Benzodiazepine derivatives useful in treating respiratory syncytial virus infections
Novel benzodiazepine derivatives with specific structural features offer potent anti-RSV activity and good pharmacokinetics, addressing the limitations of current treatments and expanding therapeutic access for RSV infections.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- Filing Date
- 2021-07-07
- Publication Date
- 2026-04-06
AI Technical Summary
There is a need for compounds with potent anti-RSV activity and good pharmacokinetic properties to address the limitations of current anti-RSV treatments, particularly for individuals beyond high-risk groups.
Development of a novel series of benzodiazepine derivatives with potent anti-RSV activity and favorable pharmacokinetic properties, characterized by specific structural formulas and substituent groups, including benzodiazepinyl-containing groups and various heteroaryl or heterocyclyl moieties, which can form morpholine or spiro rings.
The benzodiazepine derivatives exhibit effective antiviral activity against RSV with desirable pharmacokinetic properties, providing a broader therapeutic option for RSV infections beyond high-risk groups.
Smart Images
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Abstract
Description
[Technical Field]
[0001] This invention relates to benzodiazepine derivatives and their use in treating or preventing respiratory syncytial virus (RSV) infection. [Background technology]
[0002] RSV is a paramyxoviridae negative sense, single-stranded RNA virus. RSV is readily transmitted via surface migration or hand-to-hand transfer through secretions from infected individuals. Unlike influenza, RSV is not transmitted by small aerosol particles. After successful inoculation, the incubation period is between 4 and 6 days, during which the virus spreads from the nasopharynx to the lower respiratory tract by infected cells lysing uninfected cells and necrotic epithelium forming rot. In infants, coupled with increased mucus secretions and edema, the virus can cause mucous obstruction, leading to excessive swelling and collapse of peripheral 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 consists of mononuclear cells, with bronchiolar, bronchiolian, and alveolar involvement more commonly occurring. The duration and extent of viral shedding have been found to correlate with clinical signs and disease severity.
[0003] RSV is a leading cause of serious respiratory infections in infants and young children worldwide. The highest disease states and mortality rates occur in infants and young children born prematurely and those with chronic lung or heart disease, although many infants hospitalized with RSV infection are otherwise healthy. Severe RSV infection in infancy can lead to recurrent wheezing for several years and may be linked to the development of asthma later in life.
[0004] RSV is also a leading cause of pathological conditions and mortality in the elderly, immunocompromised children and adults, and those with chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).
[0005] RSV has a seasonal incidence; however, RSV is highly predictable, occurring in winter in both hemispheres, namely from September to May in Europe and North America, peaking in December and January, and potentially occurring year-round in tropical countries. RSV affects >90% of infants and young children by the age of two, and innate immunity is short-lived, with many experiencing reinfection every year. Similar to influenza, in older adults, RSV accounts for approximately 10% of winter hospitalizations and has a 10% mortality rate.
[0006] Current anti-RSV treatments include the use of a monoclonal antibody against RSV called palivizumab. Such use of palivizumab is more of a preventative treatment than a therapeutic one for RSV. While this antibody is often effective, its use is limited to premature infants and high-risk infants. In practice, its limited usefulness means it is unavailable to many people who need anti-RSV treatment. Therefore, there is an urgent need for an effective alternative to existing anti-RSV treatments.
[0007] Small molecules have been proposed as inhibitors of RSV. These include benzimidazoles and benzodiazepines. For example, the discovery and initial development of RSV604, a benzodiazepine compound with submicromolar anti-RSV activity, is described in Antimicrobial Agents and Chemotherapy, September 2007, pp. 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.). [Overview of the project] [Problems that the invention aims to solve]
[0008] There is a need to identify further compounds having anti-RSV activity, particularly compounds having a combination of potent antiviral activity and good pharmacokinetic properties.
Means for Solving the Problem
[0009] A novel series of benzodiazepine derivatives has now been found to have potent anti-RSV activity along with good pharmacokinetics and good physicochemical properties. Accordingly, the present invention provides a benzodiazepine derivative of formula (Ie):
[0010]
Chemical formula
[0011] [wherein, R 1 and R 2 one of which is a benzodiazepinyl-containing group of formula (II):
[0012]
Chemical formula
[0013] and R 8 is H or halo, R 1 and R 2 the other of which is a Z group selected from H, C3-C_{6} cycloalkyl, halo, -NHR 9 , benzyl, phenyl, 4- to 10-membered heterocyclyl and 4- to 10-membered heteroaryl, wherein phenyl, heterocyclyl and heteroaryl are unsubstituted or are selected from 4- to 10-membered heterocyclyl (unsubstituted or substituted with OR), and C1-C_{6} alkyl, C_{1}-C_{6} hydroxyalkyl, C_{1}-C_{6} haloalkyl, C_{3}-C_{6} cycloalkyl, halo, -OR, -(CH_{2}) m OR, -NR_{2}, -(CH_{2}) m NR_{2}, -NHR'', -SO m NR_{2}, -SO mR, -SR, Nitro, -CO2R, -CN, -CONR2, -NHCOR, -CH2NR 10 R 11 and -NR 10 R 11 It is substituted with one or two substituents selected from, where each R is independently H or C1-C6 alkyl, R'' is C3-C6 cycloalkyl, and m is 1 or 2. R 9 The compounds are selected from phenyl and 4- to 10-membered heteroaryls, and the phenyl and heteroaryls are either unsubstituted or substituted with a halo. R 10 and R 11 Each of these is independently either H or a C1-C6 alkyl group, or R 10 and R 11 These, together with the N atoms to which they are attached, form (a) a morpholine ring optionally bridged by a -CH2- group linking two ring carbon atoms arranged in para with each other, or (b) a spiro group of formula (b) below:
[0014] [ka]
[0015] Forming one of the following, Ring A has the following structural formulas (I-1), (I-2), and (I-3):
[0016] [ka]
[0017] It is one of the rings, where Y is selected from O, S, SO2 and NR, and R is as defined above, R 2 ~R 7 Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halo, -OR, -CH2OR, -NR2, -CH2NR 12 R 13-NRCOOR, -CH2OR, -SO m NR2, -SO m R, -CH2SO m R is nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, 12 and R 13 Each of these is independently either H, C1-C6 alkyl, benzyl, 4-10 membered heterocycline, or R 12 and R 13 These, together with the N atom to which they are attached, form an unsubstituted 4-10 membered heteroaryl or 4-10 membered heterocycline (unsubstituted or substituted with C1-C6 alkyl or halo), or R bonded to the same carbon atom. 2 ~R 7 Any two of these are a C3-C6 cycloalkyl spiro ring and a spirooxetane ring with the following structure:
[0018] [ka]
[0019] [Forms a spiro ring selected from] The present invention provides a compound or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a benzodiazepine derivative of formula (I):
[0020] [ka]
[0021] [In the formula, R 1 and R 2 One of them is the benzodiazepinyl-containing group of formula (II):
[0022] [ka]
[0023] And R8 is H or halo, R 1 and R 2 The other side consists of H, C3-C6 cycloalkyl, -NHR 9 The Z group is selected from phenyl and 4-10 membered heteroaryl groups, where phenyl and heteroaryl groups are unsubstituted or C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halo, -OR, -NHR'', -SO m NR2, -SO m R, Nitro, -CO2R, -CN, -CONR2, -NHCOR, and -NR 10 R 11 It is substituted with one or two substituents selected from, where each R is independently H or C1-C6 alkyl, R'' is C3-C6 cycloalkyl, and m is 1 or 2. R 9 These are selected from phenyl and 4-10 member heteroaryls. R 10 and R 11 Each of these is independently either H or a C1-C6 alkyl group, or R 10 and R 11 These, together with the N atoms to which they are attached, form (a) a morpholine ring optionally bridged by a -CH2- group linking two ring carbon atoms arranged in para with each other, or (b) a spiro group of formula (b) below:
[0024] [ka]
[0025] Forming one of the following, Ring A has the following structural formulas (I-1), (I-2), and (I-3):
[0026] [ka]
[0027] It is one of the rings, where Y is selected from O, S, SO2 and NR, and R is as defined above, R 2 ~R 7 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, halo, -OR, -NR2, -CH2OR, -SO m NR2, -SO m R is nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, or R bonded to the same carbon atom. 2 ~R 7 Any two of these are a C3-C6 cycloalkyl spiro ring and a spirooxetane ring with the following structure:
[0028] [ka]
[0029] [Forms a spiro ring selected from] The present invention provides a compound or a pharmaceutically acceptable salt thereof. In one embodiment, the benzodiazepine derivative of the present invention has the following structural formula (Ie'):
[0030] [ka]
[0031] [In the formula, R 8 is H or halo, (i) T is N, and V is C,
[0032] [ka]
[0033] It is a combination,
[0034] [ka]
[0035] It does not exist. Z is H, C3-C6 cycloalkyl, halo, -NHR 9 Selected from benzyl, phenyl, 4-10 membered heterocyclyl and 4-10 membered heteroaryl, where phenyl, heterocyclyl and heteroaryl are unsubstituted or 4-10 membered heterocyclyl (unsubstituted or OR substituted), as well as C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halo, -OR, -(CH2) m OR, -NR2, -(CH2) m NR2, -NHR'', -SO m NR2, -SO m R, -SR, Nitro, -CO2R, -CN, -CONR2, -NHCOR, -CH2NR 10 R 11 and -NR 10 R 11 It is substituted with one or two substituents selected from, where each R is independently H or C1-C6 alkyl, R'' is C3-C6 cycloalkyl, and m is 1 or 2. R 9 The compounds are selected from phenyl and 4- to 10-membered heteroaryls, and the phenyl and heteroaryls are either unsubstituted or substituted with a halo. R 10 and R 11 Each of these is independently either H or a C1-C6 alkyl group, or R 10 and R 11 These, together with the N atoms to which they are attached, form (a) a morpholine ring optionally bridged by a -CH2- group linking two ring carbon atoms arranged in para with each other, or (b) a spiro group of formula (b) below:
[0036] [ka]
[0037] Forming one of the following, X and U, along with the N and C atoms to which they are bonded, are given by the following formula (I'-1) or (I'-2):
[0038] [ka]
[0039] (In the formula, R 2 ~R 7 Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halo, -OR, -CH2OR, -NR2, -CH2NR 12 R 13 -NRCOOR, -CH2OR, -SO m NR2, -SO m R, -CH2SO m R is nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, 12 and R 13 Each of these is independently either H, C1-C6 alkyl, benzyl, 4-10 membered heterocycline, or R 12 and R 13 These, together with the N atom to which they are attached, form an unsubstituted 4-10 membered heteroaryl or 4-10 membered heterocycline (unsubstituted or substituted with C1-C6 alkyl or halo), or R bonded to the same carbon atom. 2 ~R 7 Any two of these are a C3-C6 cycloalkyl spiro ring and a spirooxetane ring with the following structure:
[0040] [ka]
[0041] Forming a ring (which forms a spiro ring selected from) or (ii) T is C, V is N,
[0042] [ka]
[0043] It is a combination,
[0044] [ka]
[0045] It does not exist. W adopts the definition given to Z in provision (i) above, U and Z, along with the N and C atoms to which they are bonded, are given by the following formulas (I-1) or (I-3):
[0046] [ka]
[0047] (In the formula, Y is selected from O, S, SO2 and NR, and R is as defined in provision (i) above, R 2 ~R 7 [This forms a ring as defined in provision (i) above] or a pharmaceutically acceptable salt thereof.
[0048] In one embodiment of this model, the benzodiazepine derivative of the present invention has the following structural formula (I'):
[0049] [ka]
[0050] [In the formula, R 8 is H or halo, (i) T is N and V is C
[0051] [ka]
[0052] is a bond,
[0053] [Chem.]
[0054] does not exist, Z is selected from H, C3-C6 cycloalkyl, -NHR 9 , phenyl and 4-10 member heteroaryl, and phenyl and heteroaryl are each unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, -OR, -NHR'', -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2, -NHCOR and -NR 10 R 11 from, each R is independently H or C1-C6 alkyl, R'' is C3-C6 cycloalkyl, m is 1 or 2, R 9 is selected from phenyl and 4-10 member heteroaryl, R 10 and R 11 are each independently H or C1-C6 alkyl or R 10 and R 11 together with the N atom to which they are attached form (a) a morpholine ring optionally bridged by a -CH2- group connecting two ring carbon atoms arranged para to each other, or (b) a spiro group of the following formula (b):<00
[0058] (wherein each of R 2 ~R 7 is independently H, C1 - C6 alkyl, C3 - C6 cycloalkyl, halo, -OR, -NR2, -CH2OR, -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2 or -NHCOR, and R and m are as defined above, or two of R 2 ~R 7 bonded to the same carbon atom form a spiro ring selected from a C3 - C6 cycloalkyl spiro ring and a spirooxetane ring of the following structure:
[0059]
Chemical formula
[0060] (or (ii) T is C and V is N, and (ii) T is C and V is N, and
[0061]
Chemical formula
[0062] is a bond, and
[0063]
Chemical formula
[0064] does not exist, and W adopts the definition given to Z in the above stipulation (i), and U and Z, together with the N and C atoms to which they are bonded, form the following formula (I - 1) or (I - 3):
[0065]
Chemical formula
[0066] (In the formula, Y is selected from O, S, SO2 and NR, and R is as defined in provision (i) above, R 2 ~R 7 [This forms a ring as defined in provision (i) above] or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]
[0067] Detailed description of the invention If any group, ring, substituent, or part as defined herein is substituted, it is typically substituted with Q as defined below.
[0068] C 1~6 The alkyl group or part is either linear or branched. 1~6 Alkyl alkyl groups are typically C 1~4 Alkyl alkyl group, or C 4~6 It is an alkyl group. C 1~6 Examples 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-methylbuta-1-yl), t-pentyl (i.e., 2-methylbuta-2-yl), neopentyl (i.e., 2,2-dimethylpropane-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 record, if there are two alkyl moieties in the group, these alkyl moieties may be the same or different. 1~6 Alkyl groups are either unsubstituted or substituted, typically with one or more Q groups as defined below. For example, C 1~6 The alkyl group is either unsubstituted or substituted with one, two, or three Q groups as defined below.
[0069] Q stands for 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 The compounds are cycloalkyl, 5-10 membered heterocyclyl, 5-12 membered aryl, or 5-10 membered heteroaryl, where each R' is independently H, C 1~6 Alkyl, C3~ 10 Cycloalkyl, 5-10 membered heterocyclyl, C6-C 10 Selected from aryl and 5- to 10-membered heteroaryl compounds. For the record, the alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl portions in these definitions are typically unsubstituted.
[0070] C 1~6 Alkoxy groups are either linear or branched. This is typically C 1~4 These are alkoxy groups, such as methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy, or tert-butoxy groups. 1~6 The alkoxy group is either unsubstituted or substituted, typically with one or more Q groups as defined above.
[0071] C 1~6 Alkylthio groups are either linear or branched. This is typically C 1~4 Alkylthio groups, such as methylthio, ethylthio, propylthio, i-propylthio, n-propylthio, n-butylthio, sec-butylthio, or tert-butylthio groups. 1~6 The alkylthio group is either unsubstituted or substituted, typically with one or more Q groups as defined above.
[0072] The halogen or halo group is F, Cl, Br, or I. This is typically F or Cl. C is substituted with a halogen. 1~6 Alkyl alkyl groups are "C 1~6 It can be expressed as "haloalkyl," which means that one or more hydrogens are replaced by a halo, as defined above. 1~6 This refers to alkyl groups. Similarly, C substituted with halogens. 1~6 The alkoxy group is "C 1~6 It can be expressed as "haloalkoxy," which means that one or more hydrogens are replaced by a halo, as defined above. 1~6 It means an alkoxy group. Typically, C 1~6 Haloalkyl or C 1~6 The haloalkoxy is substituted with one, two, or three of the aforementioned halogen atoms. Examples of haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups, such as -CX3 and -OCX3 (wherein X is a halogen), for example, -CF3-CCl3-OCF3 and -OCCl3.
[0073] C 1~6 A hydroxyalkyl group is defined as a C molecule substituted with one or more OH groups. 1~6 It is an alkyl group. This is typically substituted with one, two, or three OH groups. Preferably, it is substituted with a single OH group.
[0074] C6~C 10 The aryl group is an aromatic carbocyclic group containing 6 to 10 carbon atoms. It can be a monocyclic system or a fused bicyclic system where one aromatic ring is fused to another aromatic carbocyclic system. C6~C 10 Examples of aryl groups include phenyl and naphthyl. When substituted, the aryl group is typically substituted with one, two, or three groups selected from the Q groups defined above. More specifically, substituted aryl groups, such as substituted phenyl groups, are C1-C6 alkyl, halo, or -OR groups. 8 and -N(R 8 )2(wherein, R8 is H or C1-C6 alkyl, and each R 8 If two exist, they are replaced by one or two elements selected from (the same or different).
[0075] C 3~10 Cycloalkyl groups are saturated hydrocarbon rings containing 3 to 10 carbon atoms. 3~10 The cycloalkyl group may be, for example, a C3-C7 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. This is typically a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, this is cyclopropyl. 3~10 Cycloalkyl groups are either unsubstituted or substituted, typically with one or more Q groups as defined above.
[0076] 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 can be monocyclic or bicyclic. It typically contains 1 N atom and 0, 1, 2, or 3 additional heteroatoms selected from O, S, and N. This may 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, pyridadinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, and pyrazolyl groups. Furanyl, thienyl, imidazolyl, pyridyl, and pyrimidyl groups are preferred. Alternatively, this may 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, the heteroaryl group (monocyclic or bicyclic) is typically one or more, for example, C 1~4 It is substituted with one, two, or three groups selected from alkyl groups and a Q group as defined above.
[0077] A 4- to 10-membered heterocyclyl group is a monocyclic or bicyclic non-aromatic, saturated or unsaturated cyclic system containing 5- to 10 carbon atoms and at least one atom or group selected from N, O, S, SO, SO2, and CO, more typically selected from N or O. If the cyclic system is bicyclic, one ring may be saturated and the other unsaturated. This is typically the case where one, two, or three carbon atoms in the ring are replaced by atoms or groups selected from O, S, SO2, CO, and NH. 4~10It is a ring system. This is more typically a monocyclic ring, preferably a monocyclic C4-C6 ring. Examples include piperidyl, piperidine-2,6-dionyl, piperidine-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanil, pyrrolidinyl, azetidinyl, diazananil, imidazole-2-onyl, pyrrolidine-2-onyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl moieties.
[0078] For the sake of completeness, it should be noted that the above definitions of heteroaryl and heterocyclyl groups refer to the "N" atoms that can be present within the ring. However, it will be apparent to a skilled chemist that if such an N atom is bonded via a single bond to each of its adjacent ring atoms, any such N atom will be protonated (or will retain a substituent as defined above). Such protonated forms are included within the definition of the heteroaryl and heterocyclyl groups of the present invention.
[0079] In formula (Ie) or formula (I) as defined above, ring A is typically a ring of formula (I-1) where Y is O, S or SO2. More typically, ring A is a ring of formula (I-1) where Y is O.
[0080] <In formula (Ie) or (Ie') or formula (I) or (I'), if the group Z is a 4- to 10-membered heteroaryl, the group may be selected from those enumerated in the general definition above. This is typically selected from pyridyl, pyrazolyl, indazolyl, pyrimidinyl, thienyl, and furanyl. This is more typically pyridyl.
[0083] In formula (Ie) or (Ie') or formula (I) or (I'), if the Z group is a 4- to 10-membered heterocycline, the group may be selected from those enumerated in the general definition above. This is typically a monocyclic C4- to C6 ring. This is more typically a piperidyl. In formula (Ie) or (Ie') or formula (I) or (I'), if the substituent on Z is a 4- to 10-membered heterocycline, the group may be selected from those enumerated in the general definition above. This is typically a monocyclic C4-C6 ring in which one of the carbon atoms in the ring is replaced by an atom or group selected from O and NH. This is more typically selected from pyrrolidinyl, azetidinyl, oxetanyl, and tetrahydropyranyl.
[0084] In formula (Ie) or (Ie') or formula (I) or (I'), the substituent on Z is R 10 and R 11 However, together with the N atoms to which these are attached, they form a morpholine ring bridged by a -CH2- group that links two ring carbon atoms arranged in para with each other, forming a -NR group. 10 R 11 And, base-NR 10 R 11 It has the following structure (c) or (d).
[0085] [ka]
[0086] In one embodiment of formula (Ie) or formula (I) as defined above, the benzodiazepine derivative is formula (Ia):
[0087] [Chemistry]
[0088] (wherein all groups are as defined above for formula (Ie) or formula (I)) is possessed. In another embodiment of formula (Ie) or formula (I) as defined above, the benzodiazepine derivative is of formula (Ib):
[0089] [Chemistry]
[0090] (wherein all groups are as defined above for formula (Ie) or formula (I)) is possessed. In a further embodiment of formula (Ie) or formula (I) as defined above, the benzodiazepine derivative is of formula (Ic):
[0091] [Chemistry]
[0092] (wherein all groups are as defined above for formula (Ie) or formula (I)) is possessed. In a further embodiment of formula (Ie) or formula (I) as defined above, the benzodiazepine derivative is of formula (Id):
[0093] [Chemistry]
[0094] (wherein all groups are as defined above for formula (Ie) or formula (I)) is possessed. In the above formulas (Ie), (Ie’), (I), (I’), (Ia), (Ib), (Ic) and (Id), R 8 is typically H or F.
[0095] In the above equations (Ie), (Ie'), (I), (I'), and (Ic), Y is typically O, S, or SO2. More typically, Y is O or SO2. Most typically, Y is O. If Y is NR, then R is typically C1. ~4 It is an alkyl group.
[0096] In the above formulas (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), Z is typically H, halo, cyclopropyl, cyclohexyl, and the following structures:
[0097] [ka]
[0098] [wherein R and R'' are selected as defined above for formula (Ie)]. Typically, R is a C1-C3 alkyl and R'' is a cyclopropyl. The above definition of Z is also typically adopted by W in equation (Ie').
[0099] In one embodiment of the above formulas (I), (I'), (Ia), (Ib), (Ic), and (Id), Z is typically H, cyclopropyl, and the following structure:
[0100] [ka]
[0101] [wherein R and R'' are selected as defined above for formula (I)]. Typically, R is a C1-C3 alkyl and R'' is a cyclopropyl. The above definition of Z is also typically adopted by W in equation (I').
[0102] In equations (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7Each of these is typically H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -CH2OR, or -CH2NR. 12 R 13 -NRCOOR, -CH2SO m R is either a halo, and R and m are as defined above, 12 and R 13 Each of these is independently either H, C1-C6 alkyl, benzyl, 4-10 membered heterocycline, or R 12 and R 13 These, together with the N atom to which they are attached, form an unsubstituted 4-10 membered heteroaryl or 4-10 membered heterocycline (unsubstituted or substituted with C1-C6 alkyl or halo), or R bonded to the same carbon atom. 2 ~R 7 Any two of these are a C3-C6 cycloalkyl spiro ring and a spirooxetane ring with the following structure:
[0103] [ka]
[0104] A spiro ring is formed by selecting from R 2 ~R 7 The remaining value is H. In one embodiment of formulas (I), (I'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 Each of these is typically H, C1-C6 alkyl, C3-C6 cycloalkyl, or halo, or R bonded to the same carbon atom. 2 ~R 7 Any two of these are a C3-C6 cycloalkyl spiro ring and a spirooxetane ring with the following structure:
[0105] [ka]
[0106] A spiro ring is formed by selecting from R2 ~R 7 The remaining value is H. For example, in equations (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 The following values may be taken: - R 2 ~R 7 Each of them is H, or - R 2 ~R 7 One or two of them are independently C1-C3 alkyl groups, and R 2 ~R 7 The remainder is H, or - R bonded to the same carbon atom 2 ~R 7 Any two of them are C3-C6 cycloalkylspiro rings and
[0107] [ka]
[0108] A spiro ring is formed by selecting a spirooxetane ring from the structure of R 2 ~R 7 The remaining value is H. For example, in equations (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 The following values may be taken: - R 2 ~R 7 Each of them is H, or - R 4 and R 7 One of them is a C1-C3 alkyl, R 2 ~R 7 The remainder is H, or - R 4 and R 5 Both are C1-C3 alkyl groups, or R 4 and R 5Together, they form a spiro ring which is a cyclopropyl spiro ring or a spirooxetane ring of the structure defined above, R 2 ~R 7 The remainder is H, or - R 6 and R 7 They come together to form a spiro ring, which is a cyclopropyl spiro ring, R 2 ~R 7 The remaining value is H.
[0109] For example, in equations (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 It may take the following values: - R 2 ~R 7 Each of them is H, or - R 2 ~R 7 One of them is C1-C3 alkyl, C1-C3 hydroxyalkyl, -NRCOOR, for example, tert-butyl(methyl)carbamate, or -CH2NR 12 R 13 And R 12 and R 13 Each of these is independently either H, C1-C6 alkyl, benzyl, 4-10 membered heterocycline, or R 12 and R 13 These, together with the N atoms to which they are attached, form unsubstituted 4-10 membered heteroaryls, such as pyrazoles, or 4-10 membered heterocyclines (unsubstituted or substituted with C1-C6 alkyls or halos), such as morpholine or diazinanes, and R 2 ~R 7 The remainder is H, or - R bonded to the same carbon atom 2 ~R 7 Any two of them are C3-C6 cycloalkylspiro rings and structure:
[0110] [ka]
[0111] A spiro ring is formed by selecting a spirooxetane ring from R 2 ~R 7 The remaining value is H. In one embodiment, for example, in formulas (I), (I'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 The following values may be taken: - R 2 ~R 7 Each of them is H, or - R 2 ~R 7 One or two of them are independently C1-C3 alkyl groups, and R 2 ~R 7 The remainder is H, or - R bonded to the same carbon atom 2 ~R 7 Any two of them are C3-C6 cycloalkylspiro rings and structure:
[0112] [ka]
[0113] A spiro ring is formed by selecting a spirooxetane ring from R 2 ~R 7 The remaining value is H. For example, in equations (I), (I'), (Ia), (Ib), (Ic), and (Id), R 2 ~R 7 The following values may be taken: - R 2 ~R 7 Each of them is H, or - R 4 and R 7 One of them is a C1-C3 alkyl, R 2 ~R 7 The remainder is H, or - R 4 and R 5 Both are C1-C3 alkyl groups, or R4 and R 5 Together, they form a spiro ring which is a cyclopropyl spiro ring or a spirooxetane ring of the structure defined above, R 2 ~R 7 The remainder is H, or - R 6 and R 7 They come together to form a spiro ring, which is a cyclopropyl spiro ring, R 2 ~R 7 The remaining value is H.
[0114] R 2 ~R 7 The bonds connecting each of these to an adjacent C atom may be oriented above or below the plane of the 5- or 6-membered saturated ring, i.e.
[0115] [ka]
[0116] It is shown as follows. For example, the R presented above 2 ~R 7 In any of the above-defined expressions (Ie), (Ie'), (I), (I'), (Ia), (Ib), (Ic), and (Id), having any of the values of R 4 teeth,
[0117] [ka]
[0118] It may be so. Similarly and independently, R 7 teeth
[0119] [ka]
[0120] In such embodiments, R 4 and R 7These are typically C1-C3 alkyl groups. R 2 ~R 7 Any of the aforementioned values of R 2 ~R 7 In equations (Ie), (Ie'), (I), (I'), and (Ic) having any of the following directions, Y is typically O, S, or SO2. More typically, Y is O or SO2. Most typically, Y is O.
[0121] Examples of specific compounds of the present invention include: 2-(2,4-difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(ethylamino)-2-fluoropyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5,5-dimethyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)spiro[6,7-dihydropyrazolo[5,1-b][1,3]oxazine-5,1'-cyclopropane]-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(propan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; (6S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-Ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(propan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; 6-Cyclopropyl-N-[(3S)-9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-propyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; 2-[6-(cyclopropylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-pyridine-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-pyridine-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-cyclopropylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(ethylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenylspiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,3'-oxetane]-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,3'-oxetane]-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-4,4-dioxo-5H,6H,7H-4λ6-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-4,4-dioxo-5H,6H,7H-4λ6-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-5H,6H,7H-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 3-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; 7-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6,6-dimethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-chloropyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-chloropyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-Cyclopropyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-methoxypyridine-4-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-methoxypyridine-4-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxypropyl)pyridine-3-yl]-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(3-fluoropyridine-4-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(ethylamino)-3-pyridyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-cyclopropyl-2-fluoro-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethyl-2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-morpholino-3-pyridyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(6-morpholino-3-pyridyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,6-dimethyl-3-pyridyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,6-dimethyl-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-ethylpyrimidine-5-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-ethylpyrimidine-5-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-furyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(3-furyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(3-thienyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-thienyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethyl-2-methyl-3-pyridyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethyl-2-methyl-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(isopropylamino)-3-pyridyl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylpyrazole-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-2-[6-(propan-2-ylamino)pyridine-3-yl]-N-(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-propan-2-ylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(triduteriomethylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-6-methylpyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-6-methylpyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethylpyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethyl-2-fluorophenyl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-fluoropyridine-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxypropyl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-fluoro-2-methylpyridine-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-fluoropyridine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-phenyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,4-difluorophenyl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(1-methylindazole-5-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxy-2-methylpropyl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-N-[(3R)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-pyridyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-(2-oxa-6-azapiro[3,3]heptan-6-yl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-[4-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-[2-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-anilino-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-anilino-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-fluoroanilino)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-methylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[4-[(dimethylamino)methyl]-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(morpholine-4-ylmethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[4-(diethylaminomethyl)-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide-carboxamide; tert-butyl N-[3-[[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]carbamoyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl]-N-methylcarbamate; tert-butyl N-ethyl-N-[3-[[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]carbamoyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl]carbamate; (5S)-2-benzyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-cyclohexyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1,3-dimethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxetan-3-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-hydroxyethyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-methoxyethyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[1-(difluoromethyl)pyrazole-4-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1,5-dimethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-hydroxy-2-methylpropyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(pyrazole-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-cyclopropylpyrazole-4-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-cyclopropylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-6-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(6-ethylpyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(hydroxymethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoropyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-4-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(4-cyano-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-6-methoxyphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-6-methylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-4-methylsulfonylphenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(4-carbamoyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(methylsulfonimidoyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(3-methoxyazetidine-1-yl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(3R)-3-methoxypyrrolidine-1-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(3S)-3-methoxypyrrolidine-1-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-methylindazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-methylindazole-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-4-(hydroxymethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-4-(hydroxymethyl)phenyl]-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(hydroxymethyl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6-hydroxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (2S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(2-fluorophenyl)-2-methyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-7-carboxamide; 6-(diethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[1-[2-(dimethylamino)ethyl]pyrazole-4-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 5-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(morpholine-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxan-4-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxetan-3-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[4-[(dimethylamino)methyl]-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[(4-methylpiperazine-1-yl)methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(morpholine-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-[[benzyl(ethyl)amino]methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6-methoxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 2-[6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-[6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(pyrrolidine-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-4-[(propan-2-ylamino)methyl]phenyl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(methylsulfonylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 6-[(3,3-difluoropyrrolidine-1-yl)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(pyrrolidine-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-2-(2,6-difluorophenyl)-5-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2,6-difluorophenyl)-5-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2-fluorophenyl)-5-(hydroxymethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-(ethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfanylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfinylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-bromo-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethylsulfonyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-5-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluoro-4-sulfamoylphenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[4-(dimethylsulfamoyl)-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylsulfonylpiperidine-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (2R)-6-(2-fluorophenyl)-2-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-7-carboxamide; These include pharmaceutically acceptable salts thereof.
[0122] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomers. However, all stereoisomers of the compounds of the present invention, including diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Compounds of formula (Ie) or formula (I) containing one or more chiral centers can be used in pure form as enantiomers or diastereoisomers, or in the form of mixtures of isomers.
[0123] 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 double bonds or fused rings, cis- and trans-forms, as well as mixtures thereof, are included within the scope of the invention. Both single positional isomers and mixtures of positional isomers are also within the scope of the invention.
[0124] The compounds of the present invention may exist in both non-solvated and solvated forms with pharmaceutically acceptable solvents, such as water and ethanol, and the present invention is intended to encompass both solvated and non-solvated forms.
[0125] The compounds of the present invention may exist in different tautomerized forms, and all such forms are included within the scope of the invention. The terms “tautomer” or “tautomerized form” refer to structural isomers of different energies that can be interconverted across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversion via proton transfer, e.g., keto-enol tautomers. Valence tautomers include interconversion via rearrangement of some of the bonding electrons.
[0126] The present invention encompasses all isotopologues of the compounds of the present invention as defined above. Therefore, any atom present in the compounds of the present invention as defined above, or in any intermediate or starting compound, may exist in any available naturally occurring isotopic form. For example, a carbon atom 12 C or 13 It may also be C. The hydrogen atom is 1 H or 2 It may also be H (deuterium). Therefore, the compounds of the present invention as defined above have one or more hydrogen atoms 2 It may be prepared in a deuterated form existing as H. Any hydrogen atom or combination thereof can exist as deuterium.
[0127] The compounds of the present invention can be prepared by the synthetic methods described in the following examples, or by analogy to such methods using appropriate starting materials and methodologies familiar to a skilled chemist. The preparations typically include an amide coupling reaction as the final step, in which a central amide linkage is formed in formula (Ie) or formula (I) as defined above. Thus, the compounds of the present invention can be prepared by analogy to any of the amide coupling reactions specified in the examples as steps A, B, C, D, E, F, and G, or by using appropriate synthetic intermediates. Such intermediates can be prepared by methods similar to those described in the preparation examples.
[0128] Benzodiazepine derivatives of formula (Ie) or formula (I) can be converted to pharmaceutically acceptable salts, which can then be converted back to free compounds by conventional methods. For example, benzodiazepine derivatives of formula (Ie) or formula (I) can be contacted with pharmaceutically acceptable acids to form pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
[0129] Pharmacopoecitable acids include both inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphate, hydrobromic acid, or nitric acid, and organic acids, such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmacopoecitable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides and organic bases, such as alkylamines, aralkylamines, and heterocyclic amines.
[0130] The compounds of the present invention have been shown to be inhibitors of respiratory syncytial virus (RSV) in biological studies. These compounds possess a combination of potent anti-RSV activity, good bioavailability, and favorable physicochemical properties. This combination of properties makes these compounds superior therapeutic drug candidates compared to many compounds disclosed in prior art references discussed to date.
[0131] Accordingly, the present invention further provides compounds that are benzodiazepine derivatives of formula (Ie) or formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in methods of treating the human or animal body by therapy.
[0132] The present invention also provides compounds of the present invention as defined above for use in methods for treating or preventing RSV infection. Furthermore, the present invention provides the use of compounds of the present invention as defined above in the manufacture of pharmaceuticals for use in the treatment or prevention of RSV infection. Subjects suffering from or susceptible to RSV infection can thus be treated by a method comprising administering compounds of the present invention as defined above to the subject. The condition of the subject may be improved or restored therefrom.
[0133] RSV infection is typically a respiratory infection. RSV infection can occur in children, for example, in children under 10 years of age or infants under 2 years of age. In one embodiment, the present invention provides compounds as defined above for use in the treatment or prevention of RSV infection in pediatric patients. Alternatively, the infection may occur in adults or the elderly, for example, in adults over 60 years of age, over 70 years of age, or over 80 years of age. The present invention further provides compounds for use in the treatment or prevention of RSV infection in elderly patients.
[0134] RSV infection may be an infection in an immunocompromised individual or an individual suffering from COPD or CHF. In another embodiment, RSV infection is an infection in an unaffected individual, for example, an otherwise healthy individual.
[0135] The compounds of the present invention can be administered in various dosage forms, for example, orally, in the form of tablets, capsules, sugar-coated tablets or film-coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. Therefore, the compounds may be administered by injection, drip infusion, or by inhalation or spray. The compounds are preferably administered by oral administration.
[0136] The dosage depends on various factors, including the patient's age, weight, and condition, as well as the route of administration. The daily dose varies within a wide range and can be adjusted to specific individual requirements. However, typically, the dose adopted for each route of administration is 0.0001 to 650 mg / kg when the compound is administered alone to an adult human, most commonly in the range of 0.001 to 10 mg / kg (body weight), for example, 0.01 to 1 mg / kg. Such doses may be administered, for example, 1 to 5 times a day. The appropriate daily dose for intravenous injection is 0.0001 to 1 mg / kg (body weight), preferably 0.0001 to 0.1 mg / kg (body weight). The daily dose can be administered as a single dose or according to a divided dose schedule.
[0137] The unit dose form, for example, tablets or capsules, usually contains 1 to 250 mg of the active ingredient. For example, the compound of formula (Ie) or formula (I) can be administered to human patients in doses between 100 and 250 mg once, twice, or three times a day.
[0138] Compounds of formula (Ie) or formula (I) and their pharmaceutically acceptable salts can be used on their own. Alternatively, they may be administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions comprising a compound of formula (Ie) or formula (I) or a pharmaceutically acceptable salt thereof, as previously defined herein, together with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," MEAulto, Churchill Livingstone, 1988.
[0139] Depending on the administration mode, the pharmaceutical composition preferably contains 0.05 to 99% w (weight percent), more preferably 0.05 to 80% w, even more preferably 0.10 to 70% w, and even more preferably 0.10 to 50% w of the active ingredient, all weight percentages being relative to the total composition.
[0140] The present invention further provides a method for preparing a pharmaceutical composition of the present invention, comprising the step of mixing a compound of formula (Ie) or formula (I) or a pharmaceutically acceptable salt thereof, as previously defined herein, with a pharmaceutically acceptable adjuvant, diluent, or carrier.
[0141] The compounds of the present invention can be administered in various dosage forms. Therefore, they may be administered orally, for example, as tablets, lozenges, watery or oily suspensions, liquids, dispersible powders, or granules. The compounds of the present invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, or percutaneously, by infusion, inhalation, or spraying. The compounds may also be administered as suppositories.
[0142] The solid oral form of the pharmaceutical composition of the present invention may contain, together with the active compound, diluents such as lactose, glucose, sucrose, cellulose, corn starch, or potato starch; lubricants such as silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; de-aggregating agents such as starch, alginic acid, alginate, or sodium starch glycolate; saturating agents; dyes; sweeteners; wetting agents such as lecithin, polysorbate, or lauryl sulfate; and generally non-toxic and pharmacologically inert substances used in pharmaceutical formulations. Such pharmaceutical preparations can be produced by known methods, such as mixing, granulation, tableting, sugar coating, or film coating processes.
[0143] Liquid dispersions for oral administration may be syrups, emulsions, and suspensions. Syrups may contain, for example, saccharose or saccharose as a carrier, together with glycerin and / or mannitol and / or sorbitol.
[0144] 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 injection may contain, together with the active compound, pharmaceutically acceptable carriers, such as sterile water, olive oil, ethyl oleate, glycol, such as propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride. Further suitable carriers for suspensions include sterile water, hydroxypropyl methylcellulose (HPMC), polysorbate 80, polyvinylpyrrolidone (PVP), aerosol AOT (i.e., sodium 1,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate), Pluronic® F127, and / or captisol (i.e., sulfobutyl ether-β-cyclodextrin).
[0145] The compounds of the present invention can also be formulated, for example, as aqueous suspensions in a carrier selected from the following: (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 agent AOT (sodium l,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate); (iii) 1% w / v Pluronic® F127; and (iv) 0.5% w / v polysorbate 80.
[0146] The carriers 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 and placing it in a suitable container, adding approximately 80% of the final volume of water, and magnetically stirring until a solution is formed. Then, water is added to the carrier to its volume. An aqueous suspension of the compound of formula (Ie) or formula I can be prepared by weighing the required amount of the compound of formula I and placing it in a suitable container, adding 100% of the required amount of carrier, and magnetically stirring.
[0147] The solution for injection or intravenous infusion may contain, for example, sterile water as a carrier, or preferably, a sterile, aqueous, isotonic saline solution. The compounds of the present invention can also be administered in combination with other compounds used for the treatment of viral infections. Therefore, the present invention further relates to combination therapy in which the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions or formulations containing the compounds of the present invention are administered in parallel or sequentially with another therapeutic agent or drug, or as a preparation in combination with another therapeutic agent or drug, for the treatment or prevention of viral infections, particularly infections caused by RSV.
[0148] Where the term “combination” is used herein, it should be understood to refer 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 beneficial effect of the combination should not be lost, for example, even if the administration of the second component is delayed.
[0149] The following are suitable therapeutic agents for use in combination therapy. (i) RSV fusion inhibitors (ii) Other RSV nucleocapsid (N)-protein inhibitors; (iii) Other RSV protein inhibitors, such as inhibitors that inhibit phosphoprotein (P) protein and macroprotein (L); (iv) Nucleoside or polymerase inhibitors that inhibit L protein; (v) Anti-RSV monoclonal antibodies, e.g., F-protein antibodies; (vi) Immunomodulatory Toll-like receptor compounds; (vii) Antiviral properties of other respiratory viruses, e.g., anti-influenza and anti-rhinovirus compounds; and / or (viii) anti-inflammatory compounds.
[0150] The RSV nucleocapsid (N)-protein plays a central role in viral transcription and replication by mediating the interaction between genomic RNA and the RNA-dependent RNA polymerase encoded by the virus. The RSVP- and L- proteins are components of the RNA-dependent RNA polymerase encoded by the RSV virus.
[0151] In a further aspect of the present invention, for use in the treatment of RSV, a compound of formula (Ie) or formula (I) as previously defined herein, or a pharmaceutically acceptable salt thereof, is provided in combination with one or more of the therapeutic agents listed in (i) to (vi) above.
[0152] The following examples serve to further illustrate the present invention. The preparation examples relate to the preparation of starting materials and intermediates used to prepare the compounds of the examples. Neither the examples nor the preparation examples limit the present invention in any way. [Examples]
[0153] Reagents were obtained from commercial sources and used without further purification. Anhydrous solvents were purchased from suppliers, used as supplied, and stored under N2 conditions. Reactions were carried out under N2 conditions using anhydrous solvents unless otherwise specified. All temperatures are in °C. TLC was performed on aluminum-backed silica gel plates with fluorescent labeling at 254 nM (average pore size 60 Å). Flash column chromatography was performed using a Biotage Isolera One system with KP-Sil or Ultra silica gel columns, or an Isco CombiFlash Rf system with FlashPure or RediSep Rf / RediSep Rf Gold silica gel columns. Reverse-phase column chromatography was performed on an Isco CombiFlash Rf system with a Teledyne ISCO RediSep Rf C18 column. Ion exchange chromatography was performed using an Isolute SCX-2: silica-propylsulfonic acid solid-phase extraction cartridge, washed with a suitable solvent selected from water, MeCN, and MeOH.
[0154] NMR spectra were recorded on 400, 500, 600, or 700 MHz spectrometers at probe ambient temperature (nominal 298 K). Chemical shifts (δ) were assigned in ppm and calibrated using residual solvent peaks as internal standards (CDCl3, δ=7.26 ppm; DMSO-d6, δ=2.50 ppm). Coupling constants were assigned in Hertz (Hz). 0.5H is 1 In 1H NMR assignment, it corresponds to the 1H of the diastereomer peak. Advion Plate Express expression with APCI or ESI ion source that switches between positive and negative ion modes. L LRMS was recorded using a small mass spectrometer.
[0155] LC-MS analysis was performed using a Waters Acquity UPLC with either a CSH C18 or BEH C18 column (2.1 × 30 mm) at 40°C, 0.77 mL / min, with a linear 5–95% acetonitrile gradient appropriate for the lipophilicity of the compound, for 1, 3, 4, or 10 minutes. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded using a Waters Acquity photodiode array detector between 210–400 nm. Mass spectra were recorded using a Waters Acquity QDa detector with ES, switching between positive and negative ion modes. Method A: Acidic for 3 minutes Method B: Basic for 3 minutes Method C: Acidic for 10 minutes Method D: Basic for 10 minutes Method E: Acidic for 1 minute Method F: Acidic for 4 minutes Preparative HPLC was performed at ambient temperature of the column using the following methods: HPLC Method 1: Gemini NX (30mm × 150mm, 5μm), 42mL / min, and UV detection at 210nm. HPLC Method 2: Luna Phenomenex C18 (150×30mm, 5μm) column, 42mL / min, and UV detection at 210nm. HPLC Method 3: Waters X-Bridge BEH C18 (30mm × 100mm, 5μm) column, 40mL / min, and UV detection across the entire wavelength range using PDA. HPLC Method 4: XSelect CSH C18 column (30mm × 150mm, 5μm), 42mL / min, and UV detection at 220nm. Preparative chiral HPLC was performed using the following method: Preparative Chiral HPLC Method 1: ChiralPAK IC (20×250mm; 5μm), ambient temperature of the column, flow rate 20mL / min, and UV detection at 220nm. Preparative Chiral HPLC Method 2: Lux iC5 (21.2 mm × 250 mm, 5 μm), column ambient temperature, flow rate 21 mL / min, UV detection at 210 nm. Analytical chiral HPLC was performed at column ambient temperature using the following method. Analytical Chiral HPLC Method 1A: ChiralPAK IC-3 column (2.1 × 150 mm, 3 μm), 1.0 mL / min.
[0156] Preparative SFC was performed using the following methods: SFC method 1: Torus Diol (19mm × 150mm, 5μm), column temperature 40°C, flow rate 68mL / min, 100BarG pressure, detection wavelength 237nm. SFC method 2: Torus Diol (19mm × 150mm, 5μm), column temperature 40°C, flow rate 68mL / min, 150BarG pressure, detection wavelength 210nm. Preparative chiral SFC was performed using the following methods: Preparative chiral SFC method 1: Chiralpak IA (250 × 10mm, 5μm), column temperature 40°C, flow rate 15mL / min, 120BarG pressure, detection wavelength 210~400nM. Preparative chiral SFC method 2: Lux C1 (21.2mm × 250mm, 5μm), column temperature 40°C, flow rate 50mL / min, 100BarG pressure, detection wavelength 210nm. Preparative chiral SFC method 3: Lux C4 (21.2 mm × 250 mm, 5 μm), column temperature 40°C, flow rate 50 mL / min, 125 BarG pressure, detection wavelength 210 nm. Analytical chiral SFC was performed by the following methods. Analytical chiral SFC method 1A: Chiralpak IG (4.6 mm × 250 mm, 5 μm), column temperature 40°C, flow rate 4 mL / min, detection wavelength 210-400 nm, 125 BarG back pressure. Analytical chiral SFC method 2A: Lux C1 (4.6 mm × 250 mm, 5 μm), column temperature 40°C, flow rate 4 mL / min, detection wavelength 210-400 nm, 125 BarG back pressure. Analytical chiral SFC method 3A: Lux C4 (4.6 mm × 250 mm, 5 μm), column temperature 40°C, flow rate 4 mL / min, detection wavelength 210-400 nm, 125 BarG back pressure.
[0157] The preliminary intermediates 3-bromo-6-ethyl-2-methylpyridine, 5-bromo-6-methyl-N-propan-2-ylpyridine-2-amine, 1-(5-bromopyridine-2-yl)-2-methylpropan-2-ol, and 5-bromo-4-methyl-N-propan-2-ylpyridine-2-amine were prepared according to the method described in WO / 2021 / 032992. Preparation examples (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one were prepared using the methods described in WO / 2004 / 026843, WO / 2005 / 090319, and WO / 2017 / 015449.
[0158] Examples in which the stereocenter was not defined were prepared and tested as a mixture of diastereomers unless otherwise specified.
[0159] [Table A]
[0160] Preparation example 1A Ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate
[0161] [ka]
[0162] A solution of ethyl 1H-pyrazole-4-carboxylate (5.5 g, 39.3 mmol) in EtOH (60 mL) was cooled to 0°C, then sodium acetate (22.5 g, 271 mmol) in water (90 mL) was added, followed by bromine (8.25 mL, 161 mmol). The reaction mixture was stirred at room temperature over the weekend. Saturated aqueous solution Na2S2O3 (100 mL) and siRNA (50 mL) were added to the separated phase, and the aqueous phase was extracted with siRNA (2 × 50 mL). The combined organic phase was washed with brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-40%, MTBE in isohexane) to produce a white solid (10.3 g, 84%). LC-MS (Method A) 297.3 / 299.4 / 301.4 [M+H] + , at 1.10 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 14.53 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 2A [(3R)-3-hydroxybutyl]methanesulfonate
[0163] [ka]
[0164] NEt3 (1.1 mL, 7.89 mmol), followed by MsCl (0.3 mL, 3.88 mmol), was added at 0°C to a solution of (3R)-butane-1,3-diol (1.00 g, 11.1 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at 0°C for 10 minutes. The reaction was allowed to continue until it reached room temperature, then quenched with saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL) to separate the phases. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and the combined organic phase was washed with 50% brine (20 mL), dried, and concentrated under reduced pressure in (MgSO4). The mixture was purified by flash chromatography (0-50%, Â in isohexane) to produce a colorless oily substance (310 mg, 16%). 1H NMR (500 MHz, CDCl3) δ 4.49 - 4.41 (m, 1H), 4.37 - 4.30 (m, 1H), 4.06 - 3.95 (m, 1H), 3.02 (s, 3H), 2.01 - 1.84 (m, 1H), 1.83 - 1.73 (m, 1H), 1.72 (d, J = 4.8 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H). 2B [(3S)-3-hydroxybutyl]methanesulfonate
[0165] [ka]
[0166] It was prepared using a procedure similar to that described for intermediate 2A. 1 H NMR (500 MHz, CDCl3) δ 4.49 - 4.41 (m, 1H), 4.37 - 4.30 (m, 1H), 4.02 - 3.99 (m, 1H), 3.02 (s, 3H), 2.00 - 1.88 (m, 1H), 1.83 - 1.73 (m, 1H), 1.70 (d, J = 4.9 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H). 2C (3-hydroxy-3-methylbutyl)methanesulfonate
[0167] [ka]
[0168] It was prepared using a procedure similar to that described for intermediate 2A. 1 H NMR (700 MHz, CDCl3) δ 4.41 (t, J = 6.9 Hz, 2H), 3.01 (s, 3H), 1.95 (t, J = 6.9 Hz, 2H), 1.28 (d, J = 0.5 Hz, 6H). 2D 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylmethanesulfonate
[0169] [ka]
[0170] MsCl (1.53 mL, 19.750 mmol) was added dropwise to a chilled solution (0°C) of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (2 mL, 14.11 mmol) and NEt3 (5.11 mL, 36.68 mmol) in CH2Cl2 (40 mL), then warmed to room temperature and stirred for 3 hours. The reaction was quenched with 1 M aqueous HCl, the organic layer was washed with brine, passed through a phase separation cartridge, and the solvent was removed under reduced pressure to obtain a colorless oily substance (2.81 g, yield 80%). 1 H NMR (500 MHz, CDCl3) δ 4.46 - 4.32 (m, 2H), 4.29 - 4.18 (m, 1H), 4.15 - 4.09 (m, 1H), 3.65 - 3.58 (m, 1H), 3.04 (s, 3H), 2.10 - 1.90 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H). 3A [3-(hydroxymethyl)oxetan-3-yl]methyl-4-methylbenzenesulfonate
[0171] [ka]
[0172] NEt3 (3.1 mL, 22.2 mmol), followed by TsCl (2.12 g, 11.1 mmol), was added to a cooled solution of [3-(hydroxymethyl)oxetan-3-yl]methanol (1.31 g, 11.1 mmol) in CH2Cl2 (10 mL) (0°C), and the mixture was stirred at 0°C for 10 minutes. The reaction was allowed to continue until it reached room temperature, then quenched with saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL) to separate the phases. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and the combined organic phase was washed with 50% brine (20 mL), dried, and concentrated under reduced pressure in (MgSO4). Purification by flash chromatography (0-50%, siRNA in isohexane) yielded a colorless oily substance (826 mg, 26%). 1 H NMR (500 MHz, CDCl3) δ 7.84 - 7.78 (m, 2H), 7.41 - 7.35 (m, 2H), 4.43 (d, J = 6.7 Hz, 2H), 4.36 (d, J = 6.6 Hz, 2H), 4.31 (s, 2H), 3.91 (d, J = 5.5 Hz, 2H), 2.47 (s, 3H), 1.86 (t, J = 5.4 Hz, 1H). 3B (3R)-3-hydroxybutyl]4-methylbenzenesulfonate
[0173] [ka]
[0174] A solution of TsCl (11.02 g, 57.81 mmol) in CH2Cl2 (25 mL) was added dropwise over 30 minutes to a chilled solution (0°C) of (R)-(-)-1,3-butanediol (4.99 mL, 55.59 mmol) and NEt3 (11.62 mL, 83.39 mmol) in CH2Cl2 (40 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (100 mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated, washed with water and brine (80 mL each), dried (MgSO4), and the solvent was removed under reduced pressure. Purification by flash chromatography (5-60% Â:heptane) yielded a pale yellow oily substance (9.04 g, 67%). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.71 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.56 (d, J = 5.0 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.68 - 3.53 (m, 1H), 2.42 (s, 3H), 1.70 - 1.49 (m, 2H), 1.00 (d, J = 6.2 Hz, 3H).LRMS m / z(APCI+)245.0[M+H] + .
[0175] The following intermediate compounds were prepared using a method similar to that described for intermediate 3B. 4-dimethylaminopyridine (0.1 equivalent) was used in the preparation of intermediate 3D.
[0176] [Table 1]
[0177] 4A 1-(2-bromoethyl)cyclopropane-1-ol
[0178] [ka]
[0179] Titanium(IV) isopropoxide (0.35 mL, 1.20 mmol) was added to a solution of methyl 3-bromopropionate (1.31 mL, 11.98 mmol) in THF (80 mL). The solution was cooled to 0°C, and EtMgBr (3.0 M in Et2O; 8.78 mL, 26.4 mmol) was slowly added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was quenched with saturated aqueous solution NH4Cl (50 mL), stirred for 10 minutes, then 1 M aqueous solution HCl (50 mL) was added, and the mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ₹ (3 × 50 mL), the combined organic extract was washed with brine (50 mL), dried, and concentrated under reduced pressure to produce an orange oily substance (1.52 g, 77%). 1 H NMR (700 MHz, CDCl3) δ 3.61 (t, J = 7.3 Hz, 2H), 2.12 (t, J = 7.6, 2H), 0.84 - 0.75 (m, 2H), 0.65 - 0.53 (m, 2H). 5A S-(3-bromopropyl)ethanethioate
[0180] [ka]
[0181] Potassium ethanethioate (563 mg, 4.93 mmol) was gradually added to a solution of 1,3-dibromopropane (0.5 mL, 4.93 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with MTBE (3 × 20 mL). The combined organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (0-30%, MTBE in isohexane) yielded a colorless oily substance (516 mg, 53%). 1 H NMR (500 MHz, CDCl3) δ 3.47 (t, J = 6.5 Hz, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.36 (s, 3H), 2.15 (p, J = 6.7 Hz, 2H). 6A Ethyl 3,5-dibromo-1-(3-hydroxypropyl)pyrazole-4-carboxylate
[0182] [ka]
[0183] A solution of intermediate 1A (500 mg, 1.68 mmol), K2CO3 (465 mg, 3.30 mmol), and 3-bromopropan-1-ol (0.16 mL, 1.77 mmol) in MeCN (6 mL) was heated at 80°C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and washed with MeCN (3 × 20 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography (0-50%, Â in isohexane) to produce a colorless oily substance (561 mg, 89%). LC-MS (Method A) 355.1 / 357.1 / 359.1 [M+H] + , at 1:11. 1 H NMR (500 MHz, CDCl3) δ 4.40 - 4.32 (m, 4H), 3.67 (q, J = 5.7 Hz, 2H), 2.12 - 2.04 (m, 2H), 1.75 (t, J = 5.4 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H) The following intermediate compounds were prepared from intermediate 1A and the indicated reagent / intermediate using a method similar to that described for intermediate 6A.
[0184] [Table 2-1]
[0185] [Table 2-2]
[0186] 7A Ethyl 1-(3-acetylsulfanylpropyl)-3,5-dibromopyrazole-4-carboxylate
[0187] [ka]
[0188] A solution of intermediate 1A (650 mg, 2.18 mmol), K2CO3 (1.21 g, 8.73 mmol), and intermediate 5A (516 mg, 2.62 mmol) in MeCN (10 mL) was heated at 80°C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain an orange oily substance (937 mg, 79%). This was used without further purification. LC-MS (Method E): m / z 413.1 / 415.1 / 417.1 [M+H] + , at 0.70 minutes.
[0189] 8A Ethyl 3,5-dibromo-1-[2-(hydroxymethyl)butyl]pyrazole-4-carboxylate
[0190] [ka]
[0191] Imidazole (654 mg, 9.6 mmol) and PPh3 (2.52 g, 9.6 mmol) were added to a solution of 2-ethylpropane-1,3-diol (1.0 g, 9.6 mmol) in THF (30 mL), stirred for 1 minute, and then I2 (3.17 g, 12.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated aqueous solution Na2S2O3 (25 mL), and diluted with CH2Cl2 (25 mL). The separated aqueous layer was extracted with CH2Cl2 (2 × 25 mL), the combined organic extract was washed with brine (25 mL), dried (Na2SO4), and the solvent was removed under reduced pressure to produce a colorless oily substance (4.00 g), which was used directly in the next reaction without further purification. The solutions of intermediate 1A (1.00 g, 3.36 mmol), crude product 2-(iodomethyl)butan-1-ol (4.00 g, 9.60 mmol), and Cs2CO3 (1.43 g, 4.36 mmol) in MeCN (15 mL) were heated at 80°C for 3 hours, then stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature, filtered, and washed with MeCN (2 × 15 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography (10-40% siRNA:heptane) to produce a colorless oily substance (740 mg, 57%). 1 H NMR (400 MHz, DMSO-d6) δ 4.65 (t, J = 5.0 Hz, 1H), 4.31 - 4.18 (m, 3H), 4.15 - 4.04 (m, 1H), 2.00 - 1.90 (m, 1H), 1.40 - 1.26 (m, 4H), 1.25 - 1.12 (m, 1H), 0.84 (t, J = 7.5 Hz, 3H).LRMS(APCI+)m / z383.0 / 385.0 / 387.0[M+H] + .
[0192] The following intermediates were prepared using a method similar to that of intermediate 8A.
[0193] [Table 3-1]
[0194] [Table 3-2]
[0195] 9A Ethyl 2-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0196] [ka]
[0197] NaH (60% dispersion in mineral oil, 225 mg, 5.63 mmol) was added to a chilled solution (0°C) of intermediate 6A (1.00 g, 2.81 mmol) in THF (150 mL). The reaction mixture was stirred at room temperature for approximately 48 hours, quenched with water (20 mL), and diluted with RINKAN (20 mL). The separated aqueous phase was extracted with RINKAN (2 × 10 mL). The combined organic phase was washed with brine (50 mL), dried, and concentrated under reduced pressure. Purification by flash chromatography (0-80% RINKAN in isohexane) yielded a white solid (655 mg, 85%). LC-MS (Method A) 275.2 / 277.2 [M+H] + , at 0.97 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 4.45 - 4.39 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 2.24 - 2.16 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). The following intermediate compounds were prepared using a method similar to that of intermediate 9A.
[0198] [Table 4-1]
[0199] [Table 4-2]
[0200] 9N Ethyl(6R)-2-bromo-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0201] [ka]
[0202] Ethyl 2-bromo-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (1.71 g, 94%) was produced by preparing intermediate 6F (2.33 g, 6.31 mmol) with intermediate 9A according to the procedure described. Separation was performed by chiral SFC method 3 using a homogeneous mixture of 30:70EtOH:CO2 (0.2% v / vNH3); the title compound was produced as a white solid (670 mg, 40%) by the second eluted enantiomer. 1 H NMR (700 MHz, DMSO-d6) δ 4.44 (ddd, J = 10.7, 3.6, 1.3 Hz, 1H), 4.22 - 4.11 (m, 3H), 4.07 (dd, J = 10.7, 9.3 Hz, 1H), 3.70 (dd, J = 12.0, 8.9 Hz, 1H), 2.46 - 2.37 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H).LRMS (APCI+)m / z289.0 / 291.0[M+H] + .
[0203] The following intermediate compounds were prepared using a method similar to that of intermediate 9A. Intermediates 9Q, 9R, and 9T were used to prepare 1 equivalent, 1.05 equivalent, and 1.1 equivalent amounts of NaH, respectively.
[0204] [Table 5]
[0205] 10A Ethyl 2-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylate
[0206] [ka]
[0207] Crude intermediate 7A (937 mg, 2.26 mmol) was added to a solution of K2CO3 (1.56 g, 11.3 mmol) in water / EtOH (1:1; 12 mL) and heated at 70°C for 2 hours. Volatile substances were removed under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (100 mL), dried, and concentrated under reduced pressure to obtain a colorless oily substance (644 mg, 98%). This was used without further purification. LC-MS (Method E): m / z 291.7 / 293.6 [M+H] + , at 0.59 minutes.
[0208] 11A Ethyl 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate
[0209] [ka]
[0210] K2CO3 (1.98 g, 14.3 mmol), followed by 1,2-dibromoethane (0.4 mL, 3.90 mmol), was added to a solution of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (550 mg, 3.52 mmol) in MeCN (25 mL), and the reaction mixture was heated overnight at 80°C. The reaction mixture was cooled to room temperature, filtered, washed with MeCN (2 × 20 mL), and concentrated under reduced pressure. Purification by flash chromatography (40-100% isohexane, Â) yielded a white solid (690 mg, 99%). LC-MS (Method A) 169.2 (M-OEt) + , at 0.86 minutes. 1H NMR (500 MHz, CDCl3) δ 6.02 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.34 - 4.28 (m, 2H), 4.25 (t, J = 6.3 Hz, 2H), 2.32 - 2.24 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H). 11B Ethyl 2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxylate
[0211] [ka]
[0212] Using 1,3-dibromoethane, the intermediate 11A was prepared using a procedure similar to that described for intermediate 11A. LC-MS (Method A) 155.1 (M-OEt) + , at 0.78 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 5.87 (s, 1H), 5.11 (dd, J = 8.6, 7.6 Hz, 2H), 4.35 (dd, J = 8.6, 7.6 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 12A Ethyl 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate
[0213] [ka]
[0214] N-bromosuccinimide (650 mg, 3.65 mmol) was added to a cooled solution of intermediate 11A in MeCN (6 mL) (0°C), and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 (20 mL) and ethyl acetate (20 mL) were added, and the separated aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), and the solvent was removed under reduced pressure. Purification by flash chromatography (30-80%, ethyl acetate in isohexane) yielded a colorless gum-like substance (888 mg, 96%). LC-MS (Method A) 229.1 / 231.1 (M-OEt) + , at 1.07 minutes. 1 H NMR (500 MHz, CDCl3) δ 4.46 - 4.36 (m, 4H), 4.25 (t, J = 6.2 Hz, 2H), 2.37 - 2.26 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H). 12B Ethyl 7-bromo-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxylate
[0215] [ka]
[0216] It was prepared using a procedure similar to that described for intermediate 12A. 1 H NMR (500 MHz, CDCl3) δ 5.16 - 5.13 (m, 2H), 4.47 - 4.36 (m, 4H), 1.41 (t, J = 7.1 Hz, 3H). 13A Ethyl 2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0217] [ka]
[0218] Pd(PPh3)4 (74 mg, 0.060 mmol) was added to a vial containing intermediate 9A (118 mg, 0.430 mmol), 2-fluorophenylboronic acid (120 mg, 0.86 mmol), and K2CO3 (178 mg, 1.29 mmol), and 1,4-dioxane:water (2:1; 3 mL) was added. The mixture was sparged with N2 and heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, Pd(PPh3)4 (74 mg, 0.060 mmol) and 2-fluorophenylboronic acid (240 mg, 1.72 mmol) were added, the mixture was sparged with N2, and heated at 100°C for 4 hours. The reaction product was partitioned between HCl (10 mL) and water (10 mL), separated, and extracted with aqueous phase HCl (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (0-80% Â in isohexane) yielded a brown oily substance (208 mg, 63%). LC-MS (Method A) 290.9 [M+H] + , at 1:14. 1 H NMR (500 MHz, DMSO-d6) δ 7.48 - 7.40 (m, 1H), 7.39 (ddd, J = 7.6, 1.9 Hz, 1H), 7.25 - 7.17 (m, 2H), 4.48 - 4.42 (m, 2H), 4.14 (t, J = 6.1 Hz, 2H), 4.05 - 3.96 (m, 2H), 2.29 - 2.21 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H). 14A Ethyl 2-(2-fluoro-5-methylpyridine-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (Suzuki-Miyaura Procedure A)
[0219] [ka]
[0220] Intermediate 9A (140 mg, 0.510 mmol), (2-fluoro-5-methylpyridine-3-yl)boronic acid (158 mg, 1.02 mmol), K3PO4 (130 mg, 0.610 mmol), XPhos (12 mg, 0.030 mmol), and Pd-170 (XPhos Pd(clotyl)Cl; 18 mg, 0.030 mmol) were added to the reaction vessel. The reaction vessel was evacuated, filled with N2, and then THF (4 mL) and water (1 mL) were added. The reaction mixture was sparged with N2 and heated overnight at 65°C. The cooled reaction mixture was diluted with CH2Cl2 (25 mL), washed with brine (3 × 25 mL), the organic phase was dried with (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (0-100% RINKAN in isohexane) yielded a white solid (130 mg, 78%). LC-MS (Method A) 306.6 [M+H] + , at 1.03 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.11 - 8.04 (m, 1H), 7.76 (dd, J = 9.1, 2.5 Hz, 1H), 4.50 - 4.39 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.30 - 2.17 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). The following intermediate compounds were prepared using a method similar to that of intermediate 14A. The procedure may be carried out at temperatures fluctuating between 60 and 70°C, and the stoichiometric amount of K3PO4 used may vary from 1.2 to 2.0 equivalents.
[0221] Intermediates 16C, 16E, and 16F were prepared from their corresponding pinacol esters. Intermediates 16D, 16E, and 16F were prepared using Pd-170 (10 mol%), XPhos (20 mol%), and 4 equivalents of K3PO4.
[0222] [Table 6-1]
[0223] [Table 6-2]
[0224] [Table 6-3]
[0225] 21A Ethyl 2-(6-fluoropyridine-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (Suzuki-Miyaura procedure B)
[0226] [ka]
[0227] Intermediate 9A (300 mg, 1.09 mmol), XPhos Pd G2 (43 mg, 0.055 mmol), and 2-fluoropyridine-5-boronic acid (231 mg, 1.64 mmol) were combined in a microwave vial, sealed, evacuated, and sparged with N2 (3×). K3PO4 (2M aqueous solution; 1.09 mL, 2.18 mmol) and THF (3 mL) were both degassed with N2 and added. The vial was heated at 80°C for 0.5 hours using MWI. The cooled mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (50-100% Â in heptane) to obtain an off-white solid (270 mg, 85%). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.33 (m, 1H), 8.15 (td, J = 8.3, 2.5 Hz, 1H), 7.22 (ddd, J = 8.6, 2.9, 0.7 Hz, 1H), 4.55 - 4.37 (m, 2H), 4.22 - 3.99 (m, 4H), 2.31 - 2.19 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).LRMS (APCI+)m / z 292.4[M+H]+ .
[0228] The following intermediate compounds were prepared using a method similar to that of intermediate 21A. The reaction time varied between 30 minutes and 1 hour 30 minutes, and heating was performed by MWI or conventional heating.
[0229] [Table 7-1]
[0230] [Table 7-2]
[0231] [Table 7-3]
[0232] [Table 7-4]
[0233] 26A Ethyl 2-(2,4-difluorophenyl)-4,4-dioxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazidine-3-carboxylate
[0234] [ka]
[0235] mCPBA (125 mg, 0.510 mmol) was added to a cooled solution (0°C) of intermediate 20B (65.5 mg, 0.2 mmol) in CH2Cl2 (5 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and quenched with 10% w / v aqueous Na2S2O3 (100 mL). The separated organic phase was washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), passed through a phase separation cartridge, and concentrated under vacuum to obtain a white solid (60 mg, 83%). This was used without further purification. LCMS (Method E): m / z 357.2 [M+H] + , at 0.59 minutes.
[0236] 26B Ethyl 2-(2-fluorophenyl)-4,4-dioxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylate
[0237] [ka]
[0238] It was prepared using a procedure similar to that described for intermediate 26A. LC-MS (Method E): m / z 339.2 [M+H] + , at 0.57 minutes. 27A Ethyl 3-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate
[0239] [ka]
[0240] Pd-170 (20 mg, 0.030 mmol), 2-fluorophenylboronic acid (155 mg, 1.10 mmol), intermediate 12A (150 mg, 0.55 mmol), and K3PO4 (130 mg, 0.610 mmol) were placed in a vial. The vial was evacuated, filled with N2, THF (2 mL) was added, sparged with N2, and heated overnight at 70°C. The reaction mixture was partitioned between siRNA (20 mL) and 1:1 water-brine (20 mL). The aqueous phase was extracted with siRNA (2 × 10 mL), the combined organic phase was washed with brine (20 mL), dried, and concentrated under reduced pressure in (MgSO4). Purification by flash chromatography (0-80%, siRNA in isohexane) yielded a white solid (154 mg, 87%). LC-MS (Method A) 245.2 [M-OEt] + , at 1.25 minutes. 1 H NMR (500 MHz, CDCl3) δ 7.38 - 7.32 (m, 1H), 7.32 - 7.25 (m, 1H), 7.18 - 7.12 (m, 1H), 7.12 - 7.05 (m, 1H), 4.36 - 4.33 (m, 2H), 4.33 - 4.27 (m, 4H), 2.37 - 2.25 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 27B Ethyl 3-(2,6-difluoropyridine-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate
[0241] [ka]
[0242] It was prepared using a procedure similar to that described for intermediate 27A. LC-MS (Method A) 264.3 [M-OEt] + , at 1:19. 1H NMR (500 MHz, CDCl3) δ 7.93 - 7.84 (m, 1H), 6.84 (dd, J = 8.1, 2.9 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.34 - 4.30 (m, 4H), 2.39 - 2.24 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). 28A Ethyl 7-(2-fluorophenyl)-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxylate
[0243] [ka]
[0244] It was prepared using a procedure similar to that described for intermediate 27A. LC-MS (Method A) 250.2 [M-OEt] + , at 1:16. 1 H NMR (500 MHz, CDCl3) δ 7.42 - 7.35 (m, 1H), 7.32 - 7.26 (m, 1H), 7.18 - 7.12 (m, 1H), 7.11 - 7.07 (m, 1H), 5.17 - 5.11 (m, 2H), 4.48 - 4.42 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 29A Ethyl 2-[6-(ethylamino)-2-fluoropyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0245] [ka]
[0246] Ethylamine (1.46 mL, 2.91 mmol, 2M in MeOH) and DIPEA (0.2 mL, 1.16 mmol) were added to a solution of intermediate 14C (180 mg, 0.58 mmol) in DMSO (3 mL), and the mixture was heated at 130°C for 0.5 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL), extracted with SiO (3 × 10 mL), and the combined organic fraction was dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography (50-100% SiO in heptane) yielded a white solid (79 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (dd, J = 10.0, 8.2 Hz, 1H), 7.02 (t, J = 5.5 Hz, 1H), 6.32 (dd, J = 8.3, 1.9 Hz, 1H), 4.42 (dd, J = 6.0, 4.4 Hz, 2H), 4.10 (t, J = 6.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.25 - 3.18 (m, 2H), 2.26 - 2.18 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z 334.9[M+H] + .
[0247] The following intermediate compounds were prepared using a method similar to that of intermediate 29A. The stoichiometry of the amine reactant can vary from 5 to 10 equivalents. Preparations 29C and 33A were heated overnight at 50°C. Preparation 30A was heated overnight at 130°C. Preparations 30B and 30C were heated at 130°C for approximately 48 hours.
[0248] [Table 8-1]
[0249] [Table 8-2]
[0250] 34A 2-(2-fluorophenyl)-5,5-dimethyl-6,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (ester hydrolysis procedure A)
[0251] [ka]
[0252] NaOH (2.5M aqueous solution, 0.88 mL, 2.18 mmol) was added to the solution of intermediate 22A (139 mg, 0.440 mmol) in EtOH (2 mL), and the mixture was heated overnight at 60°C. Volatile substances were removed under reduced pressure, and the residue was suspended in water (15 mL) and acidified to approximately pH 2 with 1 M HCl (aqueous solution; 2.62 mL). The resulting precipitate was filtered, washed with water, and dried under reduced pressure to produce a white solid (109 mg, 86%). This was used without further purification. 1 H NMR (700 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.44 - 7.36 (m, 2H), 7.25 - 7.17 (m, 2H), 4.15 (t, J = 6.4 Hz, 2H), 2.17 (t, J = 6.4 Hz, 2H), 1.45 (s, 6H). LRMS(APCI+)m / z291.2[M+H] + .
[0253] The following intermediate compounds were prepared using a procedure similar to that described for intermediate 34A. The procedure can be carried out at temperatures ranging from 50 to 70°C, depending on the specific reaction substrate. The procedure can be modified by substituting 2.5 M aqueous NaOH (5 equivalents) with 5 M aqueous NaOH (8 equivalents).
[0254] [Table 9-1]
[0255] [Table 9-2]
[0256] 43A (5R)-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0257] [ka]
[0258] LiOH (1.5M aqueous solution; 2.52 mL, 3.78 mmol) was added to the stirred solution of intermediate 16A (115 mg, 0.380 mmol) in THF:MeOH (1:1; 6 mL) and heated overnight at 40°C. The cooled reaction mixture was washed with MTBE (3 × 10 mL), the aqueous phase was acidified to approximately pH 1 with 1M aqueous HCl, and extracted with CHCl3:iPrOH (3:1; 3 × 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to produce a white solid (92 mg, 78%). LC-MS (Method A) 277.6 [M+H] + , at 0.86 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.46 - 7.29 (m, 2H), 7.27 - 7.14 (m, 2H), 4.64 - 4.51 (m, 1H), 4.19 - 4.09 (m, 2H), 2.29 - 2.22 (m, 1H), 2.05 (d, J = 7.0 Hz, 1H), 1.44 (d, J = 6.3 Hz, 3H). The following intermediate compounds were prepared using a procedure similar to that described for intermediate 43A.
[0259] [Table B]
[0260] 46A 2-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0261] [ka]
[0262] A solution of intermediate 21B (115 mg, 0.4 mmol) and LiOH (1 M aqueous solution; 3.21 mL, 3.21 mmol) in MeOH:THF (1:1; 10 mL) was heated at 35 °C for 48 hours. Additional LiOH (1 M aqueous solution; 3.21 mL, 3.21 mmol) was added, and the reaction was heated overnight at 60 °C. Volatile substances were removed under reduced pressure, and the residue was acidified to approximately pH 2 with 1 M aqueous HCl and extracted with SiO2 (3 × 10 mL). The combined organic extracts were washed with water and brine (10 mL each), dried, and the solvent was removed under reduced pressure to produce an orange solid (78 mg, 75%). f =0.15(2:1EtOAc:heptane). LRMS(APCI+)m / z258.8[M+H] + .
[0263] 47A (5R)-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (ester hydrolysis procedure B)
[0264] [ka]
[0265] A solution of intermediate 31A (46 mg, 0.13 mmol) and LiOH (25 mg, 1.04 mmol) in 1:1:1 MeOH:THF:water (3 mL) was heated at 50°C for 2 hours. The reaction mixture was cooled to room temperature, 1 M aqueous HCl (5 mL) was added, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic fraction was passed through a phase separator containing brine, and the solvent was removed under reduced pressure to produce a white solid (38 mg, 89%). LC-MS (Method A) 335.7 [M+H] + , at 0.96 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.41 (dd, J = 9.9, 8.2 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 8.2, 1.8 Hz, 1H), 4.59 - 4.50 (m, 1H), 4.12 - 4.03 (m, 2H), 3.94 - 3.84 (m, 1H), 2.28 - 2.21 (m, 1H), 2.06 - 1.95 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.4 Hz, 6H). The following intermediate compounds were prepared using the ester hydrolysis procedure described for intermediate 47A. The procedure can also be modified by varying the stoichiometry of LiOH from 4 to 8 equivalents depending on the reaction substrate.
[0266] [Table 10]
[0267] 52A 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0268] [ka]
[0269] A solution of intermediate 21E (45 mg, 0.146 mmol) and LiOH (1 M aqueous solution; 1.17 mL, 1.17 mmol) in MeOH:THF (1:1; 4 mL) was heated at 50 °C for 16 hours. Volatile substances were removed under reduced pressure, and the residue was acidified to approximately pH 2 with 1 M aqueous HCl and extracted with SiO2 (3 × 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried, and concentrated under reduced pressure to obtain a beige solid (36 mg, 88%). 1H NMR (700 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.42 (td, J = 8.4, 6.6 Hz, 1H), 7.25 (ddd, J = 10.2, 9.4, 2.6 Hz, 1H), 7.17 - 7.01 (m, 1H), 4.48 - 4.37 (m, 2H), 4.13 (t, J = 6.1 Hz, 2H), 2.23 (tt, J = 6.0, 2.9 Hz, 2H).LRMS (APCI+)m / z 281.0[M+H] + .
[0270] The following compounds were prepared using a method similar to that of intermediate 52A. The procedure can also be carried out at temperatures ranging from 50°C to 55°C.
[0271] [Table C]
[0272] 53A 2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylic acid
[0273] [ka]
[0274] LiOH (98 mg, 4.08 mmol) was added to the solution of intermediate 20A (63 mg, 0.2 mmol) in THF:water:MeOH (1:1:1; 12 mL) and heated at 70°C for 72 hours. The reaction mixture was cooled to room temperature, acidified with 1 M aqueous HCl (10 mL), and concentrated under vacuum to obtain a white solid (57 mg, 95%). This was used without further purification. LC-MS (Method E): m / z 279.2 [M+H] + , at 0.50 minutes.
[0275] The following compounds were prepared using a method similar to that of intermediate 53A. The procedure can also be carried out at temperatures ranging from 60°C to 70°C, depending on the specific substrate. The stoichiometric amount of LiOH can vary from 8 to 20 equivalents.
[0276] [Table D]
[0277] 55A 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0278] [ka]
[0279] LiOH (1.5M aqueous solution; 1.92 mL, 2.88 mmol) was added to a stirred solution of intermediate 29C (100 mg, 0.288 mmol) in THF:MeOH (1:1; 4 mL) and heated at 40°C over the weekend. The reaction mixture was cooled to room temperature, acidified with 1M aqueous HCl (1.9 mL), and concentrated under vacuum to obtain a white solid (57 mg, 95%), which was used without further purification. LC-MS (Method E): m / z 319.6 [M+H] + , at 0.83 minutes.
[0280] The following intermediate compounds were prepared using a procedure similar to that described for intermediate 55A.
[0281] [Table E]
[0282] 59A Ethyl 3,5-dibromo-1-(3,4-dihydroxybutyl)pyrazole-4-carboxylate
[0283] [ka]
[0284] A solution of 6 J (2.91 g, 6.83 mmol) of intermediate in AcOH (20 mL) and water (10 mL) was stirred at 110 °C for 2 hours, and then concentrated under vacuum. The resulting oily substance was dissolved in CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), and then passed through a phase separation cartridge. The solvent was removed under reduced pressure to obtain a colorless oily substance (2.80 g, 85%). This was used without further purification. LC-MS (Method A) 387.1 [M+H] + , at 0.99 minutes. 1 H NMR (500 MHz, CDCl3) δ 4.50 - 4.30 (m, 4H), 3.75 - 3.67 (m, 1H), 3.55 - 3.48 (m, 1H), 2.14 - 2.10 (m, 1H), 2.10 - 1.97 (m, 1H), 2.00 - 1.89 (m, 1H), 1.45 - 1.38 (m, 3H). 60A Ethyl 3,5-dibromo-1-[3-hydroxy-2-(hydroxymethyl)propyl]pyrazole-4-carboxylate
[0285] [ka]
[0286] HCl (1M aqueous solution) (11 mL, 11 mmol) was added to a solution of intermediate 6K (12 g, 28.2 mmol) in acetone (120 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and dried, and purified using flash chromatography (30-70% siRNA:heptane) to produce a colorless oily substance (9.39 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ 4.61 (t, J = 5.0 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.20 (d, J = 7.2 Hz, 2H), 3.45 - 3.35 (m, 4H), 2.19 - 2.05 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).LRMS m / z(APCI+)385.6 / 387.6 / 389.6[M+H] + .
[0287] 61A Ethyl 5-benzyl-3-bromo-1H-pyrazole-4-carboxylate
[0288] [ka]
[0289] A solution of sodium acetate (902 mg, 10.9 mmol) in water (10 mL) was slowly added to a solution of ethyl 5-benzyl-1H-pyrazole-4-carboxylate (500 mg, 2.17 mmol) in EtOH (7 mL). The mixture was cooled to 0°C using an ice bath, and Br2 (0.22 mL, 4.34 mmol) was added over 5 minutes. After 30 minutes, the ice bath was removed. Additional EtOH (7 mL) was added, and stirring was continued for 4 hours. Saturated aqueous solution Na2S2O3 (20 mL) and ethyl (15 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl (2 × 15 mL), the combined organic matter was washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (10-50% ethyl:heptane) yielded a white solid (385 mg, 57%). LRMS m / z(APCI+)309.3 / 311.3[M+H] + TLC R f = 0.63 (1:1 dimethyl: heptane).
[0290] 62A Ethyl(5R)-2-benzyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0291] [ka]
[0292] Solutions of intermediate 3B (317 mg, 1.30 mmol), intermediate 61A (365 mg, 1.18 mmol), and K2CO3 (490 mg, 3.54 mmol) in MeCN (10 mL) were heated at 60°C for 17 hours. The reaction mixture was cooled to room temperature, filtered, washed with MeCN (3 × 10 mL), and the filtrate was concentrated under reduced pressure. A mixture of ethyl 3-benzyl-5-bromo-1-[(2R)-4-hydroxybutan-2-yl]pyrazole-4-carboxylate and ethyl 5-benzyl-3-bromo-1-[(2S)-4-hydroxybutan-2-yl]pyrazole-4-carboxylate was obtained (480 mg). This was used without further purification. The crude residue (470 mg) was dissolved in THF (20 mL), cooled to 0°C, and NaH (60% dispersion in mineral oil, 99 mg, 2.46 mmol) was added. The reaction was carried out until it reached room temperature and stirred for 24 hours. The reaction was quenched with water (10 mL) and extracted with HCl (3 × 10 mL). The organic matter was washed with water and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by flash chromatography (1:1 HCl:heptane) yielded a white solid (138 mg, 39%). 1 H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.05 (m, 5H), 4.56 - 4.47 (m, 1H), 4.11 - 3.99 (m, 5H), 2.21 (d, J = 14.4 Hz, 1H), 2.02 - 1.89 (m, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).LRMS m / z(APCI+)301.4[M+H] + .
[0293] 63A 5-bromo-2-ethylpyrimidine
[0294] [ka]
[0295] Pd(PPh3)4 (304 mg, 0.260 mmol) was added under N2 to a cooled solution (0°C) of 5-bromo-2-iodopyrimidine (1.5 g, 5.27 mmol) in dry THF (15 mL). Diethylzinc (1 M in hexane; 6.84 mL, 6.84 mmol) was added dropwise, and the reaction was stirred at 0°C for 1 hour, then at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH4Cl solution (25 mL) and diluted with HCl (10 mL). The separated aqueous layer was extracted with HCl (3 × 20 mL), the combined organic matter was dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by flash chromatography (0-10%, HCl in isohexane) yielded a colorless oily substance (560 mg, 55%). LCMS (Method E) 187.6 / 189.6 [M+H] + , at 0.51 minutes. 1 H NMR (500 MHz, CDCl3) δ 8.69 (s, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H). 64A 1-(5-bromopyridine-2-yl)propane-2-ol
[0296] [ka]
[0297] To a stirred solution of 5-bromo-2-methylpyridine (1.4 mL, 3.49 mmol) in THF (10 mL), lithium diisopropylamide (2 M in THF / heptane / ethylbenzene; 2.5 mL, 5.0 mmol) was added dropwise at -78°C. The solution was stirred at -78°C for 20 minutes, and then acetaldehyde (0.6 mL, 10.7 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then allowed to reach room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous solution NH4Cl (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic extracts were combined, dried, and concentrated under reduced pressure (Na2SO4). The solution was purified by flash chromatography (0-30% Â in CH2Cl2) followed by (0-40% MeOH in CH2Cl2) to produce a yellow oily substance (285 mg, 36%). LC-MS (Method F) 216.1 / 218.1 [M+H] + , at 0.66 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 8.3, 2.5 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.63 (d, J = 4.9 Hz, 1H), 4.03 - 3.94 (m, 1H), 2.78 (dd, J = 13.3, 7.3 Hz, 1H), 2.71 (dd, J = 13.3, 5.6 Hz, 1H), 1.07 (d, J = 6.2 Hz, 3H). 65A Ethyl(5R)-2-(2-methoxypyridine-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (Suzuki-Miyaura Procedure C)
[0298] [ka]
[0299] To a stirred solution of 2-methoxypyridine-4-boronic acid (115 mg, 0.75 mmol) in 1,4-dioxane:water (3:1; 4 mL), K3PO4 (400 mg, 1.88 mmol), XPhos Pd G2 (29 mg, 0.04 mmol), and intermediate 9B (180 mg, 0.62 mmol) were added. The reaction vessel was spurged with N2 and heated overnight at 100°C. The reaction products were partitioned between RINKAN (10 mL) and water (10 mL), and the separated aqueous phase was extracted with RINKAN (3 × 10 mL). The combined organic matter was washed with brine (30 mL), dried, and concentrated under reduced pressure in (Na2SO4). Purification by flash chromatography (30-100% RINKAN in isohexane) yielded a white solid (186 mg, 90%). LC-MS (Method A) 318.6 [M+H] + , at 1.12 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J = 5.3, 0.8 Hz, 1H), 7.18 (dd, J = 5.3, 1.4 Hz, 1H), 7.02 - 7.02 (m, 1H), 4.63 - 4.56 (m, 1H), 4.20 - 4.07 (m, 4H), 3.87 (s, 3H), 2.32 - 2.23 (m, 1H), 2.08 - 1.98 (m, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). The following intermediate compounds were prepared using a method similar to that of intermediate 65A. Intermediates 65C and 66A were prepared from their corresponding pinacol esters.
[0300] [Table 11-1]
[0301] [Table 11-2]
[0302] [Table 11-3]
[0303] 68A Ethyl(5R)-2-(6-ethyl-2-methylpyridine-3-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0304] [ka]
[0305] KOAc (981 mg, 10 mmol) and bis(pinacolato)diborone (952 mg, 3.75 mmol) were added to a solution of 3-bromo-6-ethyl-2-methylpyridine (0.5 g, 2.50 mmol) in 1,4-dioxane (8 mL). The mixture was sparged with N2 for 10 minutes, Pd(dppf)Cl2 (91 mg, 0.12 mmol) was added, and the mixture was heated at 85°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with MTBE (10 mL), filtered through Celite, and washed with siRNA (40 mL). The filtrate was concentrated under reduced pressure to produce a brown oily substance (600 mg), and the residue was used directly in the next reaction. A portion of the crude residue (246 mg, 0.99 mmol) was suspended in THF:water (3:2; 10 mL) with intermediate 9A (180 mg, 0.62 mmol), K3PO4 (529 mg, 2.49 mmol), and XPhos (59 mg, 0.125 mmol). The reaction mixture was spurged with N2, Pd-170 (42 mg, 0.06 mmol) was added, and the reaction mixture was heated at 70°C for 1 hour. The reaction mixture was diluted with  (10 mL), washed with brine (20 mL), and the organic layer was passed through a phase separation cartridge to remove the solvent under reduced pressure. Purification by flash chromatography (0-5% MeOH in CH2Cl2) yielded a brown oily substance (125 mg, 56%). LC-MS (Method E) m / z 330.3 [M+H] + , at 0.27 minutes. 1H NMR (500 MHz, DMSO-d6) 7.43 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 4.72 - 4.53 (m, 1H), 4.24 - 4.08 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 2.73 (q, J = 7.6 Hz, 2H), 2.30 - 2.26 ( m, 1 H) 2.28 (s, 3H), 2.14 - 1.99 (m, 1H), 1.45 (d, J = 6.3 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H). The following intermediate compounds were prepared using a method similar to that of intermediate 68A.
[0306] [Table F]
[0307] 69A Ethyl(5R)-2-[6-(2-hydroxypropyl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0308] [ka]
[0309] KOAc (367 mg, 3.74 mmol) and bis(pinacolato)diborone (349 mg, 1.37 mmol) were added to a solution of intermediate 64A (270 mg, 1.25 mmol) in 1,4-dioxane (5 mL). The mixture was sparged with N2, Pd(dppf)Cl2 (69 mg, 0.09 mmol) was added, and the mixture was heated overnight at 100°C. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure to produce a brown oily substance. The crude residue was suspended in 1,4-dioxane:water (4:1; 5 mL), and K3PO4 (463 mg, 2.18 mmol), intermediate 9A (210 mg, 0.73 mmol), and XPhos Pd G2 (57 mg, 0.07 mmol) were added. The reaction mixture was sparged with N2 and heated at 100°C for 16 hours. The reaction mixture was partitioned between HCl (10 mL) and water (10 mL), and the separated aqueous phase was extracted with HCl (3 × 10 mL). The organic layers were combined, washed with brine (30 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (0-6% MeOH in CH2Cl2) yielded a brown solid (221 mg, 84%). LC-MS (Method E) m / z 346.3 [M+H] + (ES+), at 0.70 minutes. 1 H NMR (500 MHz, DMSO-d6) 8.62 (dd, J = 2.3, 0.8 Hz, 1H), 7.84 (dd, J = 8.0, 2.3 Hz, 1H), 7.26 (d, J = 8.0, 0.9 Hz, 1H), 4.69 (d, J = 4.8 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.19 - 4.11 (m, 2H), 4.10 - 3.99 (m, 3H), 2.86 (dd, J = 13.3, 7.0 Hz, 1H), 2.75 (dd, J = 13.3, 5.9 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.07 - 1.97 (m, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.10 - 1.05 (m, 3H). The following intermediate compounds were prepared using a similar method to that of intermediate 69A. Intermediates 69E, 69F, and 69G were prepared using 30 mol% XPhos Pd G2 and 3 equivalents of K3PO4.
[0310] [Table G-1] [Table G-2]
[0311] 72A Ethyl(5R)-2-anilino-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0312] [ka]
[0313] XPhos (50 mg, 0.10 mmol) and Tris(dibenzylideneacetone)dipalladium (0) (48 mg, 0.05 mmol) were added to a suspension of aniline (95 μL, 1.04 mmol), Cs2CO3 (341 mg, 1.04 mmol), and intermediate 9B (150 mg, 0.52 mmol) in 1,4-dioxane (2 mL). The reaction mixture was sparged with N2 and stirred overnight at 100 °C. The reaction product was partitioned between HCl (10 mL) and water (10 mL), and the separated aqueous phase was extracted with HCl (3 × 10 mL). The organic layers were combined, washed with brine (30 mL), dried, and concentrated under reduced pressure in (Na2SO4). Purification by column chromatography (0-50% HCl in isohexane) yielded a cream-colored solid (164 mg, 96%). LCMS (Method F) m / z302.2[M+H] + , at 2:30. 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.56 - 7.53 (m, 2H), 7.27 - 7.22 (m, 2H), 6.87 - 6.83 (m, 1H), 4.60 - 4.51 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.01 - 3.96 (m, 2H), 2.28 - 2.21 (m, 1H), 2.05 - 1.96 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 72B Ethyl(5R)-2-(4-fluoroanilino)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0314] [ka]
[0315] Further purification by ion-exchange chromatography (2g SCX cartridge, elution with 0.7M NH3 in MeOH) was performed, and the intermediate was prepared in a manner similar to that of intermediate 72A. LC-MS (Method A) 320.0[M+H] + , at 1.55 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.62 - 7.55 (m, 2H), 7.13 - 7.04 (m, 2H), 4.60 - 4.51 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.01 - 3.95 (m, 2H), 2.29 - 2.20 (m, 1H), 2.06 - 1.94 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 73A Ethyl(5R)-2-(5-cyclopropyl-2-fluoropyridine-3-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0316] [ka]
[0317] Potassium cyclopropyl trifluoroborate (75.8 mg, 0.51 mmol), Pd-170 (17.3 mg, 0.03 mmol), and K2CO3 (177 mg, 1.28 mmol) were added to a reaction vessel purged with nitrogen. A solution of intermediate 65E (145 mg, 0.43 mmol) in THF:water (1:1; 4 mL) was added, the reaction vessel was spurged with nitrogen, and the mixture was heated at 70°C for 16 hours. The reaction mixture was cooled to room temperature and partitioned between water (30 mL) and pharmaceutically acceptable (30 mL). The aqueous phase was extracted with pharmaceutically acceptable (3 × 10 mL). The combined organic layers were washed with brine (40 mL), dried, and concentrated under reduced pressure in (Na2SO4). Purification by column chromatography (0-80% RINKAN in isohexane) yielded a white solid (37 mg, 25%). LCMS (Method A) m / z346.0[M+H] + , at 1:29. 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (dd, J = 2.5, 1.1 Hz, 1H), 7.56 (dd, J = 8.9, 2.5 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.23 - 4.12 (m, 2H), 4.02 (q, J = 7.1 Hz, 2H), 2.33 - 2.27 (m, 1H), 2.10 - 1.99 (m, 2H), 1.46 (d, J = 6.3 Hz, 3H), 1.08 - 0.98 (m, 5H), 0.78 - 0.74 (m, 2H). 74A Ethyl 2-(2,6-difluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0318] [ka]
[0319] Intermediate 9S (400 mg, 1.31 mmol), CsF (797 mg, 5.24 mmol), 2,6-difluorophenylboronic acid (1035 mg, 6.55 mmol), and XPhos Pd G2 (206 mg, 0.26 mmol) were combined in a vial, capped, evacuated, and sparged with N2 (3 ×). 1,4-dioxane (4.5 mL) and water (2.25 mL) were both degassed with N2 and added. The reaction mixture was heated at 100 °C for 17 hours. The reaction mixture was cooled to room temperature, and then 1,4-dioxane was removed under reduced pressure. Water (15 mL) was added, and the mixture was extracted with SiO2 (3 × 15 mL). The organic extract was washed with water and brine (15 mL each), dried, and concentrated under reduced pressure using (Na2SO4). The residue was purified by flash chromatography (70-100% ethyl heptane) to produce a colorless oily substance (180 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.42 (m, 1H), 7.22 - 7.04 (m, 2H), 5.16 (t, J = 5.6 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.28 - 4.14 (m, 2H), 3.99 - 3.92 (m, 2H), 3.76 - 3.63 (m, 2H), 2.37 - 2.25 (m, 1H), 2.25 - 2.09 (m, 1H), 0.97 (t, J = 7.1 Hz, 3H).LRMS m / z(APCI+)339.1[M+H] + .
[0320] The following intermediate compounds were prepared using a procedure similar to that described for intermediate 74A. Both were packed with 10 mol% XPhos PdG2 catalyst.
[0321] [Table 12]
[0322] 76A Ethyl 2-(2,6-difluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0323] [ka]
[0324] Intermediate 9R (142 mg, 0.47 mmol), CsF (283 mg, 1.86 mmol), 2,6-difluorophenylboronic acid (735 mg, 4.65 mmol), and XPhos Pd G2 (36 mg, 0.05 mmol) were combined in a microwave vial, capped, evacuated, and sparged with N2 (3×). Water (0.9 mL) and 1,4-dioxane (1.8 mL) were both degassed with N2 and added, and the vial was heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, an additional XPhos Pd G2 (37 mg, 0.05 mmol) was added, the vial was sealed, and then heated for a further 18 hours. A yellow oily substance (59 mg, 38%) was produced by work-up and purification similar to that described for intermediate 74A. TLCR f =0.61(EtOAc)LRMS m / z(APCI+)339.4[M+H] + .
[0325] 77A 1-Bromo-4-ethylsulfonyl-2-fluorobenzene
[0326] [ka]
[0327] Hydrazine monohydrate (12.4 mL, 255 mmol) was added dropwise to a cooled solution (0°C) of 4-bromo-3-fluorobenzenesulfonyl chloride (20.0 g, 73.1 mmol) in THF (200 mL). The reaction mixture was allowed to reach room temperature and stirred for 1 hour. Heptane (1000 mL) was added, and the resulting precipitate was collected by filtration. The white precipitate was dissolved in anhydrous EtOH (400 mL), then NaOAc (36.0 g, 439 mmol) and EtI (29.4 mL, 366 mmol) were added, and the reaction mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (600 mL) was added, and the mixture was extracted with ELISA (3 × 600 mL). The combined organic layers were washed with brine (600 mL), dried, and volatiles were removed under reduced pressure. Purification by column chromatography (15-40% dimethyl heptane) yielded a white solid (12.1 g, 62%). 1 H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 8.3, 6.4 Hz, 1H), 7.64 (dd, J = 7.5, 2.0 Hz, 1H), 7.57 (ddd, J = 8.3, 2.0, 0.8 Hz, 1H), 3.12 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H).TLCR f =0.57(τ).
[0328] 78A 2-Bromo-1-fluoro-4-methylsulfonylbenzene
[0329] [ka]
[0330] A solution of N-bromosuccinimide (8.22 g, 46.2 mmol) was added to a solution of 4-fluorophenylmethylsulfone (8.05 g, 46.2 mmol) in concentrated H2SO4 (80 mL), and the reaction mixture was heated at 50°C for 3.5 hours. The reaction mixture was cooled to room temperature, and the mixture was poured into ice water (270 mL). The resulting mixture was stirred until cooled (to approximately 10°C), and the precipitate was collected by filtration. The solid solution was washed with water, dried on filter paper, and then dried overnight under reduced pressure to obtain a white solid (10.3 g, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (dd, J = 6.4, 2.3 Hz, 1H), 7.99 (ddd, J = 8.7, 4.6, 2.3 Hz, 1H), 7.65 (t, J = 8.6 Hz, 1H), 3.30 (s, 3H).TLCR f =0.57(τ).
[0331] 79A 4-Bromo-3-fluoro-N,N-dimethylbenzenesulfonamide
[0332] [ka]
[0333] A solution of 4-bromo-3-fluorobenzenesulfonyl chloride (10.0 g, 36.6 mmol) in CH2Cl2 (120 mL) was cooled to approximately 10°C in an ice bath. A solution of dimethylamine (33% in ethanol; 13.7 mL, 76.8 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was washed with 1 M aqueous HCl (350 mL) and brine (215 mL). The organic phase was separated, dried (MgSO4), filtered, and volatiles were removed under reduced pressure to produce a white solid (10.7 g, quantified). This was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.3, 6.5 Hz, 1H), 7.51 (dd, J = 7.7, 2.0 Hz, 1H), 7.44 (ddd, J = 8.3, 2.1, 0.8 Hz, 1H), 2.73 (s, 6H).TLCR f = 0.59 (Â).
[0334] 80A 2-(4-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
[0335] [ka]
[0336] The solutions of intermediate 77A (11.6 g, 43.4 mmol), bis(pinacolato)diborone (13.2 g, 52.0 mmol), and KOAc (8.50 g, 86.7 mmol) in 1,4-dioxane (120 mL) were sparged with N2 for approximately 20 minutes. Pd(dppf)Cl2·CH2Cl2 (0.952 g, 1.30 mmol, 3 mol%) were added, and the reaction mixture was heated overnight at 85-90°C. The reaction mixture was cooled to room temperature, diluted with SiO2 (200 mL), filtered through Celite, and washed with SiO2. The filtrate was washed with H2O (100 mL) and brine (100 mL), dried, and volatiles were removed under reduced pressure using (Na2SO4). The residue was purified by column chromatography (0-100% SiO2 / heptane), then dissolved in CH2Cl2, and heptane (100 mL) was added. CH2Cl2 was removed under reduced pressure, and the suspension in heptane was stirred at room temperature for 1 hour. The solid was collected by filtration under reduced pressure, washed with heptane, and dried under reduced pressure to obtain a white solid (11.0 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.7, 5.5 Hz, 1H), 7.66 (dd, J = 7.7, 1.6 Hz, 1H), 7.57 (dd, J = 8.1, 1.5 Hz, 1H), 3.11 (q, J = 7.4 Hz, 2H), 1.37 (s, 12H), 1.27 (t, J = 7.4 Hz, 3H).TLCR f =0.43(A).
[0337] The following intermediate compounds were prepared using a method similar to that of intermediate 80A.
[0338] [Table 13]
[0339] The following intermediate compounds were prepared in a manner similar to that of intermediate 21A. Reaction times varied from 30 minutes to 3 hours, and heating was performed by MWI or conventional heating. Intermediates 88T-88W were heated overnight at 85°C by conventional heating. Catalyst packing varied from 5-10 mol% XPhos PdG2. Intermediates 81J-81W, 84B, and 85A were prepared from their corresponding pinacol esters. Unless otherwise specified, 1 1H NMR was performed in DMSO-d6 using a 400 MHz spectrometer.
[0340] [Table 14-1]
[0341] [Table 14-2]
[0342] [Table 14-3]
[0343] [Table 14-4]
[0344] [Table 14-5]
[0345] [Table 14-6]
[0346] [Table 14-7]
[0347] 90A Ethyl(5R)-2-[6-(3-methoxyazetidine-1-yl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0348] [ka]
[0349] Solutions of intermediate 81A (200 mg, 0.66 mmol), 3-methoxyazetidine hydrochloride (324 mg, 2.62 mmol), and DIPEA (913 μL, 5.24 mmol) in anhydrous DMSO (3 mL) were heated overnight at 130 °C. The reaction mixture was cooled to room temperature and partitioned between brine and SiO (10 mL each). The aqueous layer was extracted with SiO (4 × 15 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried, and the solvent was removed under reduced pressure. A light brown solid (191 mg, 78%) was obtained by purification by flash chromatography [10-36%, in CH2Cl2 (EtOH:CH2Cl2:NH4OH; 50:8:1)]. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J = 2.3, 0.8 Hz, 1H), 7.70 (dd, J = 8.6, 2.3 Hz, 1H), 6.39 (dd, J = 8.7, 0.8 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.37 - 4.29 (m, 1H), 4.19 - 4.03 (m, 6H), 3.80 - 3.73 (m, 2H), 3.25 (s, 3H), 2.31 - 2.20 (m, 1H), 2.07 - 1.93 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).LRMS m / z(APCI+)373.6[M+H] + .
[0350] The following preliminary intermediates were prepared using a procedure similar to that for intermediate 90A.
[0351] [Table H]
[0352] 90D Ethyl-(5R)-5-methyl-2-[6-(triduteriomethylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0353] [ka]
[0354] DIPEA (571 μL, 3.28 mmol) and methyl-d3-amine hydrochloride (144 mg, 2.05 mmol) were added to intermediate 81A (125 mg, 0.409 mmol) in DMSO (3 mL) and heated in MWI at 140 °C for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was washed with brine (3 × 20 mL), dried, and the solvent was removed under reduced pressure. Purification by ion-exchange chromatography (2 g SCX-2 cartridge, eluted with 2N NH3 in MeOH) yielded an orange solid (61 mg, 47%). LC-MS (Method B) m / z 385.4 [M+H] + , at 0.67 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.18 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.6, 2.4 Hz, 1H), 6.56 (s, 1H), 6.41 (d, J = 8.7 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.16 - 4.04 (m, 4H), 2.30 - 2.21 (m, 1H), 2.06 - 1.95 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 90E Ethyl(5R)-5-methyl-2-[6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0355] [ka]
[0356] Isopropylamine (156 μL, 1.82 mmol) and DIPEA (79 μL, 0.45 mmol) were added to a solution of intermediate 81A (138 mg, 0.45 mmol) in DMSO (3 mL) and heated overnight at 60°C. Further isopropylamine (312 μL, 3.64 mmol) was added, and the reaction mixture was heated overnight at 100°C, followed by heating at 100°C for 16 hours using MWI. The reaction mixture was partitioned between CH2Cl2 (10 mL) and saturated aqueous solution NH4Cl (10 mL), and the separated aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried, and concentrated under reduced pressure in (Na2SO4). Purification by flash chromatography (50-100% Â in isohexane) yielded a pink solid (56 mg, 35%). LCMS (Method B) m / z345.4[M+H] + , at 1:16. 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.7, 2.4 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 8.7 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.13 - 4.05 (m, 4H), 4.04 - 3.96 (m, 1H), 2.29 - 2.20 (m, 1H), 2.06 - 1.94 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.19 - 1.13 (m, 9H). 90F Ethyl(5R)-5-methyl-2-(6-morpholine-4-ylpyridine-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0357] [ka]
[0358] Morpholine (158 μL, 1.81 mmol) and DIPEA (79 μL, 0.45 mmol) were added to the solution of intermediate 81A (138 mg, 0.45 mmol) in DMSO (3 mL), and the mixture was heated overnight at 60°C. Further morpholine (158 μL, 1.81 mmol) was added, and the reaction mixture was heated overnight at 100°C. Similar workup and purification of intermediate 90E yielded a pink solid (130 mg, 77%). LC-MS (Method B) m / z 373.5 [M+H] + , at 1.09 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.33 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.8, 2.4 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.61 - 4.54 (m, 1H), 4.17 - 4.06 (m, 4H), 3.73 - 3.69 (m, 4H), 3.50 - 3.46 (m, 4H), 2.30 - 2.23 (m, 1H), 2.07 - 1.97 (m, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 90G Ethyl(5R)-5-methyl-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0359] [ka]
[0360] (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (115 mg, 0.85 mmol) and DIPEA (296 μL, 1.70 mmol) were added to intermediate 81A (130 mg, 0.426 mmol) in DMSO (3 mL) and heated by MWI at 130°C for 4 hours. Further (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (115 mg, 0.85 mmol) was added, and the reaction was heated by MWI at 130°C for 8 hours. A similar workup and purification for intermediate 29A yielded a pink solid (58 mg, 35%). LC-MS (Method B) m / z 385.4 [M+H] + , at 0.67 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (dd, J = 2.4, 0.8 Hz, 1H), 7.69 (dd, J = 8.7, 2.3 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 4.89 - 4.85 (m, 1H), 4.68 - 4.64 (m, 1H), 4.61 - 4.52 (m, 1H), 4.17 - 4.04 (m, 4H), 3.78 (dd, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.47 (dd, J = 10.1, 1.5 Hz, 1H), 3.33 - 3.22 (m, 1H), 2.30 - 2.22 (m, 1H), 2.10 - 1.95 (m, 1H), 1.92 (dd, J = 9.8, 2.3 Hz, 1H), 1.89 - 1.82 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 90H Ethyl(5R)-5-methyl-2-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0361] [ka]
[0362] The intermediate 90G was prepared using a procedure similar to the one described. LC-MS (Method B) was performed at m / z 385.4[M+H]+, 0.67 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.7, 2.4 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 4.87 (s, 1H), 4.66 (d, J = 2.5 Hz, 1H), 4.61 - 4.53 (m, 1H), 4.16 - 4.03 (m, 4H), 3.78 (dd, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.47 (dd, J = 10.1, 1.5 Hz, 1H), 3.25 (d, J = 10.0 Hz, 1H), 2.30 - 2.23 (m, 1H), 2.10 - 1.95 (m, 1H), 1.92 (dd, J = 9.9, 2.3 Hz, 1H), 1.85 (d, J = 9.5 Hz, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 90I Ethyl(5R)-2-[6-(ethylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0363] [ka]
[0364] The intermediate 29A was prepared using a procedure similar to that of intermediate 29A, and heating was carried out by MWI at 100°C for 30 minutes, followed by heating at 130°C for 7.5 hours. LC-MS (Method B) m / z 331.4[M+H]+, 1.05 min. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.6, 2.4 Hz, 1H), 6.59 (t, J = 5.5 Hz, 1H), 6.41 (dd, J = 8.7, 0.8 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.15 - 4.01 (m, 4H), 3.31 - 3.22 (m, 2H), 2.29 - 2.21 (m, 1H), 2.06 - 1.94 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). 91A Ethyl(5S)-5-methyl-2-[6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0365] [ka]
[0366] The intermediate 29A was prepared using a procedure similar to that of intermediate 29A, and heating was performed by MWI at 130°C for 6 hours. LC-MS (Method A) 345.4 [M+H] + , at 0.70 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.18 - 8.13 (m, 1H), 7.53 (dd, J = 8.6, 2.4 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.43 - 6.38 (m, 1H), 4.60 - 4.50 (m, 1H), 4.15 - 4.05 (m, 4H), 4.04 - 3.95 (m, 1H), 2.29 - 2.22 (m, 1H), 2.06 - 1.94 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.19 - 1.12 (m, 9H). 91B Ethyl(5S)-5-methyl-2-[6-[-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0367] [ka]
[0368] The intermediate 90G was prepared using a procedure similar to the one described. LC-MS (Method A) m / z 385.5 [M+H] + , at 0.66 minutes. 1 H NMR (500 MHz, DMSO-d6) δ (DMSO-d6) 8.29 - 8.25 (m, 1H), 7.70 (dd, J = 8.7, 2.4 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 4.88 (s, 1H), 4.69 - 4.65 (m, 1H), 4.61 - 4.52 (m, 1H), 4.17 - 4.05 (m, 4H), 3.82 - 3.76 (m, 1H), 3.65 (d, J = 7.2 Hz, 1H), 3.51 - 3.45 (m, 1H), 3.32 - 3.23 (m, 1H), 2.30 - 2.23 (m, 1H), 2.08 - 1.96 (m, 1H), 1.95 - 1.89 (m, 1H), 1.89 - 1.83 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 92A Ethyl 2-[6-(propan-2-ylamino)pyridine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxylate
[0369] [ka]
[0370] Isopropylamine (839 μL, 9.77 mmol) and DIPEA (340 μL, 1.95 mmol) were added to intermediate 84A (310 mg, 0.98 mmol) in DMSO (6 mL) and heated at 140 °C for 48 hours. A similar workup and purification for intermediate 29A yielded an orange solid (225 mg, 65%). 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.7, 2.4 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 8.7 Hz, 1H), 4.21 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.05 - 3.95 (m, 3H), 1.19 - 1.08 (m, 8H), 0.83 - 0.75 (m, 4H).LRMS(APCI+)m / z 357.4[M+H] + 93A Ethyl 2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0371] [ka]
[0372] NaH (60% dispersion in mineral oil, 17 mg, 0.43 mmol) was added to the solution of intermediate 87A (55 mg, 0.17 mmol) in THF (6 mL) and stirred at room temperature for 15 minutes. MeI (53 μL, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. Then it was quenched with saturated aqueous solution NH4Cl (10 mL) and extracted with GaN (15 mL). The organic layer was washed with brine (20 mL), passed through a phase separation cartridge, and concentrated under vacuum. Purification by flash chromatography (0-100% MTBE in isohexane, followed by 10% MeOH in MTBE) yielded a colorless oily substance (34 mg, 59%). LC-MS (Method A) m / z 335.2 [M+H] + , at 1:21.
[0373] 93B Ethyl 2-(2-fluorophenyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0374] [ka]
[0375] The intermediate 93A was prepared using a procedure similar to the one described. LRMS(APCI+)m / z 335.7[M+H] + TLCR f = 0.84 (2:1 HCl:heptane).
[0376] 94A Ethyl 2-(2-fluorophenyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0377] [ka]
[0378] The intermediate 93A was prepared using a procedure similar to the one described. LRMS(APCI+)m / z 321.2[M+H] + TLCR f =0.31(ԅ). 95A Ethyl 2-(2-fluorophenyl)-6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0379] [ka]
[0380] NaH (60% dispersion in mineral oil, 24.7 mg, 0.62 mmol) was added to the solution of intermediate 89A (100 mg, 0.25 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 0.5 hours. MeI (0.04 mL, 0.62 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. A colorless oily substance (94 mg, 91%) was produced by work-up and purification similar to that described for intermediate 93A. LRMS m / z(APCI+)420.4[M+H] + TLCR f = 0.52 (1:1 mmol: heptane).
[0381] 96A Ethyl 2-(2-fluorophenyl)-6-[(4-methylphenyl)sulfonyloxymethyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0382] [ka]
[0383] A solution of TsCl (1.34 g, 7.02 mmol) in CH2Cl2 (5 mL) was added dropwise over 5 minutes to a chilled solution (0°C) of 88A (900 mg, 2.81 mmol) and NEt3 (0.98 mL, 7.02 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at 0°C for 30 minutes, then stirred at room temperature for 19 hours. Water (20 mL) was added, the organic layer was separated, washed with water and brine (10 mL each), dried, and concentrated under reduced pressure in (Na2SO4). Purification by flash chromatography (30-60% Â:heptane) yielded a colorless oily substance (1.25 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.77 (m, 2H), 7.52 - 7.32 (m, 4H), 7.28 - 7.15 (m, 2H), 4.48 (dd, J = 10.9, 3.2 Hz, 1H), 4.32 - 4.18 (m, 3H), 4.22 - 4.12 (m, 2H), 4.05 - 3.96 (m, 2H), 3.91 (dd, J = 12.5, 7.0 Hz, 1H), 2.81 (s, 1H), 2.40 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z334.9[M+H] + .
[0384] 96B Ethyl 2-(2-fluorophenyl)-5-[(4-methylphenyl)sulfonyloxymethyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0385] [ka]
[0386] It was prepared using a procedure similar to that described for intermediate 96A. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.82 (m, 2H), 7.52 - 7.47 (m, 2H), 7.47 - 7.35 (m, 2H), 7.25 - 7.18 (m, 2H), 4.86 - 4.73 (m, 1H), 4.43 (dd, J = 11.2, 2.6 Hz, 1H), 4.31 (dd, J = 11.2, 6.3 Hz, 1H), 4.23 - 4.08 (m, 2H), 4.08 - 3.91 (m, 2H), 2.42 (s, 3H), 2.34 - 2.19 (m, 1H), 2.19 - 2.06 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z475.6[M+H] + .
[0387] 97A Ethyl 6-[(dimethylamino)methyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0388] [ka]
[0389] A solution of intermediate 96A (104 mg, 0.22 mmol) and dimethylamine (2 M in THF; 0.76 mL, 1.52 mmol) in 1,4-dioxane (1.5 mL) was heated at 120 °C for 24 hours. The reaction mixture was cooled to room temperature, volatiles were removed under reduced pressure, and the residue was purified by column chromatography to produce an orange oily substance (103 mg, 78%) [0-30%, in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)]. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.35 (m, 1H), 7.29 - 7.12 (m, 1H), 4.50 (dd, J = 10.8, 3.3 Hz, 1H), 4.31 - 4.13 (m, 1H), 4.08 - 3.96 (m, 1H), 3.88 (dd, J = 12.3, 7.9 Hz, 1H), 2.71 - 2.60 (m, 1H), 2.32 - 2.23 (m, 1H), 2.18 (s, 3H), 1.03 (t, J = 7.1 Hz, 1H).LRMS(APCI+)m / z348.4[M+H] + .
[0390] The following intermediate compounds were prepared using a method similar to that described for intermediate 97A. The procedure was carried out at temperatures in the range of 110°C to 140°C.
[0391] [Table 15-1]
[0392] [Table 15-2]
[0393] [Table 15-3]
[0394] 99A Ethyl 2-(2-fluorophenyl)-6-(methylsulfanylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0395] [ka]
[0396] Sodium methanethiophosphate (49.6 mg, 0.71 mmol) was added to a chilled solution (0°C) of intermediate 96A (280 mg, 0.59 mmol) in EtOH (4 mL). After 1 hour, the ice bath was removed and the mixture was stirred at room temperature for 16 hours. The reaction product was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography (0-50% siRNA:heptane) to produce a colorless oily substance (129 mg, 62%). 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.37 (m, 2H), 7.28 - 7.10 (m, 2H), 4.56 (dd, J = 10.7, 2.6 Hz, 1H), 4.38 - 4.22 (m, 2H), 4.08 - 3.90 (m, 3H), 2.71 - 2.56 (m, 3H), 2.12 (s, 2H), 1.03 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z351.1[M+H] + .
[0397] 100A Ethyl 2-(2-fluorophenyl)-6-(methylsulfonylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0398] [ka]
[0399] A solution of mCPBA (240 mg, 1.07 mmol) in CH2Cl2 (5 mL) was added to a chilled solution (0°C) of intermediate 99A (125 mg, 0.36 mmol) in CH2Cl2 (5 mL). After 1 hour, the ice bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was washed with saturated aqueous NaHCO3 (2 × 10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (20-100% Â:heptane) yielded a colorless oily substance (101 mg, 74%). 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.36 (m, 2H), 7.29 - 7.13 (m, 2H), 4.58 (dd, J = 10.7, 3.2 Hz, 1H), 4.47 - 4.27 (m, 2H), 4.11 (dd, J = 12.4, 7.3 Hz, 1H), 4.08 - 3.94 (m, 2H), 3.49 - 3.34 (m, 3H), 3.12 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H).LRMS(APCI+)m / z383.1[M+H] + .
[0400] 101A Ethyl(5R)-2-cyclohexyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0401] [ka]
[0402] Carbon-supported palladium (10 wt% packing; 25 mg, 0.24 mmol) was added in a pressure tube to a solution of intermediate 81R (230 mg, 0.79 mmol) in EtOH (6 mL). The container was successively purged with N2 (5 ×) and hydrogen (5 ×), and then stirred at 40 psi under a hydrogen atmosphere at room temperature for 96 hours. The mixture was filtered through a glass microfiber pad, washed with EtOH (3 × 10 mL), and the solvent was removed under reduced pressure to produce a beige solid (198 mg, 86%). LRMS(APCI+) m / z 293.5 [M+H] + TLCR f = 0.5 (2:1 toluene: heptane) 101B Ethyl(5R)-5-methyl-2-piperidine-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0403] [ka]
[0404] Further purification by flash chromatography (50:8:1 CH2Cl2:EtOH:NH4OH) was performed, and the intermediate 101A was prepared using a procedure similar to that described. 1 H NMR (700 MHz, DMSO-d6) δ 4.53 - 4.45 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.07 - 3.95 (m, 2H), 3.12 - 3.02 (m, 1H), 2.96 (d, J = 11.9 Hz, 2H), 2.23 - 2.15 (m, 1H), 1.99 - 1.89 (m, 1H), 1.73 - 1.65 (m, 2H), 1.53 - 1.42 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z294.4[M+H] + .
[0405] 102A Ethyl(5R)-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0406] [ka]
[0407] MsCl (70 μL, 0.89 mmol) was added to a chilled solution (0°C) of intermediate 101B (175 mg, 0.60 mmol) and NEt3 (0.25 mL, 1.79 mmol) in CH2Cl2 (10 mL), and the reaction mixture was stirred at room temperature for 21 hours. Volatile substances were removed under reduced pressure, and the residue was purified by flash chromatography [10-30%, in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)] to produce a white solid (203 mg, 92%). 1 H NMR (400 MHz, DMSO-d6) δ 4.58 - 4.43 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.09 - 3.97 (m, 2H), 3.62 (d, J = 11.7 Hz, 2H), 3.17 - 3.06 (m, 1H), 2.87 (s, 3H), 2.77 (td, J = 12.1, 2.6 Hz, 2H), 2.26 - 2.16 (m, 1H), 2.03 - 1.87 (m, 3H), 1.71 - 1.55 (m, 2H), 1.39 (d, J = 6.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).LRMS(APCI+)m / z372.4.
[0408] 102B Ethyl(5R)-2-(1-ethylsulfonylpiperidine-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0409] [ka]
[0410] Using ethanesulfonyl chloride, the intermediate 102A was prepared using a procedure similar to that described for intermediate 102A. LRMS APCI(+) 386.3[M+H] + TLCR f =0.53(200:8:1 CH2Cl2:EtOH:NH3) The following intermediate compounds were prepared using a procedure similar to that described for intermediate 43A.
[0411] [Table 16]
[0412] The following intermediate compounds were prepared using 5M aqueous NaOH (8 equivalents) in a procedure similar to that described for intermediate 34A. This procedure can be carried out at a temperature of 50-70°C. Intermediate 113B was prepared using 5M aqueous NaOH (16 equivalents). Unless otherwise specified, 1 1H NMR was performed in DMSO-d6 using a 400 MHz spectrometer.
[0413] [Table 17-1]
[0414] [Table 17-2]
[0415] [Table 17-3]
[0416] [Table 17-4]
[0417] [Table 17-5]
[0418] [Table 17-6]
[0419] [Table 17-7]
[0420] [Table 17-8]
[0421] 113U (5R)-5-methyl-2-(1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0422] [ka]
[0423] NaOH (5M aqueous solution, 0.3 mL, 1.49 mmol) was added to the mixture of intermediate 81F (66 mg, 0.19 mmol) in EtOH (5 mL). The mixture was heated at 60°C for 19 hours. Volatile substances were removed under reduced pressure, and the mixture was acidified with 1M aqueous HCl (pH approximately 4). The mixture was extracted with CHCl3:iPrOH (3:1; 3 × 10 mL), and the organic matter was washed with water and brine (10 mL each), dried (Na2SO4), and concentrated under reduced pressure to produce a white solid (43 mg, 93%). 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 2H), 8.05 (dd, J = 8.9, 5.0 Hz, 2H), 4.52 (ddd, J = 8.7, 6.5, 2.3 Hz, 1H), 4.15 - 4.03 (m, 2H), 3.16 (d, J = 4.9 Hz, 2H), 2.23 (d, J = 14.4 Hz, 1H), 1.98 (ddd, J = 16.7, 13.1, 8.4 Hz, 1H), 1.42 (d, J = 6.3 Hz, 3H).LRMS(APCI+)m / z249.2[M+H] + .
[0424] 113V (5R)-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0425] [ka]
[0426] NaOH (0.8 mL of 5M aqueous solution, 3.98 mmol) was added to the suspension of intermediate 102A in EtOH (20 mL). The mixture was heated at 60°C for 3 hours. NaOH (0.8 mL of 5M aqueous solution, 3.98 mmol) was added, and the mixture was heated at 70°C for 2 hours. NaOH (1.59 mL of 5M aqueous solution, 7.97 mmol) was added, and the mixture was heated at 80°C for 18 hours. EtOH was removed under reduced pressure, the mixture was acidified to approximately pH 2 with 1M aqueous solution HCl, and extracted with CHCl3:iPrOH (3:1; 3 × 20 mL). The organic matter was washed with 20 mL of water and brine (each), dried, and concentrated under reduced pressure to produce a white solid (151 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 4.55 - 4.43 (m, 1H), 4.10 - 3.95 (m, 2H), 3.60 (d, J = 11.7 Hz, 2H), 3.21 - 3.08 (m, 1H), 2.87 (s, 3H), 2.77 (td, J = 12.1, 2.6 Hz, 2H), 2.25 - 2.12 (m, 1H), 2.04 - 1.83 (m, 3H), 1.70 - 1.52 (m, 2H), 1.39 (d, J = 6.3 Hz, 3H).LRMS(APCI+)m / z344.5[M+H] + .
[0427] 113W (5R)-2-(1-ethylsulfonylpiperidine-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0428] [ka]
[0429] It was prepared using a procedure similar to that described for intermediate 113V. 1 H NMR (700 MHz, DMSO-d6) δ 11.76 (s, 1H), 4.54 - 4.43 (m, 1H), 4.08 - 3.96 (m, 2H), 3.70 - 3.58 (m, 2H), 3.23 - 3.13 (m, 1H), 3.04 (q, J = 7.4 Hz, 2H), 2.86 (td, J = 12.3, 2.6 Hz, 2H), 2.26 - 2.15 (m, 1H), 1.97 - 1.91 (m, 1H), 1.92 - 1.86 (m, 2H), 1.66 - 1.54 (m, 2H), 1.39 (d, J = 6.3 Hz, 3H), 1.21 (t, J = 7.4 Hz, 3H).LRMS(APCI+)358.1m / z[M+H] + .
[0430] 114A 6-[ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0431] [ka]
[0432] NaH (60% dispersion in mineral oil, 18.5 mg, 0.46 mmol) was added to the solution of intermediate 89A (75 mg, 0.19 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 0.5 hours. EtI (40 μL, 0.46 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction product was quenched with water (20 mL) and extracted with HCl (3 × 10 mL). The organic matter was washed with water (2 × 10 mL) and brine (10 mL), dried, and concentrated under reduced pressure in (Na₂SO₄). Purification by flash chromatography (10-35% HCl:heptane) yielded a colorless oily substance (140 mg). This was used directly in the next step. NaOH (0.3 mL of 5 M aqueous solution) was added to a portion of the crude residue (80 mg, 0.19 mmol) in EtOH (4 mL). The mixture was heated at 60°C for 2 hours, then stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure, and the residue was acidified with 1 M aqueous HCl (pH approximately 4). The mixture was extracted with toluene (3 × 10 mL), the organic matter was washed with water and brine (10 mL each), dried, and concentrated under reduced pressure with (MgSO4). The residue was pulverized with heptane (3 × 5 mL) and dried under reduced pressure to produce an off-white solid (59 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.52 - 7.28 (m, 2H), 7.28 - 7.14 (m, 2H), 4.62 - 4.39 (m, 3H), 4.39 - 4.19 (m, 2H), 3.21 (q, J = 7.0 Hz, 2H), 1.43 (s, 8H), 1.04 (t, J = 6.9 Hz, 3H).LRMS(APCI+)m / z406.5[M+H] + .
[0433] 115A Benzyl 2-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0434] [ka]
[0435] 1,8-Diazabicyclo[5.4.0]undeca-7-ene (270 μL, 1.79 mmol) was added to the solution of intermediate 104A (340 mg, 1.38 mmol) in DMSO (7 mL). After 5 minutes, benzyl bromide (0.16 mL, 1.38 mmol) in DMSO (7 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. Water (30 mL) and brine (30 mL) were added, and the mixture was extracted with HCl (3 × 25 mL). The organic matter was washed with brine (2 × 25 mL), dried, and concentrated under reduced pressure in (Na₂SO₄). Purification by flash chromatography (10-80% HCl:heptane) yielded a colorless oily substance (356 mg, 77%). 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.25 (m, 5H), 5.23 (s, 2H), 4.49 - 4.37 (m, 2H), 4.06 (t, J = 6.1 Hz, 2H), 2.27 - 2.15 (m, 2H).LRMSm / z(APCI+)337.1 / 339.1[M+H] + .
[0436] The following intermediate compounds were prepared using a method similar to that of intermediate 21A. Reaction times varied between 45 minutes and 1 hour and 20 minutes, and heating was performed by MWI or conventional heating. Intermediate 116D was prepared from the corresponding pinacol ester.
[0437] [Table 18]
[0438] 117A Benzyl 2-[2-fluoro-4-(morpholine-4-ylmethyl)phenyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0439] [ka]
[0440] AcOH (0.03 mL, 0.53 mmol) was added to a solution of intermediate 116B (200 mg, 0.53 mmol) and morpholine (0.06 mL, 0.63 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 69 hours. The mixture was diluted with CH2Cl2 (10 mL), washed with saturated aqueous Na2CO3 (2 × 10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography [Â, then 0-40% in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)] to produce a yellow oily substance (171 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.22 (m, 4H), 7.18 - 7.11 (m, 3H), 7.06 (dd, J = 11.0, 1.5 Hz, 1H), 5.07 (s, 2H), 4.49 - 4.42 (m, 2H), 4.14 (t, J = 6.1 Hz, 2H), 3.61 - 3.54 (m, 4H), 3.48 (s, 2H), 2.38 - 2.30 (m, 4H), 2.31 - 2.20 (m, 2H).LRMSm / z(APCI+)452.4[M+H] + .
[0441] The following intermediate compounds were prepared using a procedure similar to that described for intermediate 117A.
[0442] [Table 19]
[0443] 119A Benzyl 2-(2-fluoro-4-methylsulfinylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0444] [ka]
[0445] A solution of mCPBA (124 mg, 0.55 mmol) in CH2Cl2 (10 mL) was added dropwise to a chilled solution (0°C) of intermediate 116C (200 mg, 0.5 mmol) in CH2Cl2 (10 mL). After 1 hour, the ice bath was removed and the mixture was stirred at room temperature for 0.5 hours. The mixture was washed with saturated aqueous NaHCO3 (2 × 5 mL), dried (Na2SO4), and concentrated under reduced pressure. It was purified by flash chromatography [10-30% in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)] to produce a colorless oily substance (159 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J = 7.9, 6.8 Hz, 1H), 7.52 (dd, J = 7.9, 1.6 Hz, 1H), 7.47 (dd, J = 9.4, 1.6 Hz, 1H), 7.32 - 7.25 (m, 3H), 7.18 - 7.13 (m, 2H), 5.08 (s, 2H), 4.48 (dd, J = 5.8, 4.5 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 2.78 (s, 3H), 2.30 - 2.21 (m, 2H).LRMS(APCI+)m / z415.1[M+H] + .
[0446] 120A Benzyl 2-[2-fluoro-4-(methylsulfonimidoyl)phenyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0447] [ka]
[0448] (Diacetoxyiodo)benzene (404 mg, 1.25 mmol) and ammonium carbamate (78 mg, 1.0 mmol) were added to a solution of intermediate 116C (200 mg, 0.5 mmol) in MeOH (8 mL), and the reaction mixture was stirred at room temperature for 1.5 hours. Volatile substances were removed under reduced pressure, and the residue was purified by flash chromatography [0-30% in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)] to produce a colorless oily substance (185 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 - 7.55 (m, 2H), 7.37 - 7.25 (m, 3H), 7.25 - 7.16 (m, 2H), 5.10 (s, 2H), 4.49 (dd, J = 5.9, 4.4 Hz, 2H), 4.40 (d, J = 1.4 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.11 (d, J = 1.1 Hz, 3H), 2.31 - 2.22 (m, 2H).LRMS(APCI+)m / z430.1[M+H] + .
[0449] 121A Ethyl 2-(2-fluorophenyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0450] [ka]
[0451] Carbon-supported palladium hydroxide (20% by weight packing, 50% water; 35 mg, 0.22 mmol) was added in a pressure tube to a solution of intermediate 86A (650 mg, 1.64 mmol) in EtOH (15 mL). The container was successively purged with N2 (5 ×) and hydrogen (5 ×), and then stirred under a hydrogen atmosphere at 40 psi and 60°C for 21 hours. The reaction mixture was filtered through a glass microfiber pad, washed with EtOH (3 × 10 mL) and CH2Cl2 (3 × 10 mL), and the solvent was removed under reduced pressure to produce a white solid (390 mg, 78%). 1 H NMR (500 MHz, DMSO-d6) δ 7.50 - 7.31 (m, 2H), 7.31 - 7.07 (m, 2H), 5.69 (d, J = 2.8 Hz, 1H), 4.43 - 4.23 (m, 4H), 4.10 - 3.81 (m, 3H), 1.04 (t, J = 7.0 Hz, 3H).LRMS(APCI+)m / z307.4[M+H]+ .
[0452] 122A 2-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0453] [ka]
[0454] Carbon-supported palladium hydroxide (20% by weight, 50% water; 15 mg, 0.09 mmol) was added to a solution of intermediate 116D (117 mg, 0.31 mmol) in EtOH (6 mL) in a pressure tube. The container was successively purged with N2 (5 ×) and hydrogen (5 ×), and then stirred at 40 psi under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through a glass microfiber pad, washed with EtOH (3 × 5 mL) and CH2Cl2 (3 × 5 mL), and the solvent was removed under reduced pressure to produce an off-white solid (80 mg, 90%). 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.89 (dd, J = 9.8, 1.5 Hz, 1H), 7.72 (dd, J = 7.9, 1.6 Hz, 1H), 7.66 - 7.53 (m, 1H), 4.44 (dd, J = 6.0, 4.3 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.28 - 2.18 (m, 2H).LRMS(APCI+)m / z288.2[M+H] + .
[0455] The following intermediate compounds were prepared using a method similar to that of intermediate 122A.
[0456] [Table I]
[0457] 123A Ethyl(5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate 123B Ethyl(5R)-2-[6-fluoro-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxylate
[0458] [ka]
[0459] DIPEA (132 μL, 0.76 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (92 mg, 0.68 mmol) were added to intermediate 16B (200 mg, 0.62 mmol) in DMSO (3 mL) and heated at 130 °C for 7 hours by MWI. A similar workup for intermediate 90E was performed, followed by purification by flash chromatography [0-70% SiO(10% MeOH) in isohexane]. 1 ¹H NMR yielded a mixture of approximately 6:4 regioisomers of 123A and 123B. This mixture could not be separated by silica column chromatography and was used without further purification (212 mg). LC-MS (Method A) m / z 403.3 [M+H] + , at 1.12 min (major) and 1.17 min (trace).
[0460] 124A Ethyl(5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate 124B Ethyl(5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxylate
[0461] [ka]
[0462] Prepare it using a procedure similar to the one described for intermediate 123A. 1 ¹H NMR yielded a mixture of approximately 64:36 124A:124B positional isomers, which could not be separated by silica column chromatography and was used without further purification (200 mg). LC-MS (Method A) m / z 403.7 [M+H] + , at 1.11 min (major) and 1.16 min (trace).
[0463] 125A Ethyl(5R)-2-[2-fluoro-6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate 125B Ethyl(5R)-2-[6-fluoro-2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0464] [ka]
[0465] It was prepared using a procedure similar to that described for intermediate 123A. Purification by column chromatography (0-6% MeOH in DCM) was performed. 1¹H NMR yielded a mixture of approximately 62:38 125A:125B positional isomers. This mixture could not be separated by silica column chromatography and was used without further purification (118 mg). LC-MS (Method A) m / z 403.8 [M+H] + At 1.07 min (major) and 1.10 min (trace).
[0466] Example 1 2-(2,4-difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0467] [ka]
[0468] HATU (26.7 mg, 0.070 mmol), NEt3 (0.02 mL, 0.128 mmol), and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (16.1 mg, 0.064 mmol) were added to a solution of intermediate 52A (18 mg, 0.064 mmol) in DMF (1 mL) and stirred at room temperature for 16 hours. Water and brine (1:1; 20 mL) were added, and the mixture was extracted with SiO2 (3 × 10 mL). The combined organic extract was washed with water (10 mL) and brine (10 mL), dried, and concentrated under reduced pressure in (Na2SO4). Purification by flash chromatography (100% SiO2) yielded a white solid (27 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.63 (ddd, J = 8.6, 6.9, 1.8 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.47 - 7.33 (m, 5H), 7.33 - 7.10 (m, 4H), 7.10 - 6.98 (m, 1H), 5.29 (d, J = 7.8 Hz, 1H), 4.66 (t, J = 5.2 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 2.38 - 2.31 (m, 2H).LRMS(APCI+)m / z513.9[M+H] + .
[0469] The following compounds of the present invention were prepared using (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one or (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one in the amide coupling procedure described for the compounds of Example 1.
[0470] [Table 20]
[0471] Example 5 N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5,5-dimethyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3carboxamide
[0472] [ka]
[0473] DIPEA (63 μL, 0.362 mmol) was added to a solution of (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (51 mg, 0.190 mmol) and intermediate 34A (53 mg, 0.181 mmol) in DMF (1.2 mL), and the mixture was stirred for 3 minutes. Then HATU (76 mg, 0.199 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL), and the resulting precipitate was collected by filtration and washed with water (3 × 5 mL). The precipitate was dissolved in RINKAN (20 mL), the solvent was removed under reduced pressure, and the mixture was purified by flash chromatography (60-100% RINKAN in heptane) to produce a white solid (70 mg, 71%). 1 H NMR (700 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.58 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.49 - 7.43 (m, 4H), 7.42 - 7.34 (m, 2H), 7.30 (td, J = 8.0, 4.9 Hz, 1H), 7.22 - 7.08 (m, 3H), 5.33 (d, J = 7.3 Hz, 1H), 4.24 (dq, J = 10.1, 6.6Hz, 2H), 2.35 - 2.23 (m, 2H), 1.58 (d, J = 11.6 Hz, 6H).LRMS(APCI+)m / z542.4[M+H] + .
[0474] The following compounds of the present invention were prepared using the amide coupling procedure described for the compound of Example 5. Example 14 underwent further purification by preparative HPLC (Method 1) using a step gradient of 30-100% CH3CN in water (0.2% v / vNH3).
[0475] [Table 21-1]
[0476] [Table 21-2]
[0477] [Table 21-3]
[0478] Example 15 2-[6-(cyclopropylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0479] [ka]
[0480] The intermediate 30C (47 mg, 0.14 mmol) and LiOH (1.0 M aqueous solution; 2.29 mL, 2.29 mmol) were mixed in THF:MeOH (1:1; 6 mL) and heated at 50°C for 24 hours. The reaction mixture was cooled to room temperature, acidified to approximately pH 2 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The residue was suspended in DMF (1 mL), and NEt3 (0.04 mL, 0.25 mmol) and HATU (48.1 mg, 0.13 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (34.1 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and brine (10 mL each) and extracted with SiO2 (3 × 10 mL). The combined organic extracts were washed with water (10 mL) and brine (3 × 10 mL), dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by flash chromatography [0-100% in CH₂Cl₂ (EtOH:CH₂Cl₂:NH₄OH; 50:8:1)] yielded a white solid (27 mg, 34%). 1H NMR (700 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.29 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.76 (s, 1H), 7.59 (ddd, J = 10.3, 8.2, 1.3 Hz, 1H), 7.57 - 7.41 (m, 5H), 7.31 (td, J = 8.1, 5.0 Hz, 1H), 7.15 (dd, J = 8.0, 1.1 Hz, 1H), 6.88 (s, 1H), 6.56 (d, J = 8.6 Hz, 1H), 5.42 (d, J = 7.5 Hz, 1H), 4.66 - 4.59 (m, 2H), 4.17 (t, J = 6.2 Hz, 2H), 2.37 - 2.24 (m, 2H), 1.32 - 1.18 (m, 1H), 0.78 - 0.57 (m, 2H), 0.42 (d, J = 4.2 Hz, 2H).LRMS(APCI+)m / z551.6[M+H] + The following compounds were prepared using the amide coupling procedure described for the compound in Example 15. The procedure can be modified by using NEt3 instead of DIPEA.
[0481] [Table 22-1]
[0482] [Table 22-2]
[0483] Example 21 N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0484] [ka]
[0485] NEt3 (59 μL, 0.42 mmol), HATU (78 mg, 0.21 mmol), and then (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (55 mg, 0.21 mmol) were added to a solution of intermediate 45B (54 mg, 0.21 mmol) in DMF (1.5 mL), and the mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched with water, the resulting precipitate was filtered, and washed with water (100 mL). The precipitate was dissolved in CH2Cl2, dried under vacuum, and purified by flash chromatography (0-5% MeOH in CH2Cl2) to produce a white solid (81 mg, 76%). LC-MS (Method C) m / z 514.4 [M+H] + , at 3.76 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.49 - 7.42 (m, 4H), 7.42 - 7.32 (m, 2H), 7.32 - 7.26 (m, 1H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 7.15 - 7.10 (m, 2H), 5.37 (d, J = 7.7 Hz, 1H), 4.68 - 4.63 (m, 2H), 4.23 - 4.19 (m, 2H), 2.39 - 2.31 (m, 2H). The following compounds were prepared using the amide coupling procedure described for the compounds in Example 21. The procedure may be carried out at 40°C for ≥1 hour, or overnight at room temperature.
[0486] [Table 23-1]
[0487] [Table 23-2]
[0488] [Table 23-3]
[0489] [Table 23-4]
[0490] [Table 23-5]
[0491] Example 24 (5R)-2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0492] [ka]
[0493] NEt3 (47 μL, 0.34 mmol), HATU (63 mg, 0.17 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (40 mg, 0.16 mmol) were added to a solution of crude intermediate 43A (44 mg, 0.16 mmol) in DMF (1.5 mL), and the mixture was stirred at 40°C for 1 hour. The reaction mixture was diluted with SiO2 (20 mL), washed with brine (5 × 20 mL), dried, concentrated under reduced pressure in (Na2SO4), and purified by flash chromatography (0-5% MeOH in CH2Cl2) to produce a white solid (61 mg, 74%). LC-MS (Method C) m / z 510.4 [M+H] + , at 3.91 minutes. 1H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.53 - 7.47 (m, 1H), 7.45 - 7.42 (m, 4H), 7.41 - 7.33 (m, 2H), 7.32 - 7.27 (m, 2H), 7.27 - 7.22 (m, 1H), 7.19 - 7.10 (m, 2H), 5.26 (d, J = 7.6 Hz, 1H), 4.86 - 4.77 (m, 1H), 4.26 - 4.16 (m, 2H), 2.41 - 2.32 (m, 1H), 2.21 - 2.10 (m, 1H), 1.56 (d, J = 6.3 Hz, 3H). The following compounds were prepared using the amide coupling procedure described for the compounds in Example 24.
[0494] [Table 24]
[0495] Example 42 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0496] [ka]
[0497] NEt3 (54 μL, 0.39 mmol), HATU (71 mg, 0.19 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (46 mg, 0.19 mmol) were added to a solution of crude intermediate 55B (51 mg, 0.19 mmol) in DMF (1.5 mL) and stirred at 40°C for 1 hour. Further HATU (71 mg, 0.19 mmol) was added, and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was quenched with water, the resulting precipitate was filtered, dissolved in  (30 mL), washed with brine (3 × 20 mL), concentrated under reduced pressure, and purified by flash chromatography (0-5% MeOH in CH2Cl2) to produce a white solid (14 mg, 13%). LC-MS (Method C) m / z 511.4 [M+H] + , at 3:47. 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.01 - 7.99 (m, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.71 (dd, J = 8.9, 2.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.54 - 7.47 (m, 1H), 7.45 - 7.42 (m, 4H), 7.32 - 7.22 (m, 3H), 5.29 (d, J = 7.8 Hz, 1H), 4.67 (t, J = 5.3 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 2.42 - 2.32 (m, 2H), 2.28 (s, 3H). Example 43 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0498] [ka]
[0499] The sample was prepared using a procedure similar to that described for Example 42. LC-MS (Method C) m / z 529.4 [M+H] + , at 3:51. 1 H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.02 - 7.99 (m, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.71 (dd, J = 9.0, 2.5 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.54 - 7.50 (m, 1H), 7.49 - 7.42 (m, 4H), 7.33 - 7.27 (m, 1H), 7.14 - 7.09 (m, 1H), 5.37 (d, J = 7.7 Hz, 1H), 4.67 (t, J = 5.3 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 2.39 - 2.32 (m, 2H), 2.28 (s, 3H). Example 44 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0500] [ka]
[0501] NEt3 (84 μL, 0.60 mmol), HATU (110 mg, 0.29 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (72 mg, 0.29 mmol) were added to a solution of crude intermediate 55B (92 mg, 0.29 mmol) in DMF (2.65 mL), and the mixture was stirred at 40°C for 1 hour. Further NEt3 (84 μL, 0.60 mmol) was added, and the reaction mixture was stirred at 40°C for 1 hour. Further HATU (110 mg, 0.29 mmol) was added, and the reaction mixture was stirred at room temperature over the weekend. An off-white solid (89 mg, 54%) was obtained by work-up and purification similar to that described for the compound in Example 21. LC-MS (Method C) m / z 552.4 [M+H] + , at 3.72 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.53 - 7.47 (m, 2H), 7.46 - 7.41 (m, 4H), 7.32 - 7.28 (m, 2H), 7.27 - 7.22 (m, 1H), 7.19 - 7.16 (m, 1H), 6.44 - 6.39 (m, 1H), 5.30 (d, J = 7.8 Hz, 1H), 4.65 - 4.61 (m, 2H), 4.20 - 4.15 (m, 2H), 2.36 - 2.29 (m, 2H), 0.72 - 0.65 (m, 2H), 0.46 - 0.38 (m, 2H). Example 45 2-Cyclopropyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0502] [ka]
[0503] NEt3 (39 μL, 0.28 mmol), HATU (51 mg, 0.14 mmol), and then (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (36 mg, 0.14 mmol) were added to a solution of crude intermediate 56A (28 mg, 0.14 mmol) in DMF (1.5 mL), and the mixture was stirred at 40°C for 1 hour. Further HATU (26 mg, 0.07 mmol) and NEt3 (39 μL, 0.28 mmol) were added, and the reaction mixture was stirred overnight at room temperature. A white solid (37 mg, 57%) was obtained by work-up and purification similar to that described for the compound in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.57 - 7.48 (m, 3H), 7.49 - 7.42 (m, 2H), 7.36 - 7.28 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 5.49 - 5.43 (m, 1H), 4.58 - 4.53 (m, 2H), 4.04 - 3.98 (m, 2H), 2.63 - 2.54 (m, 1H), 2.29 - 2.19 (m, 2H), 0.82 - 0.70 (m, 4H). Example 48 (5R)-2-(2-methoxypyridine-4-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0504] [ka]
[0505] A solution of intermediate 65A (178 mg, 0.56 mmol) and 1.5 M aqueous LiOH (1.87 mL, 2.8 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 50 °C. The reaction mixture was cooled to room temperature, acidified to approximately pH 7 with 1 M aqueous HCl, and the solvent was removed under reduced pressure to produce an orange oily substance (162 mg, quantified). A portion of the crude residue (81 mg, 0.28 mmol) was dissolved in DMF (3 mL), and NEt3 (89 μL, 0.64 mmol) and HATU (114 mg, 0.3 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (75 mg, 0.28 mmol). The reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was quenched with water (15 mL), the resulting precipitate was isolated by filtration, and washed with water (100 mL). Purification by column chromatography (0-6% MeOH in CH2Cl2) yielded a white solid (115 mg, 73%). LC-MS (Method C) m / z 541.4 [M+H] + , at 3.69 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.40 (d, J = 7.2 H, 1H), 8.14 - 8.09 (m, 1H), 7.62 - 7.55 (m, 1H), 7.56 - 7.42 (m, 5H), 7.35 - 7.27 (m, 2H), 7.23 (s, 1H), 7.16 (d, J = 7.9 Hz, 1H), 5.39 (d, J = 7.2 Hz, 1H), 4.84 - 4.76 (m, 1H), 4.29 - 4.15 (m, 2H), 3.84 (s, 3H), 2.40 - 2.33 (m, 1H), 2.21 - 2.07 (m, 1H), 1.56 (d, J = 6.3 Hz, 3H). The following compounds were prepared using the amide coupling procedure described for the compounds in Example 48. The procedure can be carried out at 40°C for ≥1 hour, or at room temperature.
[0506] [Table 25-1]
[0507] [Table 25-2]
[0508] [Table 25-3]
[0509] [Table 25-4]
[0510] [Table 25-5]
[0511] [Table 25-6]
[0512] The following compounds were prepared using the amide coupling procedure described for the compounds in Example 48, with additional purification by HPLC / SFC as shown.
[0513] [Table 26-1]
[0514] [Table 26-2]
[0515] Example 77 (5R)-5-methyl-2-(6-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0516] [ka]
[0517] A solution of intermediate 16C (171 mg, 0.56 mmol) and 1.5 M aqueous LiOH (2 mL, 3 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 40°C. The reaction mixture was cooled to room temperature, acidified to approximately pH 7 with 1 M aqueous HCl (3.2 mL, 3.2 mmol), and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (3 mL), and HATU (213 mg, 0.56 mmol) and NEt3 (234 μL, 1.68 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (151 mg, 0.56 mmol). The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with SiO2 (2 × 20 mL). The combined organic compounds were washed with brine (3 × 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. Purification by column chromatography (0-5% MeOH in CH2Cl2) yielded a white solid (140 mg, 45%). LC-MS (Method C) m / z 525.4 [M+H] + , at 2.10 minutes. 1H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.68 (dd, J = 2.3, 0.9 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.0, 2.3 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.56 - 7.50 (m, 1H), 7.50 - 7.42 (m, 4H), 7.35 - 7.27 (m, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 5.39 (d, J = 7.1 Hz, 1H), 4.86 - 4.76 (m, 1H), 4.27 - 4.16 (m, 2H), 2.46 (s, 3H), 2.41 - 2.33 (m, 1H), 2.21 - 2.09 (m, 1H), 1.56 (d, J = 6.3 Hz, 3H). The following compounds were prepared using a procedure similar to that described for the compound in Example 77. Example 80 was further purified by reverse-phase chromatography [15-50% MeCN (0.1% formic acid) in water (0.1% formic acid)]. For the preparation of Examples 81, 82, and 83, 6 equivalents of NEt3 were used in the amide coupling step, and further purification was performed by reverse-phase chromatography [15-50% MeCN (0.1% formic acid) in water (0.1% formic acid)].
[0518] [Table 27-1]
[0519] [Table 27-2]
[0520] Example 84 (5R)-2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0521] [ka]
[0522] A solution of intermediate 65 J (88 mg, 0.197 mmol) and 1.5 M aqueous LiOH (0.657 mL, 0.985 mmol) in MeOH:THF (1:1; 2 mL) was heated overnight at 50°C. A further 1.5 M aqueous LiOH (0.131 mL, 0.197 mmol) was added, and the reaction was heated overnight at 50°C. Then, an additional portion of 1.5 M aqueous LiOH (0.131 mL, 0.197 mmol) was added, and the reaction was heated overnight at 50°C. The reaction mixture was neutralized to approximately pH 7 with 1 M aqueous citric acid and concentrated under reduced pressure. The crude residue (54 mg, 0.197 mmol) was dissolved in DMF (2 mL), and NEt3 (62 μL, 0.44 mmol) and HATU (80 mg, 0.21 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (53 mg, 0.197 mmol). The reaction mixture was stirred at 40°C for 1 hour, then stirred overnight at room temperature. Further NEt3 (62 μL, 0.44 mmol) and HATU (80 mg, 0.21 mmol) were added, and the reaction mixture was stirred at 40°C for 1 hour. Workup and purification similar to Example 48, followed by additional purification by chiral SFC method 1 [55% EtOH (0.1% NH3)], yielded a white solid (59 mg, 56%). LCMS (Method C) m / z (Method C) 528.4[M+H] + , at 3:48. 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.40 (s, 1H), 8.35 (d, J = 7.3 Hz, 1H), 7.88 (s, 1H), 7.62 - 7.57 (m, 1H), 7.55 - 7.48 (m, 3H), 7.47 - 7.43 (m, 2H), 7.36 - 7.29 (m, 1H), 7.22 - 7.17 (m, 1H), 5.44 (d, J = 7.2 Hz, 1H), 4.82 - 4.72 (m, 1H), 4.21 - 4.06 (m, 4H), 2.38 - 2.30 (m, 1H), 2.17 - 2.05 (m, 1H), 1.55 (d, J = 6.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H). Example 85 (5R)-2-[6-(2-hydroxy-2-methylpropyl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0523] [ka]
[0524] A solution of intermediate 69D (103 mg, 0.29 mmol) and 1.5 M aqueous LiOH (0.96 mL, 1.44 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 50 °C. The reaction mixture was cooled to room temperature, acidified to approximately pH 7 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (3 mL), and HATU (116 mg, 0.31 mmol) and NEt3 (91 μL, 0.65 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (77 mg, 0.29 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (15 mL), the resulting precipitate was isolated by filtration, and washed with water (100 mL). The isolated solid was purified by column chromatography (0-7% MeOH in CH2Cl2), followed by reverse-phase column chromatography [10-40% MeCN (0.1% formic acid) in water (0.1% formic acid)]. The crude product was dissolved in CH2Cl2 (10 mL), washed with saturated aqueous NaHCO3 (5 mL), passed through a phase separator, and the solvent was removed under reduced pressure. The residue was dissolved in MeCN (2 mL) and concentrated under reduced pressure (3 ×) to produce an orange solid (15 mg, 9%). LC-MS (Method C) m / z 583.5 [M+H] + , at 2:28. 1H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.97 (dd, J = 8.1, 2.3 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.54 - 7.42 (m, 5H), 7.34 - 7.28 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.17 - 7.14 (m, 1H), 5.39 (d, J = 7.2 Hz, 1H), 4.87 - 4.77 (m, 1H), 4.73 (s, 1H), 4.28 - 4.14 (m, 2H), 2.83 (s, 2H), 2.41 - 2.33 (m, 1H), 2.21 - 2.10 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H), 1.09 (s, 6H). Example 86 (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0525] [ka]
[0526] A solution of 90 G (58 mg, 0.151 mmol) of the intermediate and 1.5 M aqueous LiOH (1.5 mL, 2.25 mmol) in MeOH:THF (1:1; 3 mL) was heated overnight at 50 °C. The reaction mixture was cooled to room temperature, acidified to approximately pH 7 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (3 mL), and HATU (57 mg, 0.151 mmol) and NEt3 (63 μL, 0.453 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (41 mg, 0.151 mmol). The reaction mixture was stirred overnight at 40 °C. The reaction product was diluted with MeOH and purified by ion-exchange chromatography (SCX-2, eluted with MeOH, followed by elution of the product with approximately 2N NH3 in MeOH), and then purified by column chromatography [0-5% MeOH (0.7N NH3) in CH2Cl2]. Further purification by reverse-phase column chromatography [15-70% MeCN (0.1% formic acid) in water (0.1% formic acid)] yielded a white solid (7 mg, 8% yield). LC-MS (Method C) m / z 608.4 [M+H] + , at 2:23. 1H NMR (500 MHz, DMSO-d6) δ 8.37 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.53 - 7.40 (m, 6H), 7.18 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.84 (s, 1H), 4.79 - 4.75 (m, 1H), 4.64 (d, J = 2.4 Hz, 1H), 4.21 - 4.13 (m, 2H), 3.76 (dd, J = 7.3, 1.5 Hz, 1H), 3.63 (d, J = 7.3 Hz, 1H), 3.45 (dd, J = 10.2, 1.6 Hz, 1H), 3.22 (d, J = 10.0 Hz, 1H), 2.35 - 2.32 (m, 1H), 2.18 - 2.07 (m, 1H), 1.93 - 1.87 (m, 1H), 1.86 - 1.81 (m, 1H), 1.66 (s, 2H), 1.55 (d, J = 6.2 Hz, 3H). Example 87 (5S)-5-methyl-N-[(3R)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0527] [ka]
[0528] The compound was prepared using a procedure similar to that of Example 86, with purification by HPLC instead of reverse-phase column chromatography, using HPLC method 2 (15-100% MeCN in water containing 0.1% formic acid). LC-MS (Method A) m / z 608.6 [M+H] + , at 1.00 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.37 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.53 - 7.40 (m, 6H), 7.18 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.84 (s, 1H), 4.79 - 4.75 (m, 1H), 4.64 (d, J = 2.4 Hz, 1H), 4.21 - 4.13 (m, 2H), 3.76 (dd, J = 7.3, 1.5 Hz, 1H), 3.63 (d, J = 7.3 Hz, 1H), 3.45 (dd, J = 10.2, 1.6 Hz, 1H), 3.22 (d, J = 10.0 Hz, 1H), 2.35 - 2.32 (m, 1H), 2.18 - 2.07 (m, 1H), 1.93 - 1.87 (m, 1H), 1.86 - 1.81 (m, 1H), 1.66 (s, 2H), 1.55 (d, J = 6.2 Hz, 3H). Example 88 (5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-pyridyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide Example 89 (5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0529] [ka]
[0530] A solution of intermediates 124A / 124B (199 mg, 0.50 mmol) and 1.5 M aqueous LiOH (1.7 mL, 2.6 mmol) in MeOH:THF (1:1; 4 mL) was heated at 50°C for 72 hours. The reaction mixture was cooled to room temperature, acidified to approximately pH 7 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (3 mL), and NEt3 (136 μL, 0.98 mmol) and HATU (186 mg, 0.49 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (131 mg, 0.49 mmol). The reaction mixture was heated at 40°C for 1 hour. The reaction mixture was quenched with water, the resulting precipitate was isolated by filtration, and washed with water (100 mL). Purification by column chromatography (0-6% MeOH in CH2Cl2), followed by HPLC method 2 (33-100% MeCN in water containing 0.1% NH3, operating time 16 minutes), yielded Example 88 (the first positional isomer to elute) and Example 89 (the second positional isomer to elute).
[0531] Example 88: White solid (67 mg, 20%). LC-MS (Method C) m / z 626.5 [M+H] + , at 3.6 minutes. 1H NMR (500 MHz, DMSO-d6) 10.92 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.54 - 7.50 (m, 1H), 7.50 - 7.42 (m, 4H), 7.30 (ddd, J = 8.1, 5.0 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 5.35 (d, J = 7.5 Hz, 1H), 4.84 - 4.73 (m, 2H), 4.69 - 4.62 (m, 1H), 4.24 - 4.10 (m, 2H), 3.78 - 3.71 (m, 1H), 3.63 (d, J = 7.3 Hz, 1H), 3.44 - 3.40 (m, 1H), 3.21 (d, J = 10.1 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.20 - 2.07 (m, 1H), 1.91 - 1.80 (m, 2H), 1.55 (d, J = 6.3 Hz, 3H). Example 89: White solid (37 mg, 11%). LCMS (Method C) m / z 626.5 [M+H] + , 3.78 points において. 1H NMR (500 MHz, DMSO-d6) 10.92 (s, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.55 - 7.47 (m, 1H), 7.50 - 7.37 (m, 5H), 7.33 - 7.25 (m, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.24 (dd, J = 7.9, 3.1 Hz, 1H), 5.32 (d, J = 7.3 Hz, 1H), 4.84 - 4.74 (m, 1H), 4.55 (s, 1H), 4.46 (s, 1H), 4.24 - 4.09 (m, 2H), 3.73 - 3.64 (m, 2H), 3.04 (d, J = 10.3 Hz, 1H), 2.81 (d, J = 10.2 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.19 - 2.07 (m, 1H), 1.75 - 1.67 (m, 2H), 1.55 (d, J = 6.3 Hz, 3H). Example 90 (5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0532] [ka]
[0533] Intermediate 123A / 123B (212 mg, 0.53 mmol) was prepared using a procedure similar to that described for the compound in Example 88. Purification by HPLC method 3 (25-100% MeCN in water containing 0.1% NH3) yielded Example 90 (the first positional isomer to elute) as a white solid (71 mg, 22%). LC-MS (Method C) m / z 626.5 [M+H] + , at 3.63 minutes.1 H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.60 - 7.48 (m, 3H), 7.50 - 7.40 (m, 4H), 7.27 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 5.31 (d, J = 7.1 Hz, 1H), 4.79 (d, J = 12.3 Hz, 2H), 4.66 (d, J = 2.4 Hz, 1H), 4.24 - 4.10 (m, 2H), 3.76 (d, J = 7.4 Hz, 1H), 3.64 (d, J = 7.4 Hz, 1H), 3.42 (d, J = 10.1 Hz, 1H), 3.21 (d, J = 10.1 Hz, 1H), 2.35 (d, J = 14.4 Hz, 1H), 2.20 - 2.06 (m, 1H), 1.91 - 1.81 (m, 2H), 1.55 (d, J = 6.3 Hz, 3H). Example 91 (5R)-2-[2-fluoro-6-(2-oxa-6-azapiro[3,3]heptan-6-yl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0534] [ka]
[0535] The compound was prepared from intermediate 125A / 125B (118 mg, 0.29 mmol) using a procedure similar to that described for the compound in Example 88. Purification by HPLC method 2 (30-100% MeCN in water containing 0.1% formic acid) yielded Example 91 (the first eluting positional isomer) as a white solid (18 mg, 10%). LC-MS (Method C) m / z 626.5 [M+H] +, at 3:53. 1 H NMR (500 MHz, DMSO-d6) 10.92 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.54 - 7.49 (m, 1H), 7.48 - 7.42 (m, 4H), 7.30 (ddd, J = 8.1, 8.1, 5.0 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.21 (dd, J = 8.1, 1.7 Hz, 1H), 5.33 (d, J = 7.4 Hz, 1H), 4.82 - 4.74 (m, 1H), 4.70 (s, 4H), 4.22 - 4.14 (m, 2H), 4.11 (s, 4H), 2.38 - 2.31 (m, 1H), 2.19 - 2.06 (m, 1H), 1.54 (d, J = 6.3 Hz, 3H). Example 92 (5R)-5-methyl-2-[4-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0536] [ka]
[0537] A solution of intermediate 69E (68 mg, 0.15 mmol) and 1.5 M aqueous LiOH (0.51 mL, 0.77 mmol) in MeOH:THF (1:1; 2 mL) was heated at 50°C for 90 minutes. Further 1.5 M aqueous LiOH (0.51 mL, 0.77 mmol) was added, and the reaction mixture was heated at 50°C for 24 hours. The reaction mixture was cooled to room temperature, acidified to approximately pH 2 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (1.5 mL), and NEt3 (50 μL, 0.36 mmol) and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (32 mg, 0.12 mmol) were added, followed by HATU (48 mg, 0.13 mmol), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water (2 mL), acidified to approximately pH 4 with AcOH, and purified by ion-exchange chromatography (2 g SCX-2 cartridge, washed with water and methanol, then eluted with 7N NH3 in MeOH). The fraction containing the product was concentrated under vacuum and purified by column chromatography (0-5% MeOH in CH2Cl2) to produce a white solid (19 mg, 22%). LC-MS (Method C) m / z 582.6 [M+H] + , at 2:38. 1 H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.54 (m, 1H), 7.56 - 7.50 (m, 1H), 7.50 - 7.41 (m, 4H), 7.35 - 7.26 (m, 1H), 7.16 - 7.10 (m, 1H), 6.24 - 6.21 (m, 1H), 6.20 (d, J = 7.8 Hz, 1H), 5.33 (d, J = 7.3 Hz, 1H), 4.83 - 4.75 (m, 1H), 4.23 - 4.13 (m, 2H), 4.03 - 3.92 (m, 1H), 2.34 (s, 1H), 2.21 - 2.10 (m, 1H), 1.99 (s, 3H), 1.55 (d, J = 6.3 Hz, 3H), 1.12 (dd, J = 6.5, 1.3 Hz, 6H). Example 93 (5R)-5-methyl-2-[2-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0538] [ka]
[0539] The compound in Example 92 was prepared using a procedure similar to the one described. LC-MS (Method C) m / z 582.5 [M+H] + , at 2:38. 1 H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.10 - 8.03 (m, 1H), 7.62 - 7.55 (m, 1H), 7.55 - 7.49 (m, 1H), 7.49 - 7.41 (m, 4H), 7.35 - 7.26 (m, 1H), 7.16 - 7.11 (m, 2H), 6.22 - 6.17 (m, 2H), 5.33 (d, J = 7.3, 1.2 Hz, 1H), 4.81 - 4.75 (m, 1H), 4.20 - 4.12 (m, 2H), 4.01 - 3.90 (m, 1H), 2.38 - 2.31 (m, 1H), 2.14 (s, 4H), 1.58 - 1.52 (m, 3H), 1.13 (dd, J = 6.4, 1.4 Hz, 6H). Example 94 (5S)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0540] [ka]
[0541] A solution of intermediate 91B (116 mg, 0.30 mmol) and 1.5 M aqueous LiOH (2.1 mL, 3.0 mmol) in MeOH:THF (1:1; 3 mL) was heated at 50 °C for 64 hours. The reaction mixture was cooled to room temperature, acidified to approximately pH 2 with 1 M aqueous HCl, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (2 mL), and Et3N (85 μL, 0.61 mmol) and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (71 mg, 0.2 mmol) were added, followed by HATU (81 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (15 mL), the resulting precipitate was isolated by filtration, washed with water (2 × 10 mL), and then purified by column chromatography (0-6% MeOH in CH2Cl2). The aqueous filtrate was acidified to approximately pH 4 with AcOH, and then purified by ion-exchange chromatography (2 g SCX-2 cartridge, washed with water and methanol, then eluted with 7N NH3 in MeOH). The fraction containing the product was concentrated under vacuum and purified by column chromatography (0-5% MeOH in CH2Cl2) to produce an off-white solid (47 mg, 39%). LC-MS (Method C) m / z 608.5 [M+H] + , at 2:31. 1H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.40 - 8.36 (m, 1H), 8.32 (d, J = 7.2 Hz, 1H), 7.81 (dd, J = 8.8, 2.3 Hz, 1H), 7.59 (t, J = 9.2 Hz, 1H), 7.55 - 7.43 (m, 5H), 7.36 - 7.28 (m, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 5.39 (d, J = 7.2 Hz, 1H), 4.85 (s, 1H), 4.77 (t, J = 7.6 Hz, 1H), 4.65 (s, 1H), 4.25 - 4.14 (m, 2H), 3.80 - 3.74 (m, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.23 (d, J = 10.0 Hz, 1H), 2.40 - 2.32 (m, 1H), 2.18 - 2.10 (m, 1H), 1.93 - 1.87 (m, 1H), 1.87 - 1.81 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H). Example 95 (5R)-2-anilino-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0542] [ka]
[0543] A solution of intermediate 72A (150 mg, 0.50 mmol) and 1.5 M aqueous LiOH (0.33 mL, 0.50 mmol) in MeOH:THF (1:1; 2 mL) was heated at 50°C for approximately 3 days. Further LiOH (1.5 M aqueous, 0.33 mL, 0.50 mmol) was added, and the reaction mixture was heated for a further 24 hours. The reaction mixture was cooled to room temperature, neutralized to approximately pH 7 with 1 M aqueous citric acid, and the solvent was removed under reduced pressure to produce a brown solid (136 mg, quantified). A portion of the crude residue (82 mg, 0.30 mmol) was dissolved in DMF (2.5 mL), and HATU (122 mg, 0.32 mmol) and NEt3 (95 μL, 0.68 mmol) were added, followed by (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (81 mg, 0.32 mmol). The reaction mixture was stirred at 40°C for 1 hour. A white solid (31 mg, 19%) was obtained by workup and purification similar to Example 48. LC-MS (Method C) m / z 525.3 [M+H] + , at 4.96 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.55 - 7.48 (m, 5H), 7.48 - 7.43 (m, 2H), 7.36 - 7.29 (m, 1H), 7.25 - 7.17 (m, 3H), 6.84 - 6.79 (m, 1H), 5.45 (d, J = 7.3 Hz, 1H), 4.81 - 4.73 (m, 1H), 4.10 - 4.02 (m, 2H), 2.38 - 2.30 (m, 1H), 2.17 - 2.07 (m, 1H), 1.54 (d, J = 6.2 Hz, 3H). The following compounds were prepared using a procedure similar to that described for the compounds in Example 95. Examples 96 and 97 underwent additional purification by reverse-phase chromatography [35-65% MeCN (0.1% formic acid) in water (0.1% formic acid)].
[0544] [Table 28]
[0545] The following compounds were prepared using a procedure similar to that described for the compound in Example 1. DIPEA was used instead of NEt3.
[0546] [Table 29-1]
[0547] [Table 29-2]
[0548] The following compounds were prepared using a procedure similar to that described for the compounds in Example 5. Example 107 underwent additional purification using SFC Method 1 (25:75% MeOH / CO2). 1 Unless otherwise specified, 1H NMR was performed in DMSO-d6 using a 400 MHz spectrometer. Unless otherwise specified, LRMS was performed using an APCI ion source.
[0549] [Table 30-1]
[0550] [Table 30-2]
[0551] [Table 30-3]
[0552] [Table 30-4]
[0553] Table 30-5
[0554] Table 30-6
[0555] Table 30-7
[0556] Table 30-8
[0557] Table 30-9
[0558] Table 30-10
[0559] Table 30-11
[0560] Table 30-12
[0561] Table 30-13
[0562] Table 30-14
[0563] Table 30-15
[0564] [Table 30-16]
[0565] Example 164 6-(diethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0566] [ka]
[0567] NaOH (5M aqueous solution, 180 μL, 0.89 mmol) was added to the intermediate 97F (42 mg, 0.11 mmol) in EtOH (4 mL) and heated overnight at 60°C. The reaction mixture was cooled to room temperature, acidified to approximately pH 4 with 1 M aqueous HCl, the solvent was removed under reduced pressure, and the crude residue was used directly in the next reaction. The residue was suspended in DMF (2 mL), DIPEA (39 μL, 0.22 mmol) and HATU (47 mg, 0.12 mmol) were added, and the reaction mixture was stirred at room temperature for 10 minutes. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (39 mg, 0.11 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. A white solid (49 mg, 73%) was obtained by work-up and purification similar to that described for the compound in Example 15. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 0.5H), 10.95 (s, 0.5H), 7.99 - 7.82 (m, 1H), 7.68 - 7.21 (m, 9H), 7.21 - 7.04 (m, 3H), 5.51 - 5.30 (m, 1H), 4.79 - 4.57 (m, 1H), 4.57 - 4.42 (m, 1H), 4.34 - 4.17 (m, 1H), 4.06 - 3.88 (m, 1H), 1.07 - 0.86 (m, 6H).LRMS(APCI+)m / z599.8[M+H] + .
[0568] The following compounds were prepared using a procedure similar to that described for the compound in Example 164. Example 172 underwent additional purification by preparative SFC method 2 [10-90% CO2 / MeOH (0.2% v / v NH3)]. Example 173 underwent additional purification by preparative HPLC method 1 (10-100% CH3CN in water with 0.2% v / v formic acid).
[0569] [Table 31-1]
[0570] [Table 31-2]
[0571] [Table 31-3]
[0572] Example 174 6-[[benzyl(ethyl)amino]methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0573] [ka]
[0574] NaOH (5M aqueous solution, 370 μL, 1.83 mmol) was added to the intermediate 97H (100 mg, 0.23 mmol) in EtOH (5 mL) and heated overnight at 60°C. The reaction mixture was cooled to room temperature, acidified to approximately pH 4 with 1 M aqueous HCl, the solvent was removed under reduced pressure, and the crude residue was used directly in the next reaction. The residue was suspended in DMF (3 mL), DIPEA (80 μL, 0.46 mmol) and HATU (96 mg, 0.25 mmol) were added, and the reaction mixture was stirred at room temperature for 10 minutes. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (62 mg, 0.23 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL), the resulting precipitate was collected by filtration, and washed with water (2 × 5 mL). The precipitate was dissolved in CH2Cl2 (20 mL), the solvent was removed under reduced pressure, and the residue was purified by flash chromatography [20-60% in CH2Cl2 (EtOH:CH2Cl2:NH4OH; 50:8:1)] to produce a white solid (58 mg, 38%). 1H NMR (600 MHz, DMSO-d6) δ 10.93 (d, J = 5.0 Hz, 1H), 7.87 (dd, J = 7.7, 6.3 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.49 - 7.41 (m, 3H), 7.41 - 7.27 (m, 6H), 7.27 - 7.22 (m, 1H), 7.19 - 7.11 (m, 2H), 5.36 (dd, J = 7.7, 2.9 Hz, 1H), 4.72 (dt, J = 10.1, 4.3 Hz, 1H), 4.42 (dd, J = 10.7, 7.8 Hz, 1H), 4.28 (dd, J = 12.2, 5.3 Hz, 1H), 3.99 - 3.90 (m, 1H), 3.70 - 3.57 (m, 2H), 2.78 (s, 1H), 1.00 (td, J = 7.0, 5.5 Hz, 3H).LRMS(APCI+)m / z660.7[M+H] + .
[0575] The following compounds were prepared using a procedure similar to that described for the compounds in Example 174. Example 185 underwent additional purification by preparative HPLC method 4 [50:50 MeCN:water (0.1% v / v formic acid)].
[0576] [Table 32-1]
[0577] [Table 32-2]
[0578] [Table 32-3]
[0579] [Table 32-4]
[0580] The following compounds were prepared as single diastereomers by separation by chiral HPLC or SFC and isolated as single diastereomers with unknown absolute stereochemistry. Examples 188-1, 188-2, 189-1, and 189-2 were prepared using the amide coupling procedure described for the compounds in Example 5 and separated by the indicated chiral HPLC / SFC method. Examples 190-1, 190-2, 191-1, and 191-2 were prepared using the amide coupling procedure described for the compounds in Example 21, at room temperature for 1 hour with 5 equivalents of NEt3, and separated by the indicated chiral HPLC method. The stereochemical configuration of these compounds is designated as R* or S*, and arbitrarily defined stereocenters are indicated by asterisks. The retention times for each separated diastereomer under the indicated analytical conditions are t R It is represented as follows.
[0581] [Table 33]
[0582] [Table 34-1]
[0583] [Table 34-2]
[0584] [Table 34-3]
[0585] [Table 34-4]
[0586] Example 192 6-(ethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0587] [ka]
[0588] NaOH (0.69 mL of 5M aqueous solution, 3.45 mmol) was added to the solution of intermediate 97E (150 mg, 0.43 mmol) in EtOH (8 mL). The mixture was heated at 60°C for 18 hours. While cooling, the mixture was acidified to approximately pH 4 with 1M aqueous HCl, and then concentrated and dried. The crude residue was dissolved in DMF (9 mL), and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (349 mg, 1.3 mmol) and DIPEA (150 μL, 0.86 mmol) were added, and the reaction mixture was stirred at room temperature for 5 minutes. HATU (181 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 22 hours. The mixture was filtered and washed with ELISA (2 × 5 mL). Water (30 mL) was added to the filtrate, and this was extracted with ELISA (3 × 10 mL). The organic extract was washed with water (2 × 10 ml) and brine (3 × 10 ml), dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by flash chromatography [35-80% in CH₂Cl₂ (50:8:1 CH₂Cl₂:EtOH:NH₄OH)] yielded a white solid (112 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 7.7 Hz, 1H), 7.63 - 7.22 (m, 10H), 7.22 - 7.07 (m, 3H), 5.36 (dd, J = 7.7, 3.1 Hz, 1H), 4.74 (dd, J = 10.7, 2.8 Hz, 1H), 4.51 - 4.38 (m, 1H), 4.29 (dd, J = 12.4, 4.8 Hz, 1H), 4.01 (dd, J = 12.4, 6.9 Hz, 1H), 2.74 - 2.54 (m, 5H), 1.04 (t, J = 7.1 Hz, 4H).LRMS(APCI+)m / z571.2[M+H] + .
[0589] Example 193 2-(2-fluoro-4-methylsulfanylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide Example 194 2-(2-fluoro-4-methylsulfinylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0590] [ka]
[0591] Carbon-supported palladium hydroxide (20% by wt, 50% water, 14 mg, 0.09 mmol) was added to a solution of intermediate 119A (150 mg, 0.36 mmol) in EtOH (8 mL) in a pressure tube. The container was successively purged with N2 (5 ×) and hydrogen (5 ×), then stirred at room temperature under a hydrogen atmosphere at 40 psi for 3 hours, and then stirred at 50°C under a hydrogen atmosphere at 40 psi for 24 hours. The reaction product was filtered through a glass microfiber pad and washed with EtOH (3 × 5 mL) and CH2Cl2 (3 × 5 mL), and the solvent was removed under reduced pressure. EtOH (8 mL) and NaOH (0.36 mL of 5 M aqueous solution, 2.9 mmol) were added, and the mixture was heated at 60°C for 16 hours. EtOH was removed under reduced pressure, the mixture was acidified to approximately pH 2 with 1 M aqueous HCl, and extracted with (3:1 CHCl3:iPrOH; 3 × 10 mL). The combined organic matter was washed with water and brine (10 mL each), dried, and concentrated under reduced pressure with (Na2SO4). A mixture of 2-(2-fluoro-4-methylsulfinylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid and 2-(2-fluoro-4-methylsulfanylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid was obtained (89 mg). This was used without further purification.
[0592] The crude product mixture (89 mg) was dissolved in DMF (2 mL), DIPEA (96 μL, 0.55 mmol) and HATU (115 mg, 0.302 mmol) were added, and the reaction mixture was stirred at room temperature for 10 minutes. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (74 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Workup and purification similar to that described for the compound in Example 5, followed by purification by flash chromatography [10-70% in CH2Cl2 (50:8:1 CH2Cl2:EtOH:NH4OH)], yielded Example 193 (30 mg) and subsequently Example 194 (33 mg) as white solids.
[0593] Example 193. 1 1H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.94 - 7.81 (m, 1H), 7.61 - 7.23 (m, 8H), 7.18 - 7.00 (m, 3H), 5.37 (dd, J = 7.7, 2.4 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.26 - 4.09 (m, 2H), 2.48 (s, 3H), 2.39 - 2.28 (m, 2H).LRMS(APCI+)m / z560.5[M+H] + .
[0594] Example 194. 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.92 (dd, J = 7.7, 1.7 Hz, 1H), 7.65 - 7.38 (m, 9H), 7.30 (td, J = 8.1, 5.1 Hz, 1H), 7.21 - 7.07 (m, 1H), 5.37 (d, J = 7.7 Hz, 1H), 4.67 (t, J = 5.2 Hz, 2H), 4.23 (t, J = 6.1 Hz, 2H), 2.79 (s, 3H), 2.42 - 2.27 (m, 2H).LRMS(APCI+)m / z576.5[M+H] + .
[0595] Example 195 2-Bromo-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide Example 196 2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0596]
change
[0597] 2,6-Difluorophenylboronic acid (1148 mg, 7.27 mmol), CsF (884 mg, 5.82 mmol), XPhos Pd G2 (229 mg, 0.290 mmol), and intermediate 9A (400 mg, 1.45 mmol) were combined in a vial, capped, evacuated, and sparged with N2 (3×). 1,4-Dioxane (5 mL) and water (2 mL) were both degassed with N2 and added. The reaction mixture was heated at 100°C for 18 hours. The reaction mixture was cooled to room temperature, and then 1,4-Dioxane was removed under reduced pressure. Workup and purification similar to that for intermediate 74A yielded a mixture of ethyl 2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate and ethyl 2-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (178 mg), which could not be separated by silica column chromatography and was used without further purification. The mixture was dissolved in EtOH (5 mL), NaOH (5 M aqueous solution, 0.59 mL, 2.95 mmol) was added, and the mixture was then heated at 60°C for 20 hours. A crude mixture of 2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid and 2-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (180 mg) was prepared by a workup similar to that of intermediate 34A and used without further purification. A portion of the crude product mixture (77 mg) was dissolved in DMF (1.5 mL), and DIPEA (96 μL, 0.55 mmol) and HATU (115 mg, 0.302 mmol) were added, and the reaction was stirred at room temperature for 10 minutes. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (74 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature for approximately 72 hours. Workup and purification similar to that described for the compound of Example 5, followed by purification by flash chromatography (Â in 50-70% heptane), yielded Example 195 (36 mg) and then Example 196 (58 mg) as white solids.
[0598] Example 195. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.56 - 7.40 (m, 5H), 7.33 (td, J = 8.1, 5.0 Hz, 1H), 7.21 - 7.12 (m, 1H), 5.43 (d, J = 7.5 Hz, 1H), 4.67 - 4.57 (m, 2H), 4.12 (t, J = 6.0 Hz, 2H), 2.33 - 2.26 (m, 2H).LRMS(APCI+)m / z487.2 / 499.2[M+H] + .
[0599] Example 196. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.64 - 7.37 (m, 7H), 7.29 (td, J = 8.1, 5.1 Hz, 1H), 7.14 - 6.95 (m, 3H), 5.37 (d, J = 7.8 Hz, 1H), 4.73 - 4.63 (m, 2H), 4.23 (t, J = 6.0 Hz, 2H), 2.40 - 2.33 (m, 2H).LRMS(APCI+)m / z531.4[M+H] + .
[0600] Example 200 (5R)-2-[4-(dimethylsulfamoyl)-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0601] [ka]
[0602] DIPEA (91 μL, 0.522 mmol) was added to a solution of intermediate 103D (100 mg, 0.261 mmol) and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-one (74 mg, 0.274 mmol) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 3 minutes. HATU (109 mg, 0.287 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O (15 mL), siRNA (10 mL) was added, and the mixture was extracted with aqueous siRNA (2 × 10 mL). The combined organic extract was washed with H2O (10 mL), dried, and volatiles were removed under reduced pressure using (Na2SO4). The residue was purified by column chromatography (0-10% MeOH in CH2Cl2). The isolated material was dissolved in CH2Cl2, washed with 1M aqueous HCl (10 mL), dried (Na2SO4), and volatile matter was removed under reduced pressure. The residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3 (20 mL), dried (Na2SO4), and volatile matter was removed under reduced pressure to produce a white solid (116 mg, 70%). 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.65 (dd, J = 8.0, 6.8 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.46-7.42 (m, 1H), 7.38-7.34 (m, 2H), 7.32-7.27 (m, 1H), 7.16-7.09 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 4.73-4.66 (m, 1H), 4.36-4.31 (m, 1H), 4.28-4.21 (m, 1H), 2.71 (s, 6H), 2.39-2.32 (m, 1H), 2.31-2.22 (m, 1H), 1.70 (d, J = 6.4 Hz, 3H).LRMS(ESI+)m / z635.0[M+H] + .
[0603] The following compounds were prepared using a procedure similar to that described for the compound in Example 200.
[0604] [Table 35]
[0605] The following compounds were prepared using a procedure similar to that described for the compounds in Example 5.
[0606] [Table J]
[0607] Example 203: Preparation of salt Preparation of hydrochloride salt: Procedure 1 A 4M HCl solution in 1,4-dioxane (3 equivalents) was added to the compound in a solution of 1,4-dioxane (15-30 volumes). The mixture was stirred for up to 1 hour or until a precipitate formed. The mixture was filtered, the precipitate was washed with cold (0°C) diethyl ether, and dried under reduced pressure.
[0608] Preparation of hydrochloride: Procedure 2 A 4M HCl solution in 1,4-dioxane (1 equivalent) was added at 50°C to a solution of the compound in THF (30 vol). The mixture was allowed to cool to room temperature and stirred until a precipitate formed. The mixture was filtered, the precipitate was washed with cold (0°C) diethyl ether, and dried under reduced pressure.
[0609] Preparation of other salts: Step 3 Examples 106·BSA, 106·H2SO4, 106·MSA, and 106·pTSA were prepared by the following method. A 1M solution of the acid in THF (1.1 equivalents) was added at 50°C to the solution of Example 106 in THF (30 vol), and the mixture was slowly cooled to room temperature. For Example 106·H2SO4, the solid was precipitated, filtered, washed with cold (0°C) diethyl ether, and dried under reduced pressure. For Example 106·BSA, the mixture was concentrated under reduced pressure, the residue was ground with RINKAN (3 × 5 mL), and dried under reduced pressure. For Example 106·MSA, the addition of RINKAN to the acidic solution yielded a precipitate, which was filtered, washed with cold (0°C) diethyl ether, and dried under reduced pressure. For Example 106·pTSA, RINKAN (approximately 20 mL) was added, the formed precipitate was collected, washed with RINKAN, and discarded (approximately 2 mg). The filtrate was concentrated to a volume of approximately 5 mL and cooled to 0°C in an ice bath. The mixture was ground with toluene (3 × 5 mL) and dried under reduced pressure.
[0610] [Table K]
[0611] Example 204: In vitro efficacy The compounds were subjected to an RSV plaque reduction assay according to the following protocol. Plaque reduction assay. Hep-G2 cells (ECACC, 85011430) were subcultured in flasks and seeded in 24-well plates in DMEM supplemented with 10% FBS and containing antibiotics. Cells were cultured in DMEM containing 2% FBS during inoculation and subsequent incubation. 100 plaques forming units / well of RSV (RSV A2 ECACC, 0709161v) were mixed with eight sequential dilutions of the compound. Subsequently, 100 μL of the virus / compound mixture was added to a dense Hep-G2 cell monolayer. Cells and the virus / compound mixture were incubated in a humidified 5% CO2 incubator at 37°C for 2 hours, after which the inoculum was removed and 1 mL of overlay (DMEM containing 2% FBS and 0.8% CMC) containing dilutions of the compound was added. Cells were incubated in a humidified 5% CO2 incubator at 37°C for 2 days.
[0612] The cells were washed with PBS for 3 minutes, then 75 / 25% v / vEtOH / MeOH was added. The fixative was removed, and the plate was washed with PBS. The pre-titrated amount of primary antibody was added to 200 μL of PBS / 2% milk powder, and the plate was incubated at 37°C for 90 minutes. The plate was washed three times with PBS / 0.05% Tween20, then rabbit anti-goat horseradish peroxidase in 200 μL of PBS / 2% milk powder was added, and the plate was incubated at 37°C for 1 hour. After three washes with PBS / 0.05% Tween20, 200 μL each, ready-to-use TrueBlue was added, and the plate was incubated at room temperature for 10-15 minutes, then washed with water. After removing the water, the plate was air-dried in the dark.
[0613] Plates were scanned and analyzed using an Immunospot S6 macro analyzer. This analyzer is equipped with BioSpot analysis software for counting immunostained plaques (virospots). Using the plaque counts, the infection percentage relative to the mean plaque count in the virus control well was calculated for RSV. EC was determined by interpolation of inhibition curves fitted with a 4-parameter nonlinear regression with a variable slope in Dotmatics.50 The values were calculated assuming a 50% decrease in the signal. Unless otherwise specified, plaque EC 50 and cytotoxic CC 50 The values are the average of at least two experiments, and the numbers have been rounded to the nearest whole number. result
[0614] [Table L-1]
[0615] [Table L-2]
[0616] [Table L-3]
[0617] [Table L-4]
[0618] [Table L-5]
[0619] Example 205: In vitro pharmacokinetics The compounds were used to investigate the stability of liver microsomes and hepatocytes under the following assay conditions.
[0620] Microsome Incubation: Experimental Procedure Pooled liver microsomes were purchased from a reliable supplier and stored at -80°C before use. Microsomes (final protein concentration 0.5 mg / mL), 0.1 M phosphate buffer pH 7.4, and the test compound (final substrate concentration 1 μM; final DMSO concentration 0.25%) were pre-incubated at 37°C, and then NADPH (final concentration 1 mM) was added to initiate the reaction. The final incubation volume was 50 μL. A control incubation was included for each compound tested, in which case 0.1 M phosphate buffer pH 7.4 was added instead of NADPH (minus NADPH). Two control compounds were included for each species. All incubations were performed individually for each test compound. Each compound was incubated for 0, 5, 15, 30, and 45 minutes. The control (minus NADPH) was incubated for only 45 minutes. At appropriate time points, the reaction was stopped by transferring the incubation to acetonitrile in a 1:3 ratio. The stop plate was centrifuged at 3,000 rpm for 20 minutes at 4°C to precipitate the protein. Following protein precipitation, the supernatants of up to four compound samples were combined in a cassette, an internal standard was added, and the samples were analyzed by LC-MS / MS. The slope of the line was determined from the plot of the ln peak area ratio (compound peak area / internal standard peak area) against time. Subsequently, the half-life (t) was calculated. 1 / 2 ) and endogenous clearance (CL) int The following was calculated: Compounds with low clearance (>80% residue at 45 minutes) under assay conditions were t 1 / 2 It is expressed as 140 minutes.
[0621] Hepatocyte incubation: Experimental procedure Frozen, pooled hepatocytes were purchased from a reliable supplier and stored in liquid nitrogen before use. Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES, along with the test compound (final substrate concentration 3 μM; final DMSO concentration 0.25%), were pre-incubated at 37°C. The suspension of frozen hepatocytes (final cell density 0.5 × 10⁶ in Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES) was then used. 6The reaction was initiated by adding (number of viable cells / mL). The final incubation volume was 500 μL. Two control compounds were included for each species, along with appropriate vehicle controls. At appropriate time points, the reaction was stopped by transferring 50 μL of incubation to 100 μL of acetonitrile containing the internal standard. During the 60-minute experiment, the samples were removed at 6-hour points (0, 5, 15, 30, 45, and 60 minutes). The stop plate was centrifuged at 2500 rpm at 4°C for 30 minutes to precipitate the proteins. Following protein precipitation, the supernatants of up to four compound samples were combined in a cassette and analyzed using standard LC-MS / MS conditions. The slope of the line was determined from the plot of the ln peak area ratio (compound peak area / internal standard peak area) against time. Subsequently, the half-life (t) was calculated. 1 / 2 ) and endogenous clearance (CL) int The following was calculated: Compounds with low clearance (>80% residue at 60 minutes) under assay conditions were t 1 / 2 This is expressed as 186 minutes.
[0622] result
[0623] [Table M]
[0624] Example 206: In vivo pharmacokinetics The pharmacokinetics of the compound were studied in vivo in rats at doses of 1 mg / kg (IV) and 10 mg / kg (PO).
[0625] Pharmacokinetics in rats method Male rats [Sprague Dawley (SD)] surgically prepared using jugular vein cannulas were treated with the experimental compound via intravenous administration (IV; n=3; 1 mg / kg) or oral administration (PO; n=3; 10 mg / kg). The compound was formulated as a solution in 40:60 dimethylacetamide:physiological saline (IV administration) and in 10% DMSO, 10% cremofol water (80%) (PO administration). Animals were observed for any obvious clinical signs or symptoms. Continuous 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 the compound, and plasma was prepared by centrifugation at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration of the compound, and immediately stored at -80°C. Next, the samples were thawed and prepared for analysis by protein precipitation with acetonitrile. Analysis was then performed using serial LC-MS with electrospray ionization using a matrix-matched standard curve. The PK parameters were calculated from the generated data.
[0626] result
[0627] [Table N]
[0628] Example 207: Aqueous Formulation The compound from Example 1 was formulated as a solution in 30% w / v captisol at pH 4 (i.e., sulfobutyl ether-β-cyclodextrin) according to the following procedure.
[0629] Prepare a 30% w / v caputisol (i.e., sulfobutyl ether-β-cyclodextrin) carrier by weighing the required amount of caputisol and placing it in a suitable container. Add approximately 80% of the final volume of water and magnetically stir until a solution is formed. Then, add water to the carrier until it reaches the desired volume.
[0630] Prepare an aqueous solution of the compound from Example 1 by weighing 175 mg of the compound and placing it in a suitable container, and add approximately 80% of the required amount of carrier. Adjust the pH to pH 2 using an aqueous hydrochloric acid solution, and magnetically stir the resulting mixture until a solution is formed. Then, add the carrier to the formulation to the specified volume, and adjust the pH to pH 4 using an aqueous sodium hydroxide solution.
[0631] Example 208: Tablet Formulation Tablets containing 25 mg of the compound of the present invention, each weighing 0.15 g, are manufactured as follows: Composition per 10,000 tablets Compound of the present invention (250g) Lactose (800g) Corn starch (415g) Talc powder (30g) Magnesium stearate (5g) The compound of the present invention, lactose, and half of the corn starch are mixed. The mixture is then extruded through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is suspended in warm water (90 mL). The resulting paste is used to granulate the powder. The granules are dried and crushed into small pieces on a sieve with a mesh size of 1.4 mm. The remaining amounts of starch, talc, and magnesium are added, the mixture is carefully mixed, and processed into tablets.
[0632] Example 209: Injectable Formulation
[0633] [Table O]
[0634] The compound of the present invention is dissolved in most water (35°C to 40°C), and the pH is adjusted to between 4.0 and 7.0 using hydrochloric acid or sodium hydroxide as needed. Then, water is added to the batch to volume, filtered through a sterile micropore filter into a sterile 10 mL amber glass vial (Type 1), and sealed with a sterile seal and overseal.
[0635] Example 210: Intramuscular injection
[0636] [Table P]
[0637] The compound of the present invention is dissolved in glycoflore. Then, benzyl alcohol is added and dissolved, and water is added up to 3 mL. The mixture is then filtered through a sterile micropore filter and placed in a sterile 3 mL glass vial (Type 1) and sealed.
[0638] Example 211: Syrup formulation
[0639] [Table Q]
[0640] The compound of the present invention is dissolved in a mixture of glycerol and most purified water. Then, an aqueous solution of sodium benzoate is added to the solution, followed by a sorbitol solution, and finally the flavoring agent. Purified water is added up to the specified volume and mixed thoroughly.
Claims
1. Equation (Ie') 【Chemistry 11】 Compounds that are benzodiazepine derivatives: [In the formula, R 8 is H or halo, T is C, V is N, The substructure in equation (Ie') is represented by the following equation 【Chemistry 10】 It is a combination, The substructure in equation (Ie') is represented by the following equation 【Chemistry 11】 Furthermore, X does not exist, W is H, C ３ ~C ６ cycloalkyl, halo, -NHR ９ , benzyl, phenyl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, where phenyl, heterocyclyl, and heteroaryl are unsubstituted or 4- to 10-membered heterocyclyl (unsubstituted or substituted with OR), and unsubstituted C １ ~C ６ alkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ haloalkyl, C ３ ~C ６ cycloalkyl, halo, -OR, -(CH ２ ) ｍ OR, -NR ２ , -(CH ２ ) ｍ NR ２ , -NHR'', -SO ｍ NR ２ , -SO ｍ R, -SR, nitro, -CO ２ R, -CN, -CONR ２ , -NHCOR, -CH ２ NR １０ R １１ and -NR １０ R １１ substituted with one or two substituents selected from, and each R is independently H or unsubstituted C １ ~C ６ alkyl, and R'' is C ３ ~C ６ cycloalkyl, and m is 1 or 2 R ９ The compounds are selected from phenyl and 4- to 10-membered heteroaryls, and the phenyl and heteroaryls are either unsubstituted or substituted with a halo. R １０ and R １１ These are, independently, H or unsubstituted C. １ ~C ６ Alkyl or R １０ and R １１ These, together with the N atoms to which they are attached, (a) link two ring carbon atoms arranged in para with each other -CH ２ - A morpholine ring optionally bridged by a group, or (b) a spiro group of formula (b) below: 【Transformation 3】 Forming one of the following, U and Z, along with the N and C atoms to which they are bonded, are given by the following formula (I-1): 【Chemistry 17】 It is a ring, where Y is O, S and SO ２ Selected from, R ２ ~R ７ Each of these is independently H, unsubstituted C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C ３ ~C ６ Cycloalkyl, halo, -OR, -CH ２ OR, -NR ２ ien-CH ２ NR １２ R １３ , -NRCOOR, -CH ２ OR, -SO ｍ NR ２ , -SO ｍ R_CH ２ SO ｍ R, Nitro, -CO ２ R, -CN, -CONR ２ Or -NHCOR, where R and m are as defined above, R １２ and R １３ These are H and unsubstituted C, respectively, independently. １ ~C ６ Alkyl, benzyl, 4-10 membered heterocyclyl, or R １２ and R １３ These, together with the N atoms to which they are attached, form unsubstituted 4- to 10-membered heteroaryls or 4- to 10-membered heterocyclines (unsubstituted or unsubstituted C). １ ~C ６ R (which is substituted with alkyl or halo) or bonded to the same carbon atom ２ ~R ７ Any two of the following are C ３ ~C ６ Cycloalkyl spiro rings and spirooxetane rings with the following structures: 【Transformation 5】 [Forms a spiro ring selected from] or a pharmaceutically acceptable salt thereof.
2. W is H, halo, cyclopropyl, cyclohexyl and the following structure: 【Chemistry 14】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.
3. R ２ to R ７ each of which is independently H, unsubstituted C １ to C ６ alkyl, C １ to C ６ hydroxyalkyl, C ３ to C ６ cycloalkyl, -CH ２ OR, -CH ２ NR １２ R １３ , -NRCOOR, -CH ２ SO ｍ R, or halo, R and m are as defined in claim 1, R １２ and R １３ are each independently H, unsubstituted C １ to C ６ alkyl, benzyl, 4- to 10-membered heterocyclyl, or R １２ and R １３ together with the N atom to which they are attached form an unsubstituted 4- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl (unsubstituted or substituted with unsubstituted C １ to C ６ alkyl or halo), or any two of R ２ to R<s ７ bonded to the same carbon atom form a C ３ to C ６ cycloalkyl spiro ring and a spirooxetane ring of the following structure: 【Chemistry 15】 A spiro ring is formed by selecting from R ２ ~R ７ The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the remainder is H.
4. A compound according to any one of claims 1 to 3, wherein Y in the ring of formula (I-1) is O, or a pharmaceutically acceptable salt thereof.
5. R ８ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein is H or F.
6. W is C ３ ~C ６ The group is selected from cycloalkyl, phenyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, where phenyl, heterocyclyl, and heteroaryl are unsubstituted or unsubstituted C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, halo, -OR, -(CH ２ ) ｍ OR, -NR ２ ,-(CH ２ ) ｍ NR ２ , -NHR'', -SO ｍ NR ２ , -SO ｍ R, -SR, Nitro, -CO ２ R, -CN, -CONR ２ , -NHCOR, -CH ２ NR １０ R １１ and -NR １０ R １１ It is substituted with one or two substituents selected from, and each R is independently H or unsubstituted C １ ~C ６ It is alkyl, and R'' is C ３ ~C ６ It is a cycloalkyl group, where m is 1 or 2, and R １０ and R １１ These are, independently, H or unsubstituted C. １ ~C ６ Alkyl or R １０ and R １１ These, together with the N atoms to which they are attached, link two ring carbon atoms that are arranged in para with each other -CH ２ - Forms a morpholine ring which is sometimes bridged by a group, In equation (I-1), Y is O, and R ２ ~R ７ Each of these is independently H or unsubstituted C １ ~C ６ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.
7. W is unsubstituted C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, halo, -OR, -(CH ２ ) ｍ OR, -NR ２ ,-(CH ２ ) ｍ NR ２ , -NHR'', -SO ｍ NR ２ , -SO ｍ R, -SR, Nitro, -CO ２ R, -CN, -CONR ２ , -NHCOR, -CH ２ NR １０ R １１ and -NR １０ R １１ A phenyl molecule substituted with one or two substituents selected from the following, where each R is independently H or unsubstituted C １ ~C ６ It is alkyl, and R'' is C ３ ~C ６ It is a cycloalkyl group, where m is 1 or 2, and R １０ and R １１ These are, independently, H or unsubstituted C. １ ~C ６ Alkyl or R １０ and R １１ These, together with the N atoms to which they are attached, link two ring carbon atoms that are arranged in para with each other -CH ２ - The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein a morpholine ring is optionally crosslinked by a group.
8. W has the following structure: [Chemistry 18] It is a group having R being unsubstituted C １ ~C ６ A compound according to claim 7, wherein the compound is alkyl, or a pharmaceutically acceptable salt thereof.
9. R ８ A compound according to any one of claims 6 to 8 or a pharmaceutically acceptable salt thereof, wherein F is present.
10. 2-(2,4-difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(ethylamino)-2-fluoropyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5,5-dimethyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)spiro[6,7-dihydropyrazolo[5,1-b][1,3]oxazine-5,1'-cyclopropane]-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(propan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; (6S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-ethyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(propan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; 6-Cyclopropyl-N-[(3S)-9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-propyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide; 2-[6-(cyclopropylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-pyridine-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-pyridine-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-cyclopropylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(propan-2-ylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(ethylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-phenylspiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,3'-oxetane]-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,3'-oxetane]-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-4,4-dioxo-5H,6H,7H-4λ6-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-4,4-dioxo-5H,6H,7H-4λ6-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-5H,6H,7H-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]thiadin-3-carboxamide; 3-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; 7-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxamide; 3-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6,6-dimethyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-chloropyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-chloropyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-5-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(cyclopropylamino)-2-fluoropyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-Cyclopropyl-N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-methoxypyridine-4-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-methoxypyridine-4-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxypropyl)pyridine-3-yl]-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(3-fluoropyridine-4-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(ethylamino)-3-pyridyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-cyclopropyl-2-fluoro-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethyl-2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-morpholino-3-pyridyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(6-morpholino-3-pyridyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,6-dimethyl-3-pyridyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,6-dimethyl-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-ethylpyrimidine-5-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-ethylpyrimidine-5-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-furyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(3-furyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(3-thienyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-thienyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethyl-2-methyl-3-pyridyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethyl-2-methyl-3-pyridyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(isopropylamino)-3-pyridyl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylpyrazole-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-2-[6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-propan-2-ylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(triduteriomethylamino)pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-6-methylpyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-6-methylpyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(6-ethylpyridine-3-yl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethyl-2-fluorophenyl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-fluoropyridine-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-methylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxypropyl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(5-fluoro-2-methylpyridine-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(3-fluoropyridine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-phenyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2,4-difluorophenyl)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(1-methylindazole-5-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-(2-hydroxy-2-methylpropyl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-N-[(3R)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-pyridyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)pyridine-3-yl]-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-[4-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-[2-methyl-6-(propan-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-anilino-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-anilino-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-fluoroanilino)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-methylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[4-[(dimethylamino)methyl]-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(morpholine-4-ylmethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[4-(diethylaminomethyl)-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide-carboxamide; tert-butyl N-[3-[[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]carbamoyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-yl]-N-methylcarbamate; tert-butyl N-ethyl-N-[3-[[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]carbamoyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-yl]carbamate; (5S)-2-benzyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-cyclohexyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1,3-dimethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxetan-3-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-hydroxyethyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-methoxyethyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[1-(difluoromethyl)pyrazole-4-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1,5-dimethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2-hydroxy-2-methylpropyl)pyrazole-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(pyrazole-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-cyclopropylpyrazole-4-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-cyclopropylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,4-difluorophenyl)-6-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(6-ethylpyridine-3-yl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(hydroxymethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoropyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-4-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(4-cyano-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-6-methoxyphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-6-methylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-4-methylsulfonylphenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(4-carbamoyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[2-fluoro-4-(methylsulfonimidoyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(3-methoxyazetidine-1-yl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(3R)-3-methoxypyrrolidine-1-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-[(3S)-3-methoxypyrrolidine-1-yl]pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-methylindazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(1-propan-2-ylpyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-methylindazole-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-4-(hydroxymethyl)phenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[2-fluoro-4-(hydroxymethyl)phenyl]-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[6-(hydroxymethyl)pyridine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(1-ethylpyrazole-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6-hydroxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(1-methylsulfonylpiperidine-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (2S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(2-fluorophenyl)-2-methyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-7-carboxamide; 6-(diethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[1-[2-(dimethylamino)ethyl]pyrazole-4-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 5-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(morpholine-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxan-4-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxetan-3-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[4-[(dimethylamino)methyl]-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-[(4-methylpiperazine-1-yl)methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(morpholine-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-[[benzyl(ethyl)amino]methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-6-methoxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 2-[6-(propane-2-ylamino)pyridine-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-[6-(propane-2-ylamino)pyridine-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; 2-(6-ethylpyridine-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(pyrrolidine-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-[2-fluoro-4-[(propan-2-ylamino)methyl]phenyl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(methylsulfonylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclobutane]-3-carboxamide; 6-[(3,3-difluoropyrrolidine-1-yl)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(pyrrolidine-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6R*)-6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (6S*)-6-[(dimethylamino)methyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-2-(2,6-difluorophenyl)-5-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2,6-difluorophenyl)-5-(hydroxymethyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-2-(2-fluorophenyl)-5-(hydroxymethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S*)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 6-(ethylaminomethyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfanylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2-fluoro-4-methylsulfinylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-bromo-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(2,6-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(4-ethylsulfonyl-2-fluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-5-methylsulfonylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2-(2-fluoro-4-sulfamoylphenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[4-(dimethylsulfamoyl)-2-fluorophenyl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(1-ethylsulfonylpiperidine-4-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; and (2R)-6-(2-fluorophenyl)-2-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-yl]-2,3-dihydropyrazolo[5,1-b][1,3]oxazole-7-carboxamide; A compound selected from, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
12. The pharmaceutical composition according to claim 11 for use in the treatment or prevention of RSV infection.
13. The pharmaceutical composition according to claim 12, for use in combination with one or more further therapeutic agents.
14. Further treatments are needed. (i) RSV nucleocapsid (N)-protein inhibitors; (ii) Protein inhibitors that inhibit phosphoprotein (P) proteins and / or giant (L) proteins; (iii) Anti-RSV monoclonal antibody; (iv) Immunomodulatory Toll-like receptor compounds; (v) Antiviral agents for respiratory viruses; and / or (vi) anti-inflammatory compounds The pharmaceutical composition according to claim 13.
15. For simultaneous, separate, or sequential use in the treatment of subjects with or susceptible to RSV infection, (a) A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof; and (b) One or more additional therapeutic agents; Products containing this ingredient.
16. Further treatments are needed. (i) RSV nucleocapsid (N)-protein inhibitors; (ii) Protein inhibitors that inhibit phosphoprotein (P) proteins and / or giant (L) proteins; (iii) Anti-RSV monoclonal antibody; (iv) Immunomodulatory Toll-like receptor compounds; (v) Antiviral agents for respiratory viruses; and / or (vi) anti-inflammatory compounds The product according to claim 15.
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