loses the beneficial effect of the combination.

[0119] Suitable therapeutic agents for use in combination therapy include: (i) RSV nucleocapsid (N)-protein inhibitor; (ii) other RSV protein inhibitors, such as those that inhibit the phosphoprotein (P) protein and the large (L) protein; (iii) an anti-RSV monoclonal antibody, such as an F-protein antibody; (iv) immunomodulatory toll-like receptor compounds; (v) other respiratory virus antivirals, such as anti-influenza and anti-rhinovirus compounds; and / or (vi) anti-inflammatory compounds; Includes.

[0120] The RSV nucleocapsid (N)-protein plays a pivotal role in viral transcription and replication, mediating the interaction between the genomic RNA and the virally encoded RNA-dependent RNA polymerase. The RSV P- and L-proteins are components of the virally encoded RNA-dependent RNA polymerase of RSV.

[0121] According to a further aspect of the present invention, there is provided a compound of formula (I) as hereinbefore defined, or a pharma- ceutically acceptable salt thereof, in combination with one or more of the therapeutic agents listed as (i) to (vi) above, for use in the treatment of RSV.

[0122] The following examples serve to further illustrate the invention. The preparations relate to the preparation of starting materials and intermediates used to prepare the compounds of the examples. None of the examples or preparations limit the invention in any way. EXAMPLES

[0123] Reagents were obtained from commercial sources and used without further purification. Reactions were carried out under anhydrous conditions using anhydrous solvents obtained from commercial sources. All temperatures are °C. TLC was carried out on aluminum-backed silica gel plates with a fluorescent indicator of 254 nM (median pore size 60 Å). Microwave reactions were carried out using a Biotage Initiator. Flash column chromatography was carried out using a Biotage Isolera One system using KP-Sil or Ultra silica gel columns or an Isco CombiFlash Rf using FlashPure, RediSep Rf or RediSep Rf Gold silica gel columns. Reverse-phase flash chromatography was carried out using an Isco CombiFlash Rf and a RP Flash C18 column. NMR spectra were recorded on 400, 500, 600 or 700 MHz spectrometers at ambient probe temperature (nominal 298 K). Chemical shifts (δ) are given in ppm and are calibrated by using residual peaks of the solvent as internal standards (CDCl3, δ = 7.26 ppm; DMSO-d6, δ = 2.50 ppm). Coupling constants are given in Hertz (Hz). LRMS was performed using an Advion Plate Express expression spectrometry equipped with an APCI ion source. L Recorded using a compact mass spectrometer.

[0124] LCMS analysis was performed using a Waters Acquity UPLC with a Waters X-Select UPLC C18 column (1.7 μm; 2.1 × 30 mm) and a 3 min (Method A) or 10 min (Method B) or an Agilent UPLC with a Waters X-Select C18 (2.5 μm; 4.6 × 30 mm) and a 3 min (Method C) or 10 min (Method D) linear gradient of 5-95% acetonitrile appropriate for the lipophilicity of the compounds was performed at 0.77 mL / min at 40 °C. The aqueous part of the mobile phase was 0.1% formic acid. LC-UV chromatograms were recorded between 210 and 400 nm using a Waters Acquity photodiode array detector. Mass spectra were recorded using a Waters Acquity QDa detector with ESI switching between positive and negative ion modes.

[0125] Preparation Examples (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one were prepared using the methods described in WO / 2004 / 026843, WO / 2005 / 090319, and WO / 2017 / 015449.

[0126] [Table 1]

[0127] Preparation Example 1A Ethyl 1-ethylpyrazole-4-carboxylate

[0128] [ka]

[0129] Iodoethane (1.89 mL, 23.56 mmol) was added to a solution of ethyl 1H-pyrazole-4-carboxylate (3.00 g, 21.4 mmol) and K2CO3 (3.25 g, 23.6 mmol) in DMF (20 mL) and the reaction mixture was stirred at rt for 23 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (3 x 30 mL) and the combined organics were washed with water and brine (30 mL each), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10-50% EtOAc / heptane) afforded a white solid (3.10 g, 86%). 1 LRMS m / z 169.0[M+H] +

[0130] 2A Ethyl 1-ethyl-3-methyl-1H-pyrazole-4-carboxylate

[0131] [ka]

[0132] NaH (60% in mineral oil; 0.300 g, 7.50 mmol) was added portionwise to a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate (1.00 g, 6.49 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred for 5 min, iodoethane (0.60 mL, 7.42 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (50 mL), diluted with MTBE (50 mL), separated and the aqueous phase extracted with MTBE (2 x 20 mL). The combined organics were washed with 1:1 water / brine (2 x 50 mL), dried (MgSO4) and the solvent removed under reduced pressure. Purification by flash chromatography (0-30% EtOAc / isohexane) gave a pale yellow oil (840 mg, 47%). The material was approximately a 1:0.8 mixture of the desired regioisomer with ethyl 1-ethyl-5-methyl-1H-pyrazole-4-carboxylate as the minor product. It was used without further purification. The ratio was based on the δ pyrazole CH signal: 1 Confirmed by HNMR: 1 H NMR(500MHz,CDCl3)δ7.83(s,1H),4.27(q,J=7.1Hz,2H),4.11(q,J=7.3Hz,2H),2.46(s,3H),1.48(t,J=7.3Hz,3H),1.34(t,J=7.1Hz,3H). LCMS(Method A) 183.1[M+H] at m / z 1.00 min + Minor product: ethyl 1-ethyl-5-methyl-1H-pyrazole-4-carboxylate. 1 H NMR(500MHz,CDCl3)δ7.84(s,1H),4.28(q,J=7.1Hz,2H),4.11(q,J=7.3Hz,2H),2.54(s,3H),1.41(t,J=7.3Hz,3H),1.34(t,J=7.1Hz,3H). LCMS(Method A) 183.1[M+H] at m / z 1.00 min + .

[0133] 3A Ethyl 1-propan-2-ylpyrazole-4-carboxylate

[0134] [ka]

[0135] Cs2CO3 (3.7 g, 10.7 mmol) and 2-bromopropane (1.62 g, 13.2 mmol) were added to a solution of ethyl 1H-pyrazole-4-carboxylate (1.5 g, 10.7 mmol) in DMF (15 mL) and heated at 60 °C for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with MTBE (2 x 100 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (5-60% EtOAc / isohexane). Colourless oil (1.65 g, 81%). 1 H NMR(500MHz,CDCl3)δ7.92(s,1H),7.91(s,1H),4.59-4.49(m,1H),4.28(q,J=7.1Hz,2H),1.52(d,J=6.7Hz,6H),1.33(t,J=7.1Hz,3H). LCMS(Method C): m / z 183.2[M+H] in 1.03 minutes + .

[0136] 4A Ethyl 5-amino-1-cyclopropylpyrazole-4-carboxylate

[0137] [ka]

[0138] NEt3 (2.57 mL, 18.42 mmol) was added dropwise over 45 min to a stirred solution of cyclopropylhydrazine hydrochloride (1.00 g, 9.21 mmol) and ethyl (ethoxymethylene)cyanoacetate (1.56 g, 9.21 mmol) in EtOH (10 mL) at rt and then heated at 40 °C for 16 h. The volatiles were removed under reduced pressure and the residue was dissolved in CHCl (30 mL), washed with water (2 x 20 mL) and brine (20 mL), dried (NaSO) and the solvent removed under reduced pressure. Purification by flash chromatography (30% EtOAc:heptane) gave a yellow oil (725 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ7.37(s,1H),6.23(s,2H),4.15(q,J=7.1Hz,2H),3.26(tt,J=6.8,4.1Hz,1H),1.23(t,J=7.1Hz,3H),1.02-0.86(m,4H). LRMS:196.2[M+H] +

[0139] 5A Ethyl 5-bromo-1-cyclopropylpyrazole-4-carboxylate

[0140] [ka]

[0141] A solution of copper(II) bromide (1001 mg, 4.48 mmol) in MeCN (7.7 mL) was cooled to 0 °C. t-Butyl nitrite (0.64 mL, 5.38 mmol) was added followed by the dropwise addition of Intermediate 4A (700 mg, 3.59 mmol) in MeCN (7.7 mL) over 30 min. The reaction was stirred at 0 °C for 30 min, the ice bath was removed, and then stirred at rt for 16 h. The mixture was poured into 6 M aqueous HCl (20 mL) and extracted with CHCl (3 x 20 mL). The organics were washed with brine, dried (NaSO) and the solvent removed under reduced pressure. Purification by flash chromatography (0-10% EtOAc:heptane) gave a colorless oil (694 mg, 75%). 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),4.23(q,J=7.1Hz,2H),3.75-3.65(m,1H),1.27(t,J=7.1Hz,3H),1.12-1.03(m,4H). LRMS:259.1 / 261.1[M+H] +

[0142] 6A Ethyl 5-bromo-1-(oxan-4-yl)pyrazole-4-carboxylate 7A Ethyl 3-bromo-1-(oxan-4-yl)pyrazole-4-carboxylate

[0143] [ka]

[0144] Oxan-4-yl 4-methylbenzenesulfonate (1.67 g, 6.53 mmol) was added to a solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.30 g, 5.93 mmol) and Cs2CO3 (2.63 g, 8.01 mmol) in DMF (10 mL) and heated at 80 °C for 16 h. Upon cooling to rt, water (40 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The organics were washed with water and brine (20 mL each), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography (10-80% EtOAc:heptane) afforded intermediate 6A as a white solid (445 mg, 25%). 1 H 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 7A (second eluting regioisomer) was obtained as a white solid (1018 mg, 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] + .

[0145] 8A Ethyl 3-bromo-1-(4,4-difluorocyclohexyl)pyrazole-4-carboxylate

[0146] [ka]

[0147] Prepared by a procedure similar to that described for Intermediate 6A. 1 H NMR(400MHz,CDCl3)δ7.86(s,1H),4.28(q,J=7.1Hz,2H),4.25-4.12(m,1H),2.36-2.04(m,6H),2.04-1.73(m,2H),1.32(t,J=7.1Hz,3H). LRMS:317.3 / 319.3[M+H] + .

[0148] 9A Ethyl 5-bromo-1-(oxetan-3-yl)pyrazole-4-carboxylate 10A Ethyl 3-bromo-1-(oxetan-3-yl)pyrazole-4-carboxylate

[0149] [ka]

[0150] Prepared by a procedure similar to that described for Intermediate 6A using ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.70 g, 7.76 mmol), oxetan-3-yl 4-methylbenzenesulfonate (1.95 g, 8.50 mmol) and Cs2CO3 (3.43 g, 10.48 mmol) and heating at 90° C. for 22 h. Purification by flash chromatography (10-100% EtOAc:heptane) afforded Intermediate 9A (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 10A: (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] + .

[0151] 11A Ethyl 3-bromo-1-ethylpyrazole-4-carboxylate

[0152] [ka]

[0153] Ethyl iodide (2.02 mL, 25.11 mmol) was added to a solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate (5.00 g, 22.83 mmol) and K2CO3 (4.10 g, 29.67 mmol) in DMF (35 mL) and the reaction was stirred at rt for 16 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The organics were washed with water (2 x 50 mL) and brine (50 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography (10-25% EtOAc:heptane) gave a white solid (3.70 g, 66%). 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),4.21(q,J=7.1Hz,2H),4.15(q,J=7.3Hz,2H),1.36(t,J=7.3Hz,3H),1.26(t,J=7.1Hz,3H). LRMS:247.0 / 249.0[M+H] + .

[0154] 12A Ethyl 3-bromo-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate

[0155] [ka]

[0156] Prepared by a procedure similar to that described for intermediate 11A using ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.50 g, 6.85 mmol), 1,1,1-trifluoro-2-iodoethane (1.35 mL, 13.7 mmol) and Cs2CO3 (4.46 g, 13.7 mmol) in DMF (7 mL) and heating at 70° C. for 3 h and then at 40° C. for 16 h. 1 H NMR(400MHz,CDCl3)δ8.01(s,1H),4.71(q,J=8.1Hz,2H),4.35(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H). LRMS:301.2 / 303.2[M+H] + .

[0157] 13A 3-Bromo-1-(4,4-difluorocyclohexyl)pyrazole-4-carboxylic acid

[0158] [ka]

[0159] A solution of intermediate 8A (580 mg, 1.72 mmol) and LiOH (1 M aq, 6.88 mL, 6.88 mmol) in THF:MeOH (1:1; 14 mL) was heated at 55° C. for 1 h. The volatiles were removed under reduced pressure and the residue was acidified to pH ∼2 with HCl (1 M aq) then extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water and brine (15 mL each), dried (MgSO4) and the solvent removed under reduced pressure to give a white solid (464 mg, 87%). 1 H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.36(s,1H),4.47-4.38(m,1H),2.23-1.78(m,8H). LRMS:289.1 / 291.1[M+H] + .

[0160] The following intermediate compounds were prepared by the same general procedure as described for Intermediate 13A.

[0161] [Table 2]

[0162] 14A 3-Bromo-1-tert-butylpyrazole-4-carboxylic acid

[0163] [ka]

[0164] A solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.00 g, 4.57 mmol) in 3-methyl-1-butanol (4 mL) was warmed to 30° C. and then sulfuric acid (0.97 mL, 18.26 mmol) was added slowly. The reaction was stirred at 30° C. for 30 min and then heated to 80° C. for 1.5 h. The reaction was cooled to rt, diluted with EtOAc (15 mL), the organic layer separated, washed with water (10 mL), dried (MgSO4) and the solvent removed under reduced pressure to give crude ethyl 3-bromo-1-tert-butylpyrazole-4-carboxylate as a colorless oil (1.40 g) which was used without further purification. A solution of crude ethyl 3-bromo-1-tert-butylpyrazole-4-carboxylate (1.40 g, 5.09 mmol) and LiOH (1 M aq, 10.18 mL, 10.18 mmol) in THF:MeOH (1:1, 20 mL) was heated at 55° C. for 1 h. The volatiles were removed under reduced pressure and the residue was acidified to pH ∼2 with 1 M HCl (aq) then extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give a white solid (815 mg, 72%). 1 H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.31(s,1H),1.51(s,9H). LRMS:247.3 / 249.3[M+H] + .

[0165] 15A Benzyl 3-bromo-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate

[0166] [ka]

[0167] 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 0.97 mmol) was added to a solution of intermediate 13D (204 mg, 0.75 mmol) in DMSO (3 mL) under nitrogen atmosphere and stirred at rt for 5 min. Benzyl bromide (0.09 mL, 0.75 mmol) in DMSO (3 mL) was added and the reaction was stirred at rt for 2 h. The reaction was quenched with water and brine (20 mL each) and extracted with EtOAc (3×20 mL). The organics were washed with brine (2×20 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography (60-100% EtOAc:heptane) afforded a white solid (218 mg, 80%). 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.48-7.32(m,5H),5.28(s,2H),5.21(q,J=8.9Hz,2H). LRMS:363.3 / 365.3[M+H] +.

[0168] The following intermediate compounds were prepared by the same general procedure as described for Intermediate 15A.

[0169] [Table 3]

[0170] 16A tert-Butyl (6-chloro-5-fluoropyridin-3-yl)(methyl)carbamate

[0171] [ka]

[0172] A vial was charged with 5-bromo-2-chloro-3-fluoropyridine (100 mg, 0.475 mmol), tert-butyl methyl carbamate (75 mg, 0.572 mmol) and Cs2CO3 (217 mg, 0.665 mmol), 1,4-dioxane (2 mL) was added and the reaction mixture was degassed with nitrogen. Pd2(dba)3 (9 mg, 9.83 μmol) and Xantphos (22 mg, 0.038 mmol) were added and the reaction mixture was evacuated and purged with nitrogen (×3) and heated at 110° C. overnight. Water (10 mL) and EtOAc (10 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc / isohexane) to give a pale yellow gum (52 ​​mg, 41%). 1 H NMR(500MHz,CDCl3)δ8.17(d,J=2.4Hz,1H),7.57(d,J=9.6Hz,1H),3.31(s,3H),1.50(s,9H). LCMS(Method A): 261.1[M+H] at m / z 1.54 min + .

[0173] 17A Ethyl 5-(3,5-difluoropyridin-2-yl)-1-ethylpyrazole-4-carboxylate

[0174] [ka]

[0175] A solution of intermediate 1A (500 mg, 2.97 mmol) in anhydrous THF (5 mL) was degassed with nitrogen. The solution was cooled to -78°C and LDA (2.0 M in THF; 1.8 mL, 3.60 mmol) was added and stirred at -78°C for 1 min, then zinc(II) chloride (2-Me 2.0 M in THF; 1.8 mL, 3.60 mmol) was added. The reaction was warmed to rt and degassed with nitrogen. 2-Bromo-3,5-difluoropyridine (690 mg, 3.56 mmol) and Pd(PPh3)4 (172 mg, 0.15 mmol) were added and the reaction mixture was evacuated, purged with nitrogen, and then heated under nitrogen at 70°C overnight. 1M aqueous HCl (50 mL) and EtOAc (50 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organics were washed with brine (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (0-40% MTBE / isohexane) to give a pale yellow oil (523 mg, 62%). 1 H NMR(500MHz,CDCl3)δ8.49(d,J=2.4Hz,1H),8.02(s,1H),7.36(td,J=8.3,2.4Hz,1H),4. 18(q,J=7.1Hz,2H),4.10(q,J=7.3Hz,2H),1.39(t,J=7.2Hz,3H),1.20(t,J=7.1Hz,3H). LCMS (Method A): m / z 282.1[M+H] at 1.23 min + .

[0176] The following intermediate compounds were prepared by the same general procedure as described for Intermediate 17A.

[0177] [Table 4]

[0178] 18A Ethyl 1-cyclopropyl-5-(2,6-difluoropyridin-3-yl)pyrazole-4-carboxylate

[0179] [ka]

[0180] A solution of intermediate 5A (500 mg, 1.93 mmol), 2,6-difluoropyridine-3-boronic acid (337 mg, 2.12 mmol), K2CO3 (2 M aqueous solution; 4.82 mL, 9.65 mmol) in 1,4-dioxane (7 mL) in a microwave vial was purged with nitrogen for 15 min. Pd(PPh3)4 (223 mg, 0.19 mmol) was added and the sealed vial was heated at 110 °C for 17 h. The reaction was cooled to rt, purged with nitrogen for 15 min, and additional 2,6-difluoropyridine-3-boronic acid (61.3 mg, 0.39 mmol) and Pd(PPh3)4 (55.8 mg, 0.05 mmol) were added and heated at 110 °C for an additional 4 h. The reaction was cooled to rt, water (20 mL) was added and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography (10-35% EtOAc:heptane) afforded the product relative to the dehalogenated starting material. 1 A yellow oil (206 mg, 18%) was obtained as approximately a 1:1 ratio by H NMR and carried forward without further purification. Intermediate 18A: 1 H NMR(400MHz,DMSO-d6)δ8.51-8.42(m,1H),7.97(s,1H),7.42(ddd,J=8.2,2.5,0.7Hz,1H),4.08(q, J=7.1Hz,2H),3.58(tt,J=7.4,3.8Hz,1H),1.13-1.04(m,5H),1.04-0.92(m,4H),0.92-0.83(m,2H). LRMS m / z:294.1[M+H] + By-product: Ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H),7.81(d,J=0.7Hz,1H),4.20(q,J=7.1Hz ,2H),3.80(tt,J=7.5,3.9Hz,1H),1.25(t,J=7.1Hz,3H),1.13-0.82(m,4H). LRMS m / z:181.1[M+H]+ .

[0181] 19A Benzyl 3-(2,6-difluoropyridin-3-yl)-1-(oxetan-3-yl)pyrazole-4-carboxylate

[0182] [ka]

[0183] A microwave vial containing 2,6-difluoropyridine-3-boronic acid (413 mg, 2.60 mmol), Intermediate 15F (585 mg, 1.74 mmol) and XPhos Pd G2 (7.5 mol%; 102 mg, 0.130 mmol) was evacuated and filled with N2 (3x). THF (10 mL) and K3PO4 (2 M aq; 1.74 mL, 3.47 mmol), both degassed with N2 for approximately 15 min, were added and the vial was heated at 80 °C for 30 min on the MWI. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography (20 to 45% EtOAc:heptane) to give a yellow oil (520 mg, 81%). 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.28(q,J=8.5Hz,1H),7.39-7.21(m,6H),5.73-5.61(m,1H),5.18(s,2H),4.96-4.90(m,4H). LRMS m / z:[M+H] + 372.5.

[0184] The following intermediate compounds were prepared using similar procedures:

[0185] [Table 5]

[0186] 20A Ethyl 1-ethyl-5-(2-fluoro-6-(methylamino)pyridin-3-yl)-1H-pyrazole-4-carboxylate

[0187] [ka]

[0188] NEt3 (40 μL, 0.287 mmol) and methylamine (2.0 M in THF; 72 μL, 0.144 mmol) were added to a solution of intermediate 17B (40.5 mg, 0.144 mmol) in THF (1 mL) and stirred at rt overnight. Further methylamine (2.0 M in THF; 72 μL, 0.144 mmol) was added and the reaction was stirred at rt overnight. Water (10 mL) and EtOAc (10 mL) were added, the phases were separated and the aqueous phase was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. Purification by flash chromatography (0-50% EtOAc / isohexane) gave a colourless gum (18 mg, 42%). 1 H NMR(500MHz,CDCl3)δ8.01(s,1H),7.50(dd,J=9.5,8.3Hz,1H),6.34(dd,J=8.3,1.9Hz,1H),4.85-4.81(m,1H) ,4.19(q,J=7.1Hz,2H),4.04-4.00(m,2H),2.99(d,J=5.1Hz,3H),1.40(t,J=7.2Hz,3H),1.23(t,J=7.1Hz,3H). LCMS (Method A): m / z 293.2[M+H] at 1.19 min + .

[0189] 21A Ethyl 1-ethyl-5-(6-(ethylamino)-2-fluoropyridin-3-yl)-1H-pyrazole-4-carboxylate

[0190] [ka]

[0191] DIPEA (130 μl, 0.744 mmol) and ethylamine (68% in water, 38 μL, 0.466 mmol) were added to a solution of Intermediate 17B (100 mg, 0.356 mmol) in THF (1 mL) and the reaction was heated at 60 °C overnight. The reaction mixture was diluted with CHCl (10 mL) and water (10 mL), passed through a phase separator and dried under reduced pressure. The crude product was purified by flash chromatography (0-50% EtOAc / isohexane) to give a colorless gum (57 mg, 48%). 1 H NMR(500MHz,CDCl3)δ8.03(s,1H),7.52(dd,J=9.3,8.3Hz,1H),6.36(dd,J=8.4,1.7Hz,1H),5.31(s,1H),4.20(q,J=7 .1Hz,2H),4.11-3.98(m,2H),3.38(q,J=7.2Hz,2H),1.46-1.37(m,3H),1.31(t,J=7.2Hz,3H),1.24(t,J=7.1Hz,3H). LCMS (Method A): m / z 307.1[M+H] at 1.31 min + .

[0192] The following intermediate compounds were prepared using procedures similar to those used for Intermediate 21A.

[0193] [Table 6]

[0194] 22A Ethyl 1-cyclopropyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]pyrazole-4-carboxylate

[0195] [ka]

[0196] A solution of crude intermediate 18A (50 mg, 0.170 mmol), ethylamine (2M in MeOH; 34 μL, 0.511 mmol) and NEt3 (95 μL, 0.682 mmol) in THF (0.49 mL) was heated in a sealed vial under nitrogen at 50 °C for 18.5 h. Additional ethylamine (2M in MeOH; 34 μL, 0.511 mmol) was added and the reaction was heated at 50 °C for 4 h. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography (10-30% EtOAc / heptane) to give a colorless oil (32.0 mg, 59%). TLC R f 0.56 (heptane / EtOAc 1:1). LRMS m / z: 294.1 [M+H] +

[0197] 23A Ethyl 1-cyclopropyl-5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]pyrazole-4-carboxylate

[0198] [ka]

[0199] Prepared by a similar procedure as described for Intermediate 22A using cyclopropylamine (71 μL, 1.02 mmol) and heating at 60° C. for 19 h. TLC R f 0.45(heptane / EtOAc 1:1). LRMS m / z:331.3[M+H] + .

[0200] 24A Ethyl 5-[5-(cyclopropylamino)-3-fluoropyridin-2-yl]-1-ethylpyrazole-4-carboxylate

[0201] [ka]

[0202] Cyclopropylamine (500 μL, 7.21 mmol) was added to a solution of intermediate 17A (200 mg, 0.711 mmol) and DIPEA (150 μL, 0.861 mmol) in DMSO (1 mL) and heated at 140 °C for 3 h by MWI. Water (20 mL) and EtOAc (20 mL) were added, the phases were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organics were washed with water and brine (20 mL each), dried (MgSO4) and the solvent was evaporated under reduced pressure. Purification by flash chromatography (10-60% EtOAc / isohexane) gave a colourless oil (215 mg, 94%). 1 H NMR(500MHz, DMSO-d6)δ8.04(s,1H),8.00(s,1H),6.99-6.92(m,1H),4.62(s,1H),4.19(q,J=7.1Hz,2H),4.13(q,J=7.2Hz,2H ),2.51(s,1H),1.64(s,1H),1.39(t,J=7.1Hz,3H),1.22(t,J=7.2Hz,3H),0.90-0.82(m,2H),0.65-0.59(m,2H). LCMS (Method A) m / z 1.319.2[M+H] in 30 minutes + .

[0203] The following intermediate compounds were prepared by procedures similar to those used for Intermediate 24A.

[0204] [Table 7]

[0205] 25A Ethyl 1-ethyl-5-[2-fluoro-6-[(1-methylcyclopropyl)amino]pyridin-3-yl]pyrazole-4-carboxylate

[0206] [ka]

[0207] Prepared by a similar procedure as described for Intermediate 24A using Intermediate 17B (100 mg, 0.338 mmol), 1-methylcyclopropan-1-amine hydrochloride (182 mg, 1.69 mmol) and DIPEA (350 μL, 2.01 mmol) heated at 120 °C for 1 h via MWI. Similar work-up followed by purification by flash chromatography on a RP Flash C18 (25-75% MeCN / water 0.1% formic acid) gave a pale yellow gum (70 mg, 62%). 1 H NMR(500MHz,DMSO-d6)δ8.02(s,1H),7.55(dd,J=9.5,8.2Hz,1H),6.65(dd,J=8.2,1.9Hz,1H),4.19(q,J=7.1Hz,2H) ,4.08-3.96(m,2H),1.44(s,3H),1.41(t,J=7.2Hz,3H),1.23(t,J=7.1Hz,3H),0.88-0.85(m,2H),0.78-0.75(m,2H). LCMS (Method A): m / z 333.2[M+H] at 1.44 min + .

[0208] 26A Ethyl 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-propan-2-ylpyrazole-4-carboxylate

[0209] [ka]

[0210] A solution of intermediate 17F (100 mg, 0.339 mmol) and cyclopropylamine (117 μL, 1.693 mmol) in DMSO (1 mL) was heated at 50° C. for 16 h. Work-up and purification similar to that described for intermediate 24A afforded a colorless oil (100 mg, 82%). 1H NMR(500MHz,CDCl3)δ8.02(s,1H),7.57-7.50(m,1H),6.68(dd,J=8.2,1.8Hz,1H),5.33(s,1H),4.33-4.24(m,1H),,4.17(q,J=7.1H) z,2H),2.61-2.53(m,1H),1.49(d,J=6.6Hz,3H),1.39(d,J=6.6Hz,3H),1.21(t,J=7.1Hz,3H),0.87-0.80(m,2H),0.64-0.59(m,2H). LCMS (Method A) m / z 333[M+H] in 1.35 min + .

[0211] 27A Ethyl 1-ethyl-5-[2-fluoro-4-(propan-2-ylamino)phenyl]pyrazole-4-carboxylate

[0212] [ka]

[0213] A microwave vial (29 μL, 0.35 mmol) containing intermediate 17D (100 mg, 0.29 mmol), Pd2(dba)3 (13 mg, 0.010 mmol), BINAP (18 mg, 0.030 mmol), potassium tert-butoxide (43 mg, 0.38 mmol) and isopropylamine was evacuated and purged with N2, then DMSO (1 mL) was added. The reaction mixture was degassed with nitrogen and then heated at 110 °C for 1 h. Water (20 mL) and EtOAc (10 mL) were added, the phases were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water, brine (20 mL each), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-50% EtOAc / isohexane) to give a colourless gum (22.0 mg, 23%). LCMS (Method A) m / z 320.2 at 1.52 min [M+H] + .

[0214] 28A Ethyl 1-ethyl-5-(6-(ethylamino)-2-fluoropyridin-3-yl)-3-methyl-1H-pyrazole-4-carboxylate

[0215] [ka]

[0216] Prepared by a similar procedure to intermediate 21A using intermediate 17E (100 mg, 0.254 mmol), DIPEA (0.1 mL, 0.573 mmol) and ethylamine 68% in water (0.4 mL, 4.9 mmol) in THF (1 mL). The reaction was carried out at 50° C. for 2 h. 1 H NMR(500MHz,CDCl3)δ7.49-7.39(m,1H),6.34-6.28(m,1H),4.15(q,J=7.1Hz,2H),3.99(q,J=7.3Hz,2H ),3.42-3.33(m,2H),2.53(s,3H),1.38(t,J=7.2Hz,3H),1.29(t,J=7.2Hz,3H),1.17(t,J=7.1Hz,3H). LCMS (Method A) m / z 1.36 min 321.2[M+H] + .

[0217] 29A Ethyl 5-(5-((tert-butoxycarbonyl)(ethyl)amino)-3-fluoropyridin-2-yl)-1-ethyl-1H-pyrazole-4-carboxylate

[0218] [ka]

[0219] A vial was charged with intermediate 17C (130 mg, 0.380 mmol), tert-butyl ethyl carbamate (56 mg, 0.386 mmol) and CsCO3 (173 mg, 0.532 mmol). 1,4-Dioxane (2 mL) was added and the reaction mixture was degassed with nitrogen. Pd2(dba)3 (7 mg, 7.64 μmol) and Xantphos (11 mg, 0.019 mmol) were added and the reaction mixture was evacuated and purged with nitrogen (3×) then heated at 110° C. overnight. Water (20 mL), brine (10 mL) and EtOAc (20 mL) were added, separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-50% EtOAc / isohexane) to give a pale yellow gum (144 mg, 88%). 1 H NMR(500MHz,CDCl3)δ8.55-8.50(m,1H),8.03(s,1H),7.59(d,J=10.3Hz,1H),4.19(q,J=7.1Hz,2H),4.14(q,J=7. 2Hz,2H),3.81(q,J=7.1Hz,2H),1.52(s,9H),1.39(t,J=7.3Hz,3H),1.29(t,J=7.1Hz,3H),1.20(t,J=7.1Hz,3H). LCMS (Method A): m / z 407.2[M+H] at 1.63 min + .

[0220] 30A Benzyl 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethylpyrazole-4-carboxylate

[0221] [ka]

[0222] Cyclopropylamine (0.2 mL, 2.91 mmol) and DIPEA (0.2 mL, 1.17 mmol) were added to a solution of Intermediate 19B (200 mg, 0.58 mmol) in DMSO (3 mL) and the reaction was heated at 120° C. for 30 min by MWI. Water (40 mL) and brine (40 mL) were added and the mixture was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (2×40 mL), dried (MgSO4) and the solvent was removed under reduced pressure. Purification by flash chromatography (1:9 to 3:7 EtOAc:heptane) gave benzyl 3-[2-(cyclopropylamino)-6-fluoropyridin-3-yl]-1-ethylpyrazole-4-carboxylate as the first eluting regioisomer (colorless oil, 90 mg, 41%) followed by intermediate 30A as the second eluting regioisomer (white oil, 95 mg, 43%). Benzyl 3-[2-(cyclopropylamino)-6-fluoropyridin-3-yl]-1-ethylpyrazole-4-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.60(dd,J=9.9,8.2Hz,1H),7.40-7.23(m,5H),6.48(dd,J=8.2,1.9Hz,1 H),5.17(s,2H),4.19(q,J=7.2Hz,2H),1.41(t,J=7.3Hz,3H),0.73(td,J=6.8,4.6Hz,2H),0.58-0.37(m,2H). LRMS m / z:381.4[M+H] + Intermediate 30A: 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.81(t,J=8.3Hz,1H),7.45-7.25(m,5H),7.02(s,1H),6.24(dd,J=8.0,2.9H z,1H),5.18(s,2H),4.21(q,J=7.2Hz,2H),1.41(t,J=7.3Hz,3H),0.67(td,J=6.9,4.7Hz,2H),0.43-0.35(m,2H). LRMS m / z:381.3[M+H] + .

[0223] The following intermediate compounds were prepared by procedures similar to that used for Intermediate 30A, with variations to the reaction times and / or temperatures indicated: Intermediates 30N, 30O, 30P were prepared by conventional heating.

[0224] [Table 8]

[0225] [Table 9]

[0226] [Table 10]

[0227] 31A 5-(6-(cyclopropylamino)-2-fluoropyridin-3-yl)-1-ethyl-1H-pyrazole-4-carboxylic acid

[0228] [ka]

[0229] To a solution of intermediate 21C (231 mg, 0.730 mmol) in 1:1:1 MeOH:THF:water (3 mL) was added LiOH (140 mg, 5.850 mmol). The reaction mixture was heated to 50° C. and stirred for 2 h. HCl (1M aq, 5 mL) and CHCl (10 mL) were added, the phases were separated and the aqueous phase was extracted with 10% IPA / CHCl (5×10 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO) and the solvent was removed under reduced pressure to give a pale yellow solid (195 mg, 93%). LCMS (Method A) m / z 291.2 [M+H] at 1.03 min. + . 1H NMR(500MHz,DMSO-d6)δ12.10(s,1H),7.90(s,1H),7.63-7.56(m,1H),7.54(d,J=2.6Hz,1H),6.56(d,J=8.3 Hz,1H),3.95-3.90(m,2H),2.59-2.54(m,1H),1.26(t,J=7.2Hz,3H),0.78-0.71(m,2H),0.51-0.45(m,2H).

[0230] The following intermediate compounds were prepared by the same general procedure.

[0231] [Table 11]

[0232] [Table 12]

[0233] 32A 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxylic acid

[0234] [ka]

[0235] A solution of intermediate 30J (56 mg, 0.15 mmol) and LiOH (1 M aq, 1.2 mL, 1.2 mmol) in THF:MeOH (1:1; 6 mL) was heated at 55° C. for 4 h. The volatiles were removed under reduced pressure and the residue was acidified to pH ∼2 with HCl (1 M aq) 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 removed under reduced pressure to give a white solid (50 mg, 97%). 1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.95(s,1H),7.66-7.51(m,2H),6.57(d,J=8.2Hz,1H),4.21-4.07 (m,1H),3.95-3.81(m,2H),2.16-2.04(m,2H),1.85-1.63(m,2H),0.86-0.70(m,2H),0.64-0.41(m,2H). LCMS (Method C), m / z 1.60 min 347[M+H] + .

[0236] The following intermediate compounds were prepared by the same general procedure.

[0237] [Table 13]

[0238] [Table 14]

[0239] 33A 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxylic acid

[0240] [ka]

[0241] Palladium hydroxide on carbon (20 wt% loading, 50% water; 34.9 mg, 0.22 mmol) was added to a solution of Intermediate 35D (96 mg, 0.22 mmol) in ethanol (5 mL) in a pressure tube, the vessel was purged successively with N (5x) and hydrogen (5x), then stirred under H at 40 psi for 70 min. The reaction was diluted with CHCl (15 mL) and EtOH (5 mL), filtered through a glass microfiber pad, washed with CHCl, and the solvent removed under reduced pressure to give a white solid (58 mg, 76%). 1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.31(s,1H),7.60(dd,J=9.9,8.2Hz,1H),7.27(d,J=2.5Hz,1H),6.49(dd,J=8.2,1.9Hz,1H),4.44(dq, J=10.4,5.4Hz,1H),3.96(dt,J=11.7,3.2Hz,2H),3.45(td,J=11.5,3.5Hz,3H),1.99(q,J=4.4Hz,4H),0.84-0.69(m,2H),0.57-0.38(m,2H). LRMS m / z:347.5[M+H] +

[0242] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 33A.

[0243] [Table 15]

[0244] 34A tert-Butyl (6-(1-ethyl-4-(((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamoyl)-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)(methyl)carbamate

[0245] [ka]

[0246] HATU (28 mg, 0.074 mmol), NEt3 (20 μL, 0.143 mmol), then (S)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (18 mg, 0.072 mmol) were added to a solution of intermediate 31H in DMF (1 mL) and the reaction was stirred at rt for 16 h. Water (20 mL) was added and the resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in CHCl2 (10 mL) and passed through a phase separator containing brine (10 mL) and the solvent was removed under reduced pressure. Purification by flash chromatography [20-80% (10% MeOH / EtOAc) / isohexane] gave a white solid (35 mg, 81%). 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.8Hz,1H),8.27(s,1H),7.92(t,J=1.9H z,1H),7.62(ddd,J=8.6,7.2,1.6Hz,1H),7.55-7.48(m,1H),7.51-7.45(m,2H),7.48-7.41 (m,2H),7.32-7.26(m,2H),7.26-7.20(m,1H),6.80(dd,J=12.5,2.3Hz,1H),6.67(s,1H), 5.32(d,J=7.8Hz,1H),3.99(q,J=7.2Hz,2H),2.74(d,J=5.0Hz,3H),1.25(t,J=7.2Hz,3H). LCMS (Method B) m / z 498.2[M+H] at 3.49 min + .

[0247] 34B tert-Butyl N-ethyl-N-[6-[2-ethyl-4-[[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamoyl]pyrazol-3-yl]-5-fluoropyridin-3-yl]carbamate

[0248] [ka]

[0249] Prepared by a procedure similar to that described for Intermediate 34A.1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.8Hz,1H),8.27(s,1H),7.93(t,J=1.9Hz,1H) ,7.62(ddd,J=8.6,7.1,1.6Hz,1H),7.55-7.48(m,1H),7.51-7.45(m,2H),7.48-7.41(m,2H),7.3 2-7.26(m,2H),7.26-7.20(m,1H),6.81(dd,J=12.6,2.3Hz,1H),6.65-6.59(m,1H),5.32(d,J=7. 8Hz,1H),3.99(q,J=7.2Hz,2H),3.15-3.06(m,2H),1.25(t,J=7.2Hz,3H),1.17(t,J=7.1Hz,3H). LCMS (Method B) m / z 512.3[M+H] at 3.86 min + .

[0250] 35A Ethyl 3-ethoxy-1-ethylpyrazole-4-carboxylate

[0251] [ka]

[0252] K2CO3 (1.7 g, 12.3 mmol) followed by EtI (1 mL, 12.4 mmol) were added to a solution of ethyl 3-oxo-1,2-dihydropyrazole-4-carboxylate (0.9 g, 5.76 mmol) in MeCN (20 mL) and the reaction was heated at 60 °C over the weekend. The reaction was cooled to rt, filtered and washed with MeCN (2 x 20 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography (0-50% MTBE / isohexane) to give a colorless oil (943 mg, 39%). 1 Based on the H NMR δ pyrazole CH signal, a 1:1 mixture with the desired regioisomer ethyl 5-ethoxy-1-ethylpyrazole-4-carboxylate was obtained and used without further purification. 1H NMR(500MHz,CDCl3)δ7.71(s,1H),4.40-4.32(m,2H),4.32-4.24(m,2H),4.07-3.98(m,2H),1.51-1.43(m,6H),1.38-1.30(m,3H). LCMS(Method A) 213.5[M+H] in 1.08 minutes + .

[0253] 36A Ethyl 3-ethoxy-1-ethyl-5-(2-fluorophenyl)pyrazole-4-carboxylate

[0254] [ka]

[0255] A solution of crude intermediate 35A (300 mg, 1.41 mmol, ca. 50% purity) in anhydrous THF (4 mL) was degassed with N2. The solution was cooled to -78°C and LDA (2.0 M in THF; 0.9 mL, 1.8 mmol) was added followed by zinc(II) chloride (2-Me 2.0 M in THF; 0.9 mL, 1.8 mmol). The reaction mixture was warmed to rt and degassed with N2. 1-Bromo-2-fluorobenzene (0.19 mL, 1.74 mmol), Pd-170; 38 mg, 0.06 mmol) and XPhos (27 mg, 0.06 mmol) were added and the reaction mixture was evacuated and purged with N2, then heated to 70°C for 5 h. 1M aqueous HCl (30 mL) and EtOAc (30 mL) were added and the separated aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (0-50% MTBE / isohexane) gave a yellow gum (193 mg, 45%). 1H NMR(500MHz,CDCl3)δ7.50-7.42(m,1H),7.33-7.26(m,1H),7.26-7.20(m,1H),7.20-7.13(m,1H),4.38(q,J=7.0H z,2H),4.10-4.02(m,2H),3.86-3.77(m,2H),1.47(t,J=7.0Hz,3H),1.30(t,J=7.2Hz,3H),1.02(t,J=7.1Hz,3H). LCMS (Method A) 307.3[M+H] in 1.50 minutes + .

[0256] 37A Ethyl 5-(5-chloro-2-fluoropyridin-3-yl)-1-ethylpyrazole-4-carboxylate

[0257] [ka]

[0258] A solution of intermediate 1A (1 g, 5.95 mmol) in anhydrous THF (10 mL) was degassed with N2. The solution was cooled to -78 °C and LDA (2.0 M in THF; 3.4 mL, 6.8 mmol) was added followed by zinc(II) chloride (2-Me 2.0 M in THF; 3.4 mL, 6.8 mmol). The reaction was warmed to rt and degassed with N2. Pd(PPh3)4 (350 mg, 0.3 mmol) and 3-bromo-5-chloro-2-fluoropyridine (1.3 g, 6.18 mmol) were added and the reaction was evacuated and purged with N2, then heated to 70 °C overnight. 1M aqueous HCl (50 mL) and EtOAc (50 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (0-10% MTBE / isohexane) gave a yellow gum (1.2 g, 68%). 1H NMR(500MHz,CDCl3)δ8.33-8.28(m,1H),8.05(s,1H),7.83-7.77(m,1H),4.21 -4.13(m,2H),4.04-3.98(m,2H),1.41(t,J=7.2Hz,3H),1.19(t,J=7.1Hz,3H). LCMS (Method A) 298.3[M+H] in 1.36 min + .

[0259] 38A Ethyl (E)-2-(4-bromo-2-fluorobenzoyl)-3-(dimethylamino)prop-2-enoate

[0260] [ka]

[0261] DMF (0.07 mL, 0.91 mmol) and thionyl chloride (1.67 mL, 22.8 mmol) were added to a suspension of 4-bromo-2-fluorobenzoic acid (1 g, 4.57 mmol) in toluene (13 mL). The mixture was heated at 110° C. for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and NEt3 (0.96 mL, 6.85 mmol) was added followed by dropwise addition of ethyl-N,N-dimethylaminoacrylate (0.65 mL, 4.57 mmol). The reaction was heated to reflux for 2 h, cooled to rt and water and EtOAc (30 mL each) were added. The mixture was extracted with EtOAc (3×30 ml) and the combined organics were washed with water (30 mL), brine (30 mL) and dried (N a 2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10-100% EtOAc / heptane) gave a yellow oil (1.16 g, 74%). 1 H NMR(700MHz,DMSO-d6)δ7.75(s,1H),7.53(dd,J=9.8,1.8Hz,1H),7.43(dd,J=8.2,1.8H z,1H),7.37(d,J=7.9Hz,1H),3.87(q,J=7.1Hz,2H),2.77(s,3H),0.89(t,J=7.1Hz,3H). LRMS m / z 343.9 / 345.9[M+H]+ .

[0262] The following intermediate compounds were prepared using the same general procedure as described for Intermediate 38A.

[0263] [Table 16]

[0264] 39A Ethyl 5-(4-bromo-2-fluorophenyl)-1-(oxan-4-yl)pyrazole-4-carboxylate

[0265] [ka]

[0266] Tetrahydro-2H-pyran-4-ylhydrazine hydrochloride (377 mg, 2.47 mmol) and NEt3 (0.34 mL, 2.47 mmol) were added to a cooled (0 °C) suspension of Intermediate 38A (850 mg, 2.47 mmol) in EtOH (25 mL). The mixture was warmed to rt over 10 min, stirred at rt for 16 h, then heated at 40 °C for 3 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (10-50% EtOAc / heptane) to give a colorless oil (833 mg, 84%). 1 H NMR(700MHz,DMSO-d6)δ8.05(s,1H),7.77(dd,J=9.3,1.9Hz,1H),7.59(dd,J=8.2,1.9Hz,1H),7.46(t,J=8.0Hz,1H),4.14-3.9 9(m,3H),3.92-3.83(m,2H),3.36-3.29(m,2H),2.14-2.02(m,2H),1.85-1.76(m,1H),1.68-1.58(m,1H),1.06(t,J=7.1Hz,3H). LRMS m / z:397.6 / 399.7[M+H] + .

[0267] 39B Ethyl 5-(6-bromo-2-fluoropyridin-3-yl)-1-(oxan-4-yl)pyrazole-4-carboxylate

[0268] [ka]

[0269] NEt3 (0.25 mL, 1.8 mmol) was added to a suspension of tetrahydro-2H-pyran-4-ylhydrazine hydrochloride (274 mg, 1.80 mmol) in CH2Cl2 (20 mL) and the reaction was stirred at rt for 2 h. The reaction was concentrated under reduced pressure and placed under N2. Intermediate 38B (620 mg, 1.8 mmol) in EtOH (20 mL) was added and the mixture was stirred at rt for 18 h and then heated at 40 °C for 3 h. The mixture was concentrated under reduced pressure and purified by flash chromatography (10-50% EtOAc / heptane) to give an off-white solid (340 mg, 48%). 1 H NMR(400MHz,DMSO-d6)δ8.13-8.04(m,2H),7.84(dd,J=7.8,1.1Hz,1H),4.31-4.17(m,1H),4.14-4.01(m,2H),3.94-3. 79(m,2H),3.40-3.34(m,2H),2.15-1.99(m,2H),1.84(d,J=12.7Hz,1H),1.66(d,J=12.7Hz,1H),1.07(t,J=7.1Hz,3H). LRMS m / z:398.1 / 400.0[M+H] + .

[0270] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 39B.

[0271] [Table 17]

[0272] 39E Ethyl 5-(2,6-difluoropyridin-3-yl)-1-(1-methylpiperidin-4-yl)pyrazole-4-carboxylate

[0273] [ka]

[0274] A solution of 4-hydrazino-1-methylpiperidine (450 mg, 3.48 mmol) and Intermediate 38D (990 mg, 3.48 mmol) in EtOH (30 mL) was stirred at rt for 44 h. The reaction was concentrated under reduced pressure and purified by flash chromatography [0-60% (EtOH:CH2Cl2:NH4OH; 50:8:1) in CHCl2] to give a yellow oil (480 mg, 39%). 1 H NMR(400MHz,DMSO-d6)δ8.33(q,J=8.2Hz,1H),8.07(s,1H),7.39(dd,J=8.1,2.4Hz,1H),4.16-4.01(m,2H),3.96-3.78( m,1H),2.90-2.70(m,2H),2.13(s,3H),2.12-1.95(m,2H),1.94-1.78(m,3H),1.73-1.60(m,1H),1.05(t,J=7.1Hz,3H). LRMS m / z:351.3[M+H] + .

[0275] 39F Ethyl 5-(4-bromo-2-fluorophenyl)-1-(1-methylpiperidin-4-yl)pyrazole-4-carboxylate

[0276] [ka]

[0277] Prepared by a procedure similar to Intermediate 39E from Intermediate 38A and 4-hydrazino-1-methylpiperidine dihydrochloride. 1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.80(dd,J=9.3,1.9Hz,1H),7.61(dd,J=8.2,1.9Hz,1H),7.48(t,J=8.0Hz,1H), 4.16-3.94(m,3H),3.25-3.08(m,3H),2.32-2.15(m,2H),2.08-1.88(m,1H),1.88-1.73(m,1H),1.07(t,J=7.1Hz,3H). LRMS m / z:410.4 / 412.4[M+H] + .

[0278] 40A Ethyl 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-ethylpyrazole-4-carboxylate

[0279] [ka]

[0280] A reaction vessel was charged with Pd-170 (20 mg, 0.030 mmol), K2CO3 (209 mg, 1.51 mmol) and potassium cyclopropyltrifluoroborate (90 mg, 0.61 mmol). The vessel was evacuated and purged with N2, then a solution of Intermediate 37A (150 mg, 0.50 mmol) in THF:water (1:1, 2 mL) was added. The reaction mixture was sparged with N2 and then heated to 70 °C overnight. Water (50 mL) and EtOAc (50 mL) were added and the separated aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (0-10% MTBE / isohexane) afforded a pale yellow oil (98 mg, 61%). 1H NMR(500MHz,CDCl3)δ8.14-8.10(m,1H),8.04(s,1H),7.42(dd,J=8.6,2.6Hz,1H),4.15(q,J=7.1Hz,2H),4.02- 3.95(m,2H),2.01-1.92(m,1H),1.39(t,J=7.2Hz,3H),1.18-1.15(m,3H),1.10-1.06(m,2H),0.75-0.72(m,2H). LCMS (Method A) 304.3[M+H] in 1.37 minutes + .

[0281] 40B Ethyl 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)pyrazole-4-carboxylate

[0282] [ka]

[0283] A solution of intermediate 39C (300 mg, 0.75 mmol) in toluene (3 mL) and water (0.3 mL) was degassed with N2 for 15 min. K2CO3 (312 mg, 2.26 mmol) and potassium cyclopropyltrifluoroborate (167 mg, 1.13 mmol) were added, followed by RuPhos (35.1 mg, 0.08 mmol) and Pd(OAc)2 (10.2 mg, 0.05 mmol). The vial was sealed and heated at 100 °C for 2 h and then at 80 °C overnight. The mixture was sparged with N2 for 15 min, additional Pd(OAc)2 (5.1 mg, 0.02 mmol) and RuPhos (17.6 mg, 0.04 mmol) were added, and the reaction was heated at 100 °C for 4 h. After cooling to rt, the reaction was diluted with CH2Cl2 (20 mL), filtered through a pad of Celite, and washed with CH2Cl2 (2 x 15 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10-50% EtOAc / heptane) afforded a colorless oil (85 mg, 31%). LRMS m / z: 360.3 [M+H] + .TLC R f =0.23(2:1 EtOAc / heptane).

[0284] 40C Ethyl 5-(2-fluoro-4-prop-1-en-2-ylphenyl)-1-(oxan-4-yl)pyrazole-4-carboxylate

[0285] [ka]

[0286] A solution of intermediate 39A (120 mg, 0.3 mmol) in toluene (1.5 mL) and water (0.1 mL) was degassed with N2 for 15 min. Potassium trifluoro(prop-1-en-2-yl)borate (67 mg, 0.45 mmol) was added followed by K2CO3 (125 mg, 0.91 mmol), RuPhos (14.1 mg, 0.03 mmol) and Pd(OAc)2 (4.1 mg, 0.02 mmol) and the reaction was heated at 100 °C for 6 h. Upon cooling to rt, the mixture was diluted with CHCl2 (10 mL) and filtered through a pad of Celite, washing with CHCl2 (3 x 10 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography (10-50% EtOAc / heptane) to give a yellow solid (92 mg, 85%). LRMS m / z: 359.2 [M+H] + .TLC R f =0.63(1:1 EtOAc / heptane).

[0287] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 40C.

[0288] [Table 18]

[0289] 41A Ethyl 5-(2-fluoro-4-propan-2-ylphenyl)-1-(oxan-4-yl)pyrazole-4-carboxylate

[0290] [ka]

[0291] A solution of intermediate 40C (92 mg, 0.26 mmol) in EtOH (10 mL) in a pressure tube was evacuated and filled with N2 (3x). Pd / C (10 wt% loading; 27.3 mg, 0.26 mmol) was added and the reaction was stirred under H2 (20 psi) at rt for 2 h. The mixture was filtered, washed with EtOH (2x10 mL) and CHCl2 (2x10 mL) and the filtrate was concentrated under reduced pressure to give a colorless oil (70 mg, 76%). LRMS m / z: 361.1 [M+H] + .TLC R f =0.63(1:1 EtOAc / heptane).

[0292] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 41A.

[0293] [Table 19]

[0294] Working Example 1. 1-Ethyl-5-[2-fluoro-6-(methylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide

[0295] [ka]

[0296] NEt3 (15 μL, 0.108 mmol), HATU (22 mg, 0.058 mmol) and then (S)-3-amino-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (14 mg, 0.056 mmol) were added to a solution of intermediate 31E (14 mg, 0.056 mmol) in DMF (1 mL). The reaction mixture was stirred at rt overnight. Water (20 mL) was added and the precipitate was collected by filtration and washed with water. The precipitate was taken up in CHCl (10 mL), passed through a phase separator containing brine (10 mL) and the solvent was removed under reduced pressure. Purification by flash chromatography [0-60% (10% MeOH / EtOAc) / isohexane] gave a white solid (21 mg, 76%). 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.82(d,J=8.0Hz,1H),8.37(s,1H),7 .62(ddd,J=8.6,7.2,1.6Hz,1H),7.56-7.47(m,3H),7.47-7.41(m,3H),7.32 -7.26(m,2H),7.27-7.19(m,2H),6.38(dd,J=8.2,1.8Hz,1H),5.34(d,J=7.9 Hz,1H),3.92(q,J=7.2Hz,2H),2.76(d,J=4.8Hz,3H),1.26(t,J=7.2Hz,3H). LCMS (Method B) m / z 498.2[M+H] in 3.52 minutes + .

[0297] The following compounds of the invention were prepared by the amide coupling procedure described for the compound of Example 1 using (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one or (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one.

[0298] Compound prepared by amide coupling in Example 1.

[0299] [ka]

[0300]

Table 20

[0301]

Table 21

[0302]

Table 22

[0303]

Table 23

[0304]

Table 24

[0305]

Table 25

[0306]

Table 26

[0307]

Table 27

[0308]

Table 28

[0309]

Table 29

[0310] [Table 30]

[0311] [Table 31]

[0312] 38. 1-Ethyl-5-(3-fluoro-5-(methylamino)pyridin-2-yl)-N-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-1H-pyrazole-4-carboxamide

[0313] [ka]

[0314] HCl (4.0M in dioxane; 50 μL, 0.200 mmol) was added to a solution of intermediate 34A (30 mg, 0.050 mmol) in CHCl (1 mL) and stirred at rt. After 1 h, additional HCl (4.0M in dioxane; 200 μL, 0.800 mmol) was added and the reaction was stirred at rt over the weekend. The reaction was partitioned between CHCl (10 mL) and saturated aqueous NaHCO (10 mL), separated and the aqueous phase extracted with CHCl (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO) and the solvent removed under reduced pressure. Purification by flash chromatography [50-100% (10% MeOH / EtOAc) / isohexane] gave a white solid (14 mg, 56%). 1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.8Hz,1H),8.27(s,1H),7.92(t,J=1.9H z,1H),7.62(ddd,J=8.6,7.2,1.6Hz,1H),7.55-7.48(m,1H),7.51-7.45(m,2H),7.48-7.41 (m,2H),7.32-7.26(m,2H),7.26-7.20(m,1H),6.80(dd,J=12.5,2.3Hz,1H),6.67(s,1H), 5.32(d,J=7.8Hz,1H),3.99(q,J=7.2Hz,2H),2.74(d,J=5.0Hz,3H),1.25(t,J=7.2Hz,3H). LCMS (Method B) m / z 498.2[M+H] at 3.49 min + .

[0315] 39. 1-Ethyl-5-[5-(ethylamino)-3-fluoropyridin-2-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide

[0316] [ka]

[0317] Prepared from Intermediate 34B by a procedure similar to that described for Example 38 compound. 1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.8Hz,1H),8.27(s,1H),7.93(t,J=1.9Hz,1H) ,7.62(ddd,J=8.6,7.1,1.6Hz,1H),7.55-7.48(m,1H),7.51-7.45(m,2H),7.48-7.41(m,2H),7.3 2-7.26(m,2H),7.26-7.20(m,1H),6.81(dd,J=12.6,2.3Hz,1H),6.65-6.59(m,1H),5.32(d,J=7. 8Hz,1H),3.99(q,J=7.2Hz,2H),3.15-3.06(m,2H),1.25(t,J=7.2Hz,3H),1.17(t,J=7.1Hz,3H). LCMS (Method B) m / z 512.3[M+H] at 3.86 min + .

[0318] 56. 5-[6-(cyclopropylamino)pyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide

[0319] [ka]

[0320] A solution of intermediate 30O (296 mg, 0.83 mmol) and LiOH (1 M aq, 6.64 mL, 6.64 mmol) in THF:MeOH (16 mL) was heated at 55° C. for 3 h. The reaction was cooled to rt, acidified (pH approx. 2) with 1 M aq HCl, and the solvent was removed under reduced pressure. The residue was suspended in DMF (6 mL), then DIPEA (0.23 mL, 1.33 mmol) and HATU (278 mg, 0.732 mmol) were added and the reaction was stirred at rt for 10 min. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (179 mg, 0.67 mmol) was added and the reaction was stirred at rt for 4 h. The mixture was poured into water (50 mL) and the resulting precipitate was collected by filtration and washed with water (2×15 mL). The precipitate was dissolved in CH2Cl2 (50 mL), dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (EtOAc) to give a white solid (105 mg, 27%). 1 H NMR(600MHz,DMSO-d6)δ10.79(s,1H),8.66(d,J=7.8Hz,1H),8.33(s,1H),8.02-7. 93(m,1H),7.60-7.49(m,4H),7.51-7.41(m,3H),7.32-7.25(m,1H),7.17-7.09(m, 2H),6.65(d,J=8.6Hz,1H),5.38(d,J=7.7Hz,1H),4.20-4.11(m,1H),3.95-3.85(m ,2H),2.18-2.06(m,2H),1.81-1.72(m,2H),0.74-0.62(m,2H),0.48-0.33(m,2H). LRMS m / z:580.1[M+H] +

[0321] The following compounds of the invention were prepared by procedures similar to those described for the compound of Example 56.

[0322] Compound prepared by amide coupling in Example 56.

[0323] [ka]

[0324] [Table 32]

[0325] Example 60: In vitro efficacy Compounds were subjected to an RSV plaque reduction assay according to the following protocol.

[0326] Plaque reduction assay. Hep-G2 cells (ECACC, 85011430) were passaged in flasks and seeded in 24-well plates in DMEM supplemented with 10% FBS containing antibiotics. During inoculation and subsequent incubation, cells were cultured in DMEM containing 2% FBS. 100 plaque-forming units of RSV (RSV A2 ECACC, 0709161v) per well were mixed with 8 serial dilutions of compound. 100 μL of virus / compound mixture was subsequently added to the confluent Hep-G2 cell monolayer. The cells and virus / compound mixture were incubated for 2 hours at 37° C. in a humidified 5% CO2 incubator before removal of the inoculum and addition of 1 mL of overlay (DMEM containing 2% FBS and 0.8% CMC) containing compound dilutions. The cells and were incubated for 2 days at 37° C. in a humidified 5% CO2 incubator.

[0327] Cells were washed with PBS for 3 min before adding 75 / 25% v / v EtOH / MeOH. Fixative was removed and plates were washed with PBS. A pre-titrated amount of primary antibody was added in 200 μL PBS / 2% dry milk and plates were incubated for 90 min at 37°C. Plates were washed 3 times with PBS / 0.05% Tween20 and incubated for 1 h at 37°C before the addition of rabbit anti-goat horseradish peroxidase in 200 μL PBS / 2% dry milk. Following three washing steps with PBS / 0.05% Tween20, 200 μL of ready-to-use TrueBlue was added and plates were incubated for 10-15 min at rt before washing with water. After removal of water, plates were air-dried in the dark.

[0328] 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 % infection relative to the average plaque counts in virus control wells for RSV. EC 50 Values ​​were calculated as 50% reduction in signal, respectively, by interpolation of inhibition curves fitted to a 4-parameter nonlinear regression with variable slope in Dotmatics. 50 and cytotoxic CC 50 Values ​​are the average of at least two experiments and numbers are rounded to the nearest whole unit.

[0329] result

[0330] [Table 33]

[0331] [Table 34]

[0332] Example 61: In vitro pharmacokinetics Compounds were subjected to the following assays to investigate liver microsomal stability, permeability and plasma protein binding.

[0333] Microsomal incubation: Experimental procedure Pooled liver microsomes were purchased from a reliable commercial supplier and stored at -80°C prior to use. Microsomes (final protein concentration 0.5mg / mL), 0.1M phosphate buffer pH 7.4 and test compound (final substrate concentration 1μM; final DMSO concentration 0.25%) were pre-incubated at 37°C before the addition of NADPH (final concentration 1mM) to initiate the reaction. The final incubation volume was 50μL. A control incubation was included for each tested compound, in which 0.1M phosphate buffer pH 7.4 was added instead of NADPH (minus NADPH). Two control compounds were included for each species. All incubations were performed singly for each test compound. Each compound was incubated for 0, 5, 15, 30 and 45 minutes. The control (minus NADPH) was incubated for 45 minutes only. Reactions were terminated at the appropriate time points by transferring the incubations into acetonitrile in a 1:3 ratio. The terminated plates were centrifuged at 3,000 rpm for 20 min at 4° C. to precipitate the proteins. Following protein precipitation, sample supernatants were combined in cassettes of up to four compounds, internal standards were added, and samples were analyzed by LC-MS / MS. The slope of the line was determined from a plot of the ln peak area ratio (compound peak area / internal standard peak area) versus time. The half-life (t 1 / 2 ) and intrinsic clearance (CL int ) was calculated. Compounds with low clearance (>80% remaining at 45 min) under the assay conditions were 1 / 2 Shown as >140 minutes.

[0334] result

[0335] [Table 35]

[0336] Hepatocyte incubation: experimental procedure Cryopreserved pooled hepatocytes were purchased from a reliable commercial supplier and stored in liquid nitrogen prior to use. Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES and test compounds (final substrate concentration 3 μM; final DMSO concentration 0.25%) was incubated with a suspension of cryopreserved hepatocytes (final cell density 0.5 × 10 in Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES). 6 The reaction is initiated by pre-incubation at 37°C prior to the addition of 100 ng / mL (viable cells). The final incubation volume is 500 μL. Two control compounds were included in each species along with the appropriate vehicle control. The reaction is stopped at the appropriate time points by transferring 50 μL of the incubation into 100 μL of acetonitrile containing the internal standard. Samples were removed at six time points (0, 5, 15, 30, 45 and 60 min) over the course of a 60 min experiment. The stopped plate was centrifuged at 2500 rpm at 4°C for 30 min to precipitate proteins. Following protein precipitation, sample supernatants were combined in cassettes of up to four compounds and analyzed using generic LC-MS / MS conditions. From a plot of the ln peak area ratio (compound peak area / internal standard peak area) versus time, the slope of the line is determined. Subsequently, the half-life (t 1 / 2 ) and intrinsic clearance (CL int ) was calculated. Compounds with low clearance (>80% remaining at 60 min) under the assay conditions were 1 / 2 Shown as >186 minutes.

[0337] result

[0338] [Table 36]

[0339] Example 62: In vivo pharmacokinetics The pharmacokinetics of the compound was studied in vivo in rats at doses of 1 mg / kg (IV) and 10 mg / kg (PO).

[0340] Pharmacokinetics in rats method Male rats (Sprague Dawley) surgically prepared with a jugular cannula were treated with experimental compounds via intravenous administration (IV; n=3; 1 mg / kg) or oral administration (PO; n=3; 10 mg / kg). Compounds were formulated as a solution in 40:60 dimethylacetamide:saline (IV administration), 1% methylcellulose in water (viscosity: 15 cP), a suspension in 0.1% Tween 80 (PO administration: Example 3), a solution in 10% DMSO / 10% Cremaphor / 80% water (PO administration: Examples 4, 11, 21, 23, 25, 26, 32) or a solution in 10% DMSO / 20% Cremaphor / 70% water (PO administration: Examples 19, 20, 22, 24, 30). Animals were observed for any obvious clinical signs or symptoms. Serial blood samples were collected via cannula at 0.02, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after IV administration of compound and 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration of compound, and plasma was prepared by centrifugation and immediately stored at -80°C. Samples were subsequently thawed and prepared for analysis by protein precipitation with acetonitrile and analyzed by tandem LCMS with electrospray ionization using a matrix-matched calibration curve. PK parameters were calculated from the resulting data.

[0341] result

[0342] [Table 37]

[0343] [Table 38]

[0344] Dog Pharmacokinetics The pharmacokinetics of the compounds of the invention were studied in vivo in dogs.

[0345] method Male beagle dogs were treated with experimental compounds via intravenous (n=2; 0.5 mg / kg) or oral administration (n=2; 3 mg / kg or 4 mg / kg). Compounds were formulated as a solution in 20% dimethylacetamide / 80% (2-hydroxypropyl)-β-cyclodextrin (20% w / v) (IV administration) or 10% dimethylacetamide / 90% (2-hydroxypropyl)-β-cyclodextrin (20% w / v) (PO administration). Animals were observed for any overt clinical signs or symptoms. Serial blood samples were collected from the jugular vein at 0.03, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after IV administration of compound and at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration of compound, and plasma was prepared by centrifugation and immediately stored at -80°C. Samples were subsequently thawed and prepared for analysis by protein precipitation with acetonitrile and analyzed by tandem LCMS with electrospray ionization using a matrix-matched calibration curve. PK parameters were calculated from the resulting data.

[0346] result

[0347] [Table 39]

[0348] Example 63: Aqueous Formulation The compound of Example 1 is formulated as a solution in 30% w / v captisol (ie, sulfobutylether-beta-cyclodextrin) at pH 4 according to the following procedure.

[0349] A 30% w / v captisol (i.e., sulfobutylether-beta-cyclodextrin) carrier is prepared by weighing the required amount of captisol into a suitable container, adding approximately 80% of the final volume of water, and magnetically stirring until a solution is formed. The carrier is then made up to volume with water.

[0350] An aqueous solution of the compound of Example 1 is prepared by weighing 175 mg of the compound into a suitable container and adding about 80% of the required volume of carrier. The pH is adjusted to pH 2 using an aqueous solution of hydrochloric acid, and the resulting mixture is magnetically stirred until a solution is formed. The formulation is then made up to volume with carrier, and the pH is adjusted to pH 4 using an aqueous solution of sodium hydroxide.

[0351] Example 64: Tablet Composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention, are prepared as follows.

[0352] [Table 40]

[0353] The compound of the invention, lactose and half of the cornstarch are mixed. The mixture is then passed through a sieve with a mesh size of 0.5 mm. Cornstarch (10 g) is suspended in warm water (90 mL). The resulting paste is used to granulate the powder. The granules are dried and crushed into small fragments 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.

[0354] Example 65: Injection formulation

[0355] [Table 41]

[0356] A compound of the invention is dissolved in most of the water (35° C.-40° C.) and the pH adjusted to between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as necessary. The batch is then made up to volume with water, filtered through a sterile fine pore filter into a sterile 10 mL amber glass vial (Type 1) and sealed with a sterile closure and overseal.

[0357] Example 66: Intramuscular injection

[0358] [Table 42]

[0359] The compound of the present invention is dissolved in glycofurol. Benzyl alcohol is then added and dissolved, and water is added to 3 mL. The mixture is then filtered through a sterile fine pore filter and sealed in a sterile 3 mL glass vial (type 1).

[0360] Example 67: Syrup formulation

[0361] [Table 43]

[0362] The compound of the present invention is dissolved in a mixture of glycerol and purified water in large part. An aqueous solution of sodium benzoate is then added to the solution, followed by a sorbital solution and finally flavoring. Make up to volume with purified water and mix well.

Claims

1. 1-ethyl-5-[2-fluoro-6-(methylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[2-fluoro-6-(cyclopropylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclobutylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[2-fluoro-6-[(1-methylcyclopropyl)amino]pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[5-(cyclopropylamino)-3-fluoropyridin-2-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[3-fluoro-5-(propan-2-ylamino)pyridin-2-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[2-fluoro-4-(propan-2-ylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-3-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[5-(cyclopropylamino)-3-fluoropyridin-2-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-[5-(ethylamino)-3-fluoropyridin-2-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-cyclopropyl-5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-cyclopropyl-5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-propan-2-ylpyrazole-4-carboxamide; 1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[3-fluoro-5-(propan-2-ylamino)pyridin-2-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-3-[2-fluoro-6-(propylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-[2-fluoro-6-(propylamino)pyridin-3-yl]pyrazole-4-carboxamide; 1-tert-butyl-3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-tert-butyl-3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)-1H-pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; (3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(4,4-difluorocyclohexyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(4,4-difluorocyclohexyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-1-(oxetan-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 1-ethyl-5-(3-fluoro-5-(methylamino)pyridin-2-yl)-N-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-1H-pyrazole-4-carboxamide; 1-ethyl-5-(5-(ethylamino)-3-fluoropyridin-2-yl)-N-((S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-1H-pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]-1-(oxetan-3-yl)pyrazole-4-carboxamide; 5-[6-(ethylamino)-2-fluoropyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-cyclopropyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-cyclopropyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(2-fluoro-4-propan-2-ylphenyl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(6-cyclopropyl-2-fluoropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(5-cyclopropyl-2-fluoropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(oxan-4-yl)pyrazole-4-carboxamide; 5-(6-ethyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(6-ethyl-2-fluoropyridin-3-yl)-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-ethoxy-1-ethyl-5-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 3-ethoxy-1-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-(2-fluorophenyl)pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)pyridin-3-yl]-1-(oxan-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-1-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide; 1-(oxan-4-yl)-5-[6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; 5-(4-ethyl-2-fluorophenyl)-1-(1-methylpiperidin-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazole-4-carboxamide; or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising a compound as defined in claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or diluent.

3. 3. A pharmaceutical composition as defined in claim 2 for use in the treatment or prevention of an RSV infection.

4. (a) a compound as defined in claim 1 or a pharma- ceutically acceptable salt thereof; and (b) one or more additional therapeutic agents; 23. A product for simultaneous, separate or sequential use in the treatment of a subject suffering from or susceptible to RSV infection, comprising:

5. Further treatments include: (i) RSV nucleocapsid (N)-protein inhibitors; (ii) a protein inhibitor; (iii) an anti-RSV monoclonal antibody; (iv) immunomodulatory toll-like receptor compounds; (v) respiratory virus antivirals; and / or (vi) anti-inflammatory compounds 5. The product of claim 4,

6. A pharmaceutical composition as defined in claim 3 for use in combination with one or more further therapeutic agents as defined in claim 5.

7. 10. A pharmaceutical composition comprising: (a) a compound as defined in claim 1 or a pharma- ceutically acceptable salt thereof; and (b) one or more further therapeutic agents as defined in claim 5, together with a pharma- ceutically acceptable carrier or diluent.

8. 13. A method for preparing a pharma- ceutically acceptable salt as defined in claim 1, the method comprising treating a compound as defined in claim 1 with a suitable acid in a suitable solvent.

9. 9. The method of claim 8, wherein the acid is selected from 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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