Benzodiazepine derivatives useful in the treatment of respiratory syncytial virus infection
By developing benzodiazepine derivatives with specific structures, the limitations of existing anti-RSV treatments have been addressed, providing potent antiviral activity and favorable pharmacokinetic properties, thus achieving effective treatment for RSV infection.
Patent Information
- Application Number
- CN202180053511.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Priority Date
- 2020-07-07
- Filing Date
- 2021-07-07
- Publication Date
- 2026-02-03
- Estimated Expiration
- 2041-07-07
AI Technical Summary
Existing anti-RSV treatments are limited, especially for non-premature infants and high-risk infants. There is an urgent need for compounds with potent antiviral activity and favorable pharmacokinetic properties to treat respiratory syncytial virus (RSV) infection.
A series of novel benzodiazepine derivatives with the structure of formula (Ie), including specific benzodiazepine groups and ring systems, have been developed for the preparation of compounds with potent anti-RSV activity and good physicochemical properties.
These compounds exhibit significant anti-RSV activity and favorable pharmacokinetic properties, enabling them to effectively treat RSV infection, particularly providing therapeutic treatment for infants, the elderly, and immunocompromised individuals.
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Figure CN116075516B_ABST
Abstract
Description
Invention Field
[0001] This invention relates to benzodiazepines Derivatives and their use in the treatment or prevention of respiratory syncytial virus (RSV) infection. Background of the Invention
[0003] RSV is a negative-sense single-stranded RNA virus belonging to the Paramyxoviridae family. RSV is easily transmitted via secretions from infected individuals through surfaces or hand-to-hand transfer. Unlike influenza, it is not transmitted via small aerosol particles. Following successful vaccination, the incubation period is 4–6 days, during which the virus spreads from the nasopharynx to the lower respiratory tract through the fusion of infected and uninfected cells and the shedding of necrotic epithelium. In infants, this, coupled with increased mucus secretion and edema, can lead to mucus blockage, causing overinflation and collapse of distal lung tissue, manifesting as bronchiolitis. Hypoxia is common, and feeding ability is often impaired due to respiratory distress. In RSV pneumonia, the inflammatory infiltration of the airways consists of mononuclear cells and is more diffuse, involving the bronchioles, bronchi, and alveoli. The duration and extent of viral shedding have been found to correlate with the clinical signs and severity of the disease.
[0004] RSV is a leading cause of severe respiratory infections in infants and young children worldwide. The highest morbidity and mortality rates occur in premature infants and those with chronic lung or heart disease, although many infants hospitalized for RSV infection are otherwise healthy. Severe RSV infection in infancy can lead to recurrent wheezing for several years and is associated with the later development of asthma.
[0005] RSV is also a leading cause of morbidity and mortality in older adults, immunocompromised children and adults, and people with chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).
[0006] RSV has a seasonal incidence; it is highly predictable and occurs during the winter months in both hemispheres, from September to May in Europe and North America, peaking in December and January, and can occur year-round in tropical countries. It affects >90% of infants and children under two years old because natural immunity is short-lived; many people are reinfected each year. Similar to influenza, RSV causes approximately 10% of winter hospitalizations among the elderly, with an associated mortality rate of 10%.
[0007] Current anti-RSV treatments involve the use of a monoclonal antibody against RSV called palizumab. This use of palizumab is for the prophylactic rather than therapeutic treatment of RSV. Although this antibody is generally effective, its use is limited to preterm infants and high-risk babies. In fact, its limited utility means it is unavailable to many people who require anti-RSV treatment. Therefore, there is an urgent need for effective alternatives to existing anti-RSV therapies.
[0008] Small molecules have also been proposed as inhibitors of RSV. These include benzimidazoles and benzodiazepines. Such compounds. For example, RSV604 (a benzodiazepine with submicromolar concentration anti-RSV activity) is described in Antimicrobial Agents and Chemotherapy, September 2007, 3346-3353 (Chapman et al.). The discovery and initial development of the compound. Benzodiazepines of RSV are also disclosed in publications including WO2004 / 026843 and WO2005 / 089770 (Arrow Therapeutics Limited); WO2016 / 166546 and WO2018 / 033714 (Durham University); and WO2017 / 015449, WO2018 / 129287 and WO2018 / 226801 (Enanta Pharmaceuticals, Inc.). Inhibitors.
[0009] It is necessary to identify other compounds with anti-RSV activity, especially compounds with a combination of potent antiviral activity and favorable pharmacokinetic properties. Invention Overview
[0011] A series of new benzodiazepines have now been discovered. The derivatives possess potent anti-RSV activity, favorable pharmacokinetics, and good physicochemical properties. Therefore, this invention provides a compound of formula (Ie) benzodiazepine derivative:
[0012]
[0013] in:
[0014] R 1 and R 2 One of them is a benzodiazepine containing formula (II). The radical group:
[0015]
[0016] Where R 8 It is H or halogen;
[0017] R 1 and R 2 The other is a group Z, which is selected from H, C3-C6 cycloalkyl, halogen, -NHR 9Benzyl, phenyl, 4- to 10-membered heterocyclic or 4- to 10-membered heteroaryl, wherein the phenyl, heterocyclic, and heteroaryl groups are unsubstituted or substituted with one or two substituents, wherein the substituents are selected from unsubstituted or OR-substituted 4- to 10-membered heterocyclic groups and are selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -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 In each of these, R is independently H or a C1-C6 alkyl group, R″ is a C3-C6 cycloalkyl group, and m is 1 or 2.
[0018] R 9 Selected from phenyl and 4- to 10-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by halogens;
[0019] R 10 and R 11 Each is independently H or C1-C6 alkyl; or R 10 and R 11 Together with the N atoms to which they are attached, they form (a) a morpholine ring, which is optionally bridged by a -CH2- group connecting two cyclic carbon atoms in para position to each other, or (b) a spiro group of formula (b):
[0020]
[0021] and
[0022] Ring A is a ring with one of the following structural formulas (I-1), (I-2), and (I-3):
[0023]
[0024] Where Y is selected from O, S, SO2 and NR, and R is as defined above, and R 2 To R 7 Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, -OR, -CH2OR, -NR2, -CH2NR 12 R 13 -NRCOOR, -CH2OR, -SO m NR2, -SO m R, -CH2SOm R, nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, and R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atom to which they are attached, they form unsubstituted 4- to 10-membered heteroaryl groups or unsubstituted or C1-C6 alkyl or halogen-substituted 4- to 10-membered heterocyclic groups, or R groups bonded to the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings and spirooxobutane rings with the following structures:
[0025]
[0026] Or its pharmaceutically acceptable salt.
[0027] In one embodiment, the present invention provides a benzodiazepine of formula (I). Derivative compounds:
[0028]
[0029] in:
[0030] R 1 and R 2 One of them is a benzodiazepine containing formula (II). The radical group:
[0031]
[0032] Where R 8 It is H or halogen;
[0033] R 1 and R 2 The other is selected from H, C3-C6 cycloalkyl, -NHR 9 Z, consisting of phenyl and 4- to 10-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or two substituents selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -OR, -NHR″, -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2, -NHCOR, and -NR 10 R 11 In each of these, R is independently H or a C1-C6 alkyl group, R″ is a C3-C6 cycloalkyl group, and m is 1 or 2.
[0034] R 9 Selected from phenyl and 4- to 10-membered heteroaryl groups;
[0035] R 10 and R 11 Each is independently H or C1-C6 alkyl; or R 10 and R 11 Together with the N atoms to which they are attached, they form (a) a morpholine ring, which is optionally bridged by a -CH2- group connecting two cyclic carbon atoms in para position to each other, or (b) a spiro group of formula (b):
[0036]
[0037] and
[0038] Ring A is a ring with one of the following structural formulas (I-1), (I-2), and (I-3):
[0039]
[0040] Where Y is selected from O, S, SO2 and NR, and R is as defined above, and R 2 To R 7 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -OR, -NR2, -CH2OR, -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, or R bonded to the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings or spirooxobutane rings with the following structures:
[0041]
[0042] Or its pharmaceutically acceptable salt.
[0043] In one aspect, the benzodiazepine of the present invention The derivative has the following structural formula (Ie′):
[0044]
[0045] in:
[0046] R 8 It is H or halogen;
[0047] and
[0048] (i) T is N and V is C;
[0049] and For valence bonds, and and It does not exist;
[0050] Z is selected from H, C3-C6 cycloalkyl groups, halogens, and -NHR. 9 Benzyl, phenyl, 4- to 10-membered heterocyclic groups and 4- to 10-membered heteroaryl groups, wherein the phenyl, heterocyclic, and heteroaryl groups are unsubstituted or substituted with one or two substituents, said substituents being selected from unsubstituted or OR-substituted 4- to 10-membered heterocyclic groups and selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -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 In each of these, R is independently H or a C1-C6 alkyl group, R″ is a C3-C6 cycloalkyl group, and m is 1 or 2.
[0051] R 9 Selected from phenyl and 4- to 10-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by halogens;
[0052] R 10 and R 11 Each is independently H or C1-C6 alkyl; or R 10 and R 11 Together with the N atoms to which they are attached, they form (a) a morpholine ring, which is optionally bridged by a -CH2- group connecting two cyclic carbon atoms in the para position, or (b) a spiro group of formula (b):
[0053]
[0054] and
[0055] X and U form rings with the N and C atoms they are attached to, according to formula (I′-1) or (I′-2):
[0056]
[0057] Where R 2 To R 7Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, -OR, -CH2OR, -NR2, -CH2NR 12 R 13 -NRCOOR, -CH2OR, -SO m NR2, -SO m R, -CH2SO m R, nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above and R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atom to which they are attached, they form unsubstituted 4- to 10-membered heteroaryl groups or unsubstituted or C1-C6 alkyl or halogen-substituted 4- to 10-membered heterocyclic groups, or R groups bonded to the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings or spirooxobutane rings with the following structures:
[0058]
[0059] or
[0060] (ii) T is C, V is N. and For valence bonds, and
[0061] and It does not exist;
[0062] W has the definition of Z given in item (i) above; and
[0063] U and Z form rings with the N and C atoms they are attached to, as shown in equation (I-1) or (I-3):
[0064]
[0065] Where Y is selected from O, S, SO2 and NR, and R is as defined in item (i) above; and R 2 To R 7 As defined in item (i) above;
[0066] Or its pharmaceutically acceptable salt.
[0067] In one embodiment of this aspect, the benzodiazepine of the present invention The derivative has the following structural formula (I′):
[0068]
[0069] in:
[0070] R 8 It is H or halogen;
[0071] and
[0072] (i) T is N and V is C;
[0073] and For valence bonds, and and It does not exist;
[0074] Z is selected from H, C3-C6 cycloalkyl groups, and -NHR. 9 , phenyl and 4- to 10-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are either unsubstituted or substituted by one or two substituents selected from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -OR, -NHR″, -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2, -NHCOR, and -NR 10 R 11 In each of these, R is independently H or a C1-C6 alkyl group, R″ is a C3-C6 cycloalkyl group, and m is 1 or 2.
[0075] R 9 Selected from phenyl and 4- to 10-membered heteroaryl groups;
[0076] R 10 and R 11 Each is independently H or C1-C6 alkyl; or R 10 and R 11 Together with the N atoms to which they are attached, they form (a) a morpholine ring, which is optionally bridged by a -CH2- group connecting two cyclic carbon atoms in the para position, or (b) a spiro group of formula (b):
[0077]
[0078] and
[0079] X and U form rings with the N and C atoms they are attached to, according to formula (I′-1) or (I′-2):
[0080]
[0081] Where R 2 To R 7Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -OR, -NR2, -CH2OR, -SO m NR2, -SO m R, nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, or R bonded to the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings or spirooxobutane rings with the following structures:
[0082]
[0083] or
[0084] (ii) T is C, V is N. and For valence bonds, and and It does not exist;
[0085] W has the definition of Z given in item (i) above; and
[0086] U and Z form rings with the N and C atoms they are attached to, as shown in equation (I-1) or (I-3):
[0087]
[0088] Where Y is selected from O, S, SO2 and NR, and R is as defined in item (i) above; and R 2 To R 7 As defined in item (i) above;
[0089] Or its pharmaceutically acceptable salt. Invention Details
[0091] When any group, ring, substituent, or portion defined in this application is substituted, it is typically substituted with Q as defined below.
[0092] C 1-6 The alkyl group or part of it is straight-chain or branched. C 1-6 Alkyl groups are typically C10-3 ... 1-4 Alkyl or C 4-6 Alkyl group. C 1-6Examples of alkyl groups and moiety include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl (i.e., 3-methylbut-1-yl), tert-pentyl (i.e., 2-methylbut-2-yl), neopentyl (i.e., 2,2-dimethylpropyl-1-yl), n-hexyl, isohexyl (i.e., 4-methylpent-1-yl), tert-hexyl (i.e., 3-methylpent-3-yl), and neopentyl (i.e., 3,3-dimethylbut-1-yl). For the avoidance of ambiguity, when two alkyl moiety are present in a group, the alkyl moiety may be the same or different. C 1-6 Alkyl groups are either unsubstituted or substituted, and are typically substituted by one or more groups Q as defined below. For example, C 1-6 The alkyl group is either unsubstituted or substituted with one, two, or three groups Q as defined below.
[0093] Q represents halogen, nitro, -CN, OH, or C. 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylthio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Haloalkoxy groups, -CO2R', -NR'2, -SR', -S(=O)R', -S(=O)2R', C3-C 10 Cycloalkyl, 5- to 10-membered heterocyclic, 5- to 12-membered aryl, or 5- to 10-membered heteroaryl, wherein each of R' is independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclic groups, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups. To avoid ambiguity, the alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl, and heteroaryl portions in these definitions are typically not substituted.
[0094] C 1-6 Alkyl groups can be straight-chain or branched. They are typically C10-3 ... 1-4 Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, or tert-butoxy. C 1-6 The alkoxy group is either unsubstituted or substituted, typically substituted by one or more groups Q as defined above.
[0095] C 1-6 The alkylthio group can be straight-chain or branched. Typically, it is C10. 1-4 Alkylthio groups, such as methylthio, ethylthio, propylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, or tert-butylthio. C 1-6 The alkylthio group is either unsubstituted or substituted, typically substituted by one or more groups Q as defined above.
[0096] The halogen or halogen group is F, Cl, Br, or I. Typically, it is F or Cl. The C substituted with a halogen... 1-6 Alkyl groups can be represented as "C 1-6 "Haloalkyl" refers to a C14 alkyl group in which one or more hydrogen atoms are replaced by halogens, as defined above. 1-6 Alkyl groups. Similarly, C groups substituted with halogens. 1-6 Alkyl groups can be represented as "C 1-6 "Haloalkoxy" refers to a C-type compound in which one or more hydrogen atoms are replaced by halogens, as defined above. 1-6 Alkyl group. Typically, C 1-6 Halogenated alkyl or C 1-6 The haloalkoxy group is substituted by one, two, or three of the halogen atoms. The haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups, such as -CX3 and -OCX3, where X is a halogen, such as -CF3-CCl3-OCF3 and -OCCl3.
[0097] C 1-6 Hydroxyalkyl is a C14 alkyl group substituted with one or more OH groups as defined above. 1-6 Alkyl group. Typically, it is substituted with one, two, or three OH groups. Preferably, it is substituted with one OH group.
[0098] C6-C 10 Aryl groups are aromatic carbocyclic groups containing 6 to 10 carbon atoms. They are monocyclic or fused bicyclic systems, where the aromatic ring is fused with another aromatic carbocyclic ring. (C6-C) 10 Examples of aryl groups include phenyl and naphthyl groups. When substituted, the aryl group is typically substituted with a group Q as defined above, for example, by one, two, or three groups selected from group Q as defined above. More specifically, the substituted aryl group, such as a substituted phenyl group, is substituted with one or two groups selected from C1-C6 alkyl groups, halogens, -OR groups. 8 and -N(R) 8 The group substituted by )2, wherein R 8 It is an H or C1-C6 alkyl group, and when two are present, each R 8 Same or different.
[0099] C 3-10 Cycloalkyl groups are saturated hydrocarbon rings with 3 to 10 carbon atoms. 3-10 The cycloalkyl group can be, for example, a C3-C7 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typically, it is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, it is cyclopropyl. 3-10 The cycloalkyl group is either unsubstituted or typically substituted with one or more groups Q as defined above.
[0100] A 4- to 10-membered heteroaryl group or part thereof is a 4- to 10-membered aromatic heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, and S. It can be monocyclic or bicyclic. Typically, it contains one N atom and 0, 1, 2, or 3 other heteroatoms selected from O, S, and N. It can be, for example, a monocyclic 5- to 7-membered heteroaryl, such as a 5- or 6-membered N-containing heteroaryl. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrazolylalkyl, pyrroleyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazoleyl, and pyrazolyl. Furanyl, thiopheneyl, imidazoleyl, pyridinyl, and pyrimidinyl are preferred. Alternatively, it can be a bicyclic heteroaryl, such as an 8- to 10-membered bicyclic heteroaryl. Examples include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalolinyl, indolyl, isoindolyl, indolyl, imidazopyridazinyl, pyrrolopyridyl, pyrazolopyrimidinyl, and pyrrolopyrimidinyl. When substituted, the heteroaryl group (monocyclic or bicyclic) is typically replaced by one or more, for example, 1, 2, or 3 C groups selected from those defined above. 1-4 Alkyl groups and group Q are substituted.
[0101] Four- to ten-membered heterocyclic groups are monocyclic or bicyclic non-aromatic saturated or unsaturated ring systems containing 5-10 carbon atoms and at least one atom or group selected from N, O, S, SO, SO2, and CO, more typically N or O. When the ring system is bicyclic, one ring can be saturated and the other ring can be unsaturated. Typically, it is C 4-10 A cyclic system in which one, two, or three carbon atoms in the ring are replaced by atoms or groups selected from O, S, SO2, CO, and NH. More typically, it is a monocyclic ring, preferably a monocyclic C4-C6 ring. Examples include piperidinyl, piperidin-2,6-diketone, piperidin-2-keto, piperazine, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanecycloyl, pyrrolyl, aziridine, diaziridine, imidazole-2-keto, pyrrolidine-2-keto, oxacyclobutane, tetrahydrofuranyl, and tetrahydropyranyl moieties.
[0102] To avoid ambiguity, although the above definitions of heteroaryl and heterocyclic groups refer to "N" atoms that may be present in a ring, it will be apparent to skilled chemists that if any such N atom is attached to each of its adjacent ring atoms by a single bond, then any such N atom will be protonated (or will carry substituents as defined above). Such protonated forms are included within the definitions of heteroaryl and heterocyclic groups of this invention.
[0103] In equation (Ie) or equation (I) as defined above, ring A is typically a ring of equation (I-1), where Y is O, S, or SO2. More typically, ring A is a ring of equation (I-1), where Y is O.
[0104] In equation (Ie) or equation (I), when R 1 It is a group of formula (II) and R 2 When it is Z, A is typically a ring of equation (I-1), where Y is O, or a ring of equation (I-2).
[0105] In equation (Ie) or equation (I), when R 1 For Z and R 2 When A is a group of formula (II), it is typically a ring of formula (I-1), where Y is O, S, or SO2, or a ring of formula (I-3). In this embodiment, Y is most typically O.
[0106] When group Z in formula (Ie) or (Ie') or formula (I) or (I') is a 4- to 10-membered heteroaryl group, the group may be selected from those listed in the general definition above. Typically, it is selected from pyridinyl, pyrazolyl, indazoleyl, pyrimidinyl, thiophenyl, and furanyl. More typically, it is pyridinyl.
[0107] When group Z is a 4- to 10-membered heterocyclic group in formula (Ie), (Ie'), (I), or (I'), the group may be selected from those listed in the general definition above. Typically, it is a monocyclic C4-C6 ring. More typically, it is a piperidinyl group.
[0108] In formula (Ie), (Ie′), (I), or (I′), when the substituent on Z is a 4- to 10-membered heterocyclic group, the group may be selected from those listed in the general definition above. Typically, it is a monocyclic C4-C6 ring, wherein one carbon atom in the ring is replaced by an atom or group selected from O and NH. More typically, it is selected from pyrrolidinyl, azirrobutylyl, oxobutylyl, and tetrahydropyranyl.
[0109] In formula (Ie) or (Ie') or formula (I) or (I'), when the substituent on Z is the group -NR 10 R 11 When, R 10 and R 11 Together with the N atoms they are attached to, they form a morpholine ring, which is bridged by -CH2- groups connecting two cyclic carbon atoms in para-position, the -NR group. 10 R 11 It has the following structure (c) or (d):
[0110]
[0111] In one embodiment of formula (Ie) or formula (I) as defined above, benzodiazepine The derivative has formula (Ia):
[0112]
[0113] All groups are as defined above for formula (Ie) or formula (I).
[0114] In another embodiment of formula (Ie) or formula (I) as defined above, benzodiazepine The derivative has the formula (Ib):
[0115]
[0116] All groups are as defined above for formula (Ie) or formula (I).
[0117] In another embodiment of formula (Ie) or formula (I) as defined above, benzodiazepine The derivative has the formula (Ic):
[0118]
[0119] All groups are as defined above for formula (Ie) or formula (I).
[0120] In another embodiment of formula (Ie) or formula (I) as defined above, benzodiazepine The derivative has the formula (Id):
[0121]
[0122] All groups are as defined above for formula (Ie) or formula (I).
[0123] In the above equations (Ie), (Ie′), (I), (I′), (Ia), (Ib), (Ic), and (Id), R 8 Typically H or F.
[0124] 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. When Y is NR, R is typically C. 1-4 alkyl.
[0125] In the above formulas (Ie), (Ie′), (Ia), (Ib), (Ic), and (Id), Z is typically selected from H, halogens, cyclopropyl, cyclohexyl, and the following structures:
[0126]
[0127] R and R″ are as defined above for formula (Ie). Typically, R is a C1-C3 alkyl group and R″ is a cyclopropyl group.
[0128] The above definition of Z is typically also derived from W in equation (Ie′).
[0129] In one embodiment of the above formulas (I), (I'), (Ia), (Ib), (Ic), and (Id), Z is typically selected from H, cyclopropyl, and the following structures:
[0130]
[0131] R and R″ are as defined above for formula (I). Typically, R is a C1-C3 alkyl group and R″ is a cyclopropyl group.
[0132] The above definition of Z is typically also derived from W in equation (I′).
[0133] In equations (Ie), (Ie′), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 Each of these is typically H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -CH2OR, -CH2NR 12 R 13 -NRCOOR, -CH2SO m R or halogen, where R and m are as defined above, and R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atom to which they are attached, they form unsubstituted 4- to 10-membered heteroaryl or 4- to 10-membered heterocyclic groups, which are unsubstituted or substituted by C1-C6 alkyl or halogen groups, or bonded to the R atom of the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings or spirooxobutane rings with the following structures:
[0134] And R 2 To R 7 The rest are H.
[0135] In one implementation of equations (I), (I′), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 Each of these is typically H, C1-C6 alkyl, C3-C6 cycloalkyl, or halogen, or R bonded to the same carbon atom. 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings or spirooxobutane rings with the following structures:
[0136] And R 2 To R 7 The rest are H.
[0137] For example, in equations (Ie), (Ie'), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 The following values are possible:
[0138] -R 2 To R 7 Each of them is H; or
[0139] -R 2 To R 7 One or two of them are independently C1-C3 alkyl groups; and R 2 To R 7 The rest are H; or
[0140] - R bonded to the same carbon atom 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings and spirooxobutane rings with the following structures:
[0141] And R 2 To R 7 The rest are H.
[0142] For example, in equations (Ie), (Ie′), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 The following values are possible:
[0143] -R 2 To R 7 Each of them is H; or
[0144] -R 4 and R 7 One of them is a C1-C3 alkyl group; and R 2 To R 7 The rest are H; or
[0145] -R 4 and R 5 All are C1-C3 alkyl groups, or R 4 and R 5 Together they form a spirocyclic ring, which is a cyclopropyl spirocyclic ring or a spirooxocyclic butane ring with the structure defined above; and R 2 To R 7 The rest are H; or
[0146] -R 6 and R 7Together they form a spiroring, which is a cyclopropyl spiroring; and R 2 To R 7 The rest are H.
[0147] For example, in equations (Ie), (Ie′), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 The following values are possible:
[0148] -R 2 To R 7 Each of them is H; or
[0149] -R 2 To R 7 One of them is C1-C3 alkyl, C1-C3 hydroxyalkyl, -NRCOOR such as tert-butyl (methyl)carbamate or -CH2NR 12 R 13 , where R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atoms they are attached to, they form unsubstituted 4- to 10-membered heteroaryl groups, such as pyrazoles, or 4- to 10-membered heterocyclic groups, such as morpholine or diazinanes, which are unsubstituted or substituted with C1-C6 alkyl groups or halogens; and R 2 To R 7 The rest are H; or
[0150] - R bonded to the same carbon atom 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings and spirooxobutane rings with the following structures:
[0151] And its R 2 To R 7 The remainder is H.
[0152] For example, in one of the embodiments of equations (I), (I'), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 The following values are possible:
[0153] -R 2 To R 7 Each of them is H; or
[0154] -R 2 To R 7 One or two of them are independently C1-C3 alkyl groups; and R 2 To R7 The rest are H; or
[0155] - R bonded to the same carbon atom 2 To R 7 Any two of them form a spiroring, which is selected from C3-C6 cycloalkyl spirorings and spirooxobutane rings with the following structures:
[0156] And R 2 To R 7 The rest are H.
[0157] For example, in equations (I), (I′), (Ia), (Ib), (Ic), and (Id), R 2 To R 7 The following values are possible:
[0158] -R 2 To R 7 Each of them is H; or
[0159] -R 4 and R 7 One of them is a C1-C3 alkyl group; and R 2 To R 7 The rest are H; or
[0160] -R 4 and R 5 All are C1-C3 alkyl groups, or R 4 and R 5 Together they form a spirocyclic ring, which is a cyclopropyl spirocyclic ring or a spirooxocyclic butane ring with the structure defined above; and R 2 To R 7 The rest are H; or
[0161] -R 6 and R 7 Together they form a spiroring, which is a cyclopropyl spiroring; and R 2 To R 7 The rest are H.
[0162] R 2 To R 7 Each bond connecting to an adjacent C atom can be oriented above or below the plane of the five- or six-membered saturated ring, i.e., depicted as or
[0163] For example, in any of the equations (Ie), (Ie′), (I), (I′), (Ia), (Ib), (Ic), and (Id) as defined above, where R 2 To R 7 For any value of R as described above, 4It can be R 4 or R 4 Similarly and independently, R 7 It can be R 7 or R 7 In this type of implementation, R 4 and R 7 Typically C1-C3 alkyl groups.
[0164] With the above R 2 To R 7 any value and R 2 To R 7 In any of the equations (Ie), (Ie′), (I), (I′), and (Ic) in any direction, Y is typically O, S, or SO2. More typically, Y is O or SO2. Most typically, Y is O.
[0165] The specific compounds of this invention include the following compounds:
[0166] 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;
[0167] 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;
[0168] 2-[6-(ethylamino)-2-fluoropyridin-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;
[0169] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[2-fluoro-6-(propyl-2-ylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0170] 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;
[0171] 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;
[0172] 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;
[0173] N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-5-(propyl-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide;
[0174] (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;
[0175] (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;
[0176] 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;
[0177] N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-(propyl-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxamide;
[0178] 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;
[0179] 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;
[0180] 2-[6-(cyclopropylamino)pyridin-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;
[0181] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-pyridin-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0182] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-pyridin-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0183] 2-(6-Cyclopropylpyridin-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;
[0184] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-(propyl-2-ylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0185] 2-[6-(ethylamino)pyridin-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;
[0186] 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;
[0187] 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;
[0188] 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;
[0189] (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;
[0190] 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;
[0191] 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;
[0192] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[2-fluoro-6-(propyl-2-ylamino)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0193] (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[2-fluoro-6-(propyl-2-ylamino)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0194] 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]thiazine-3-carboxamide;
[0195] 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]thiazine-3-carboxamide;
[0196] 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]thiazine-3-carboxamide;
[0197] 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]thiazine-3-carboxamide;
[0198] 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;
[0199] 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]oxazol-6-carboxamide;
[0200] 3-[6-(cyclopropylamino)-2-fluoropyridin-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;
[0201] 2-[6-(cyclopropylamino)-2-fluoropyridin-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;
[0202] 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;
[0203] 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;
[0204] (5R)-2-(5-chloropyridin-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;
[0205] (5R)-2-(5-chloropyridin-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;
[0206] (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;
[0207] (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;
[0208] (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;
[0209] 2-(2-fluoro-5-methylpyridin-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;
[0210] 2-(2-fluoro-5-methylpyridin-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;
[0211] 2-[6-(cyclopropylamino)-2-fluoropyridin-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;
[0212] 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;
[0213] (5R)-2-(2-methoxypyridin-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;
[0214] (5R)-2-(2-methoxypyridin-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;
[0215] (5R)-2-[6-(2-hydroxypropyl)pyridin-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;
[0216] (5R)-2-(3-Fluoropyridin-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;
[0217] (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;
[0218] (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;
[0219] (5R)-2-(4-ethyl-2-fluoro-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;
[0220] (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;
[0221] (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;
[0222] (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;
[0223] (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;
[0224] (5R)-2-(2-ethylpyrimidin-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;
[0225] (5R)-2-(2-ethylpyrimidin-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;
[0226] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(3-furanyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0227] (5R)-2-(3-furanyl)-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;
[0228] (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;
[0229] (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;
[0230] (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;
[0231] (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;
[0232] (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;
[0233] (5R)-2-(1-Ethylpyrazol-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;
[0234] (5S)-5-methyl-2-[6-(propyl-2-ylamino)pyridin-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;
[0235] (5R)-5-methyl-2-(6-propyl-2-pyridin-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;
[0236] (5R)-5-methyl-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-(trideuterated methylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0237] (5R)-2-(2-fluoro-6-methylpyridin-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;
[0238] (5R)-2-(2-fluoro-6-methylpyridin-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;
[0239] (5R)-2-(6-ethylpyridin-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;
[0240] (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;
[0241] (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(3-fluoropyridin-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0242] (5R)-5-methyl-2-(6-methylpyridin-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;
[0243] (5R)-2-[6-(2-hydroxypropyl)pyridin-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;
[0244] (5R)-2-(5-fluoro-2-methylpyridin-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;
[0245] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(3-fluoropyridin-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0246] (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;
[0247] (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;
[0248] (5R)-5-methyl-2-(1-methylindazol-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;
[0249] (5R)-2-(1-Ethylpyrazol-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;
[0250] (5R)-2-[6-(2-hydroxy-2-methylpropyl)pyridin-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;
[0251] (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]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0252] (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]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0253] (5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-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;
[0254] (5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-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;
[0255] (5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-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;
[0256] (5R)-2-[2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-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;
[0257] (5R)-5-methyl-2-[4-methyl-6-(propyl-2-ylamino)pyridin-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;
[0258] (5R)-5-methyl-2-[2-methyl-6-(propyl-2-ylamino)pyridin-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;
[0259] (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]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0260] (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;
[0261] (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;
[0262] (5R)-2-(4-fluoroaniline)-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;
[0263] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0264] 2-(1-Ethylpyrazol-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;
[0265] 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;
[0266] 2-[2-fluoro-4-(morpholin-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;
[0267] 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;
[0268] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(1-propyl-2-ylpyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0269] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-[(3-methyloxetane-3-yl)methyl]pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0270] 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;
[0271] 2-(6-Ethylpyridin-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;
[0272] 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 ester;
[0273] 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 tert-butyl ester;
[0274] (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;
[0275] 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;
[0276] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0277] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-(1-propyl-2-pyrazole-4-yl)-6,7-dihydro-5H-pyrazole[5,1-b][1,3]oxazine-3-carboxamide;
[0278] 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;
[0279] (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;
[0280] (5R)-2-(1,3-dimethylpyrazol-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;
[0281] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0282] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(2-hydroxyethyl)pyrazol-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0283] (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)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0284] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0285] (5R)-2-[1-(difluoromethyl)pyrazol-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;
[0286] (5R)-2-(1,5-dimethylpyrazol-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;
[0287] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0288] 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;
[0289] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-(pyrazol-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0290] (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;
[0291] (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;
[0292] (5S)-2-(6-ethylpyridin-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;
[0293] 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;
[0294] 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;
[0295] 2-(1-Ethylpyrazol-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;
[0296] 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;
[0297] (5S)-2-(6-ethylpyridin-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;
[0298] 2-(6-Ethylpyridin-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;
[0299] 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;
[0300] 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;
[0301] 2-(2-Fluoropyridin-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;
[0302] (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;
[0303] 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;
[0304] 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;
[0305] 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;
[0306] (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;
[0307] 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;
[0308] 2-[2-fluoro-4-(methyliminosulfonyl)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;
[0309] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-(3-methoxyazacyclobutane-1-yl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0310] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-[(3R)-3-methoxypyrrolidone-1-yl]pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0311] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-[(3S)-3-methoxypyrrolidone-1-yl]pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0312] 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;
[0313] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(1-propyl-2-ylpyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0314] 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;
[0315] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0316] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0317] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[1-(oxan-4-yl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0318] (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;
[0319] (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;
[0320] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[6-(hydroxymethyl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0321] (5S)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-[1-(oxan-4-yl)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0322] (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)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0323] (5S)-2-(1-Ethylpyrazol-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;
[0324] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0325] 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;
[0326] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-5-methyl-2-(1-methylsulfonylpiperidin-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0327] (5R)-5-methyl-2-(1-methylsulfonylpiperidin-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;
[0328] (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]oxazol-7-carboxamide;
[0329] 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;
[0330] (5R)-2-[1-[2-(dimethylamino)ethyl]pyrazol-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;
[0331] 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;
[0332] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-5-(morpholin-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0333] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxane-4-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0334] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-[[methyl(oxetane-3-yl)amino]methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0335] (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;
[0336] 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;
[0337] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0338] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-(morpholin-4-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0339] 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;
[0340] 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;
[0341] 2-(6-Ethylpyridin-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;
[0342] 2-(6-Ethylpyridin-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;
[0343] 2-[6-(propyl-2-ylamino)pyridin-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;
[0344] 2-[6-(propyl-2-ylamino)pyridin-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;
[0345] 2-(6-Ethylpyridin-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;
[0346] 2-(6-Ethylpyridin-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;
[0347] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-6-(pyrrolidone-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0348] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-[2-fluoro-4-[(propyl-2-ylamino)methyl]phenyl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0349] 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;
[0350] 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;
[0351] 6-[(3,3-difluoropyrrolidone-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;
[0352] N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluorophenyl)-5-(pyrrolidone-1-ylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0353] (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;
[0354] (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;
[0355] (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;
[0356] (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;
[0357] (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;
[0358] (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;
[0359] (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;
[0360] (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;
[0361] (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;
[0362] (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;
[0363] (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;
[0364] (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;
[0365] (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;
[0366] (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;
[0367] 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;
[0368] 2-(2-Fluoro-4-methylthiophenyl)-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;
[0369] 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;
[0370] 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;
[0371] 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;
[0372] (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;
[0373] (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;
[0374] (5R)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine] -3-yl]-2-(2-fluoro-4-aminosulfonylphenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide;
[0375] (5R)-2-[4-(dimethylaminosulfonyl)-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;
[0376] (5R)-2-(1-Ethylsulfonylpiperidin-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;
[0377] (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]oxazol-7-carboxamide;
[0378] And its pharmaceutically acceptable salts.
[0379] The compounds of the present invention may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are envisioned, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof, such as racemic mixtures, forming part of the present invention. Compounds of formula (Ie) or formula (I) containing one or more chiral centers may be used in enantiomeric or diastereomeric pure forms or in mixtures of isomers.
[0380] This invention includes all geometrical and positional isomers of the compounds as defined above. For example, if the compounds of this invention contain a double bond or a fused ring, the cis and trans forms, and mixtures thereof, are included within the scope of this invention. Single positional isomers and mixtures of positional isomers are also within the scope of this invention.
[0381] The compounds of the present invention may exist in a non-solventized form as well as in a solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is envisioned to include both solvated and non-solventized forms.
[0382] The compounds of this invention can exist in different tautomeric forms, and all such forms are included within the scope of this invention. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that can be interconverted via low energy barriers. For example, proton tautomers (also called proton shift tautomers) include interconversions via proton migration, such as keto-enol tautomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.
[0383] This invention includes all isotopes of the compounds of this invention as defined above. Therefore, any atom present in the compounds of this invention as defined above, or in any intermediate or starting compound, can be in any available, naturally occurring isotopic form. For example, a carbon atom can be... 12 C or 13 C. A hydrogen atom can be 1 H or 2 H (deuterium). Therefore, the compounds of the present invention as defined above can be prepared in a deuterated form, wherein one or more hydrogen atoms serve as... 2 H exists. Any hydrogen atom or combination thereof can exist as deuterium.
[0384] The compounds of the present invention can be prepared by the synthetic methods described in the following examples, or by methods similar to these methods using suitable starting materials and methods familiar to a skilled chemist. Preparation typically includes an amide coupling reaction as a final step, in which a central amide bond is formed as defined above in formula (Ie) or formula (I). Therefore, the compounds of the present invention can be prepared by amide coupling reactions specified in the examples as methods A, B, C, D, E, F, and G, or by methods similar to methods A, B, C, D, E, F, and G, using suitable synthetic intermediates. Such intermediates can be prepared by methods similar to those described in the preparation examples.
[0385] Using conventional methods, benzodiazepines of formula (Ie) or formula (I) can be... The derivative is converted into its pharmaceutically acceptable salt, and the salt can be converted back into a free compound. For example, a benzodiazepine of formula (Ie) or (I) can be contacted with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is a salt formed with a pharmaceutically acceptable acid or base.
[0386] Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, pyrophosphate, hydrobromic acid, or nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides, and organic bases such as alkylamines, aralkylamines, and heterocyclic amines.
[0387] In biological experiments, the compounds of the present invention have been found to be inhibitors of respiratory syncytial virus (RSV). They possess a combination of potent anti-RSV activity, good bioavailability, and favorable physicochemical properties. This combination of properties makes the compounds therapeutically useful as drug candidates and superior to many compounds disclosed in the prior art references discussed above.
[0388] Therefore, the present invention also provides a compound for use in a method of treating a human or animal body by means of a therapy, the compound being a benzodiazepine of formula (Ie) or formula (I) as defined above. Derivatives or their pharmaceutically acceptable salts.
[0389] The present invention also provides compounds of the invention as defined above for use in methods of treating or preventing RSV infection. Furthermore, the present invention provides use of the compounds of the invention as defined above in the preparation of medicaments for treating or preventing RSV infection. Therefore, subjects suffering from or susceptible to RSV infection can be treated by methods including administering to them the compounds of the invention as defined above. This can thereby improve or enhance the condition of the subjects.
[0390] RSV infection is typically a respiratory infection. RSV infection can occur in children, such as children under ten years of age or infants under two years of age. In one embodiment, the invention provides compounds as defined above for the treatment or prevention of RSV infection in pediatric patients. Alternatively, the infection can occur in mature or elderly adults, such as adults over 60 years of age, adults over 70 years of age, or adults over 80 years of age. The invention also provides compounds for the treatment or prevention of RSV infection in elderly patients.
[0391] RSV infection can occur in immunocompromised individuals or individuals with COPD or CHF. In another embodiment, RSV infection can occur in uncompromised individuals (e.g., otherwise healthy individuals).
[0392] The compounds of the present invention can be administered in various dosage forms, such as oral administration, for example in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions, or parenteral administration, such as intramuscular, intravenous or subcutaneous administration. Therefore, the compounds can be administered by injection, infusion or by inhalation or nebulization. The compounds are preferably administered orally.
[0393] Dosage depends on a variety of factors, including the patient's age, weight, condition, and route of administration. Daily doses can vary widely and will be adjusted according to individual needs in each specific situation. However, typically, when the compound is administered alone to adults, the dose for each route of administration is 0.0001–650 mg / kg, with the most common range being 0.001–10 mg / kg body weight, for example, 0.01–1 mg / kg. These doses can be given, for example, 1–5 times daily. For intravenous injection, a suitable daily dose is 0.0001–1 mg / kg body weight, preferably 0.0001–0.1 mg / kg body weight. Daily doses can be administered as a single dose or according to a divided dose regimen.
[0394] Unit dosage forms such as tablets or capsules typically contain 1-250 mg of the active ingredient. For example, compounds of formula (Ie) or (I) can be administered to human patients at a dose of 100-250 mg once, twice, or three times daily.
[0395] Compounds of formula (Ie) or (I) and their pharmaceutically acceptable salts may be used alone. Alternatively, they may be administered in the form of pharmaceutical compositions. Therefore, the present invention also provides pharmaceutical compositions comprising a compound of formula (Ie) or (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals—The Science of Dosage Form Designs," MEAulton, Churchill Livingstone, 1988.
[0396] Depending on the method of application, the pharmaceutical composition preferably contains 0.05-99% w (weight percentage), more preferably 0.05-80% w, even more preferably 0.10-70% w, and even more preferably 0.10-50% w of active ingredient, all weight percentages being based on the total composition.
[0397] The present invention also provides a method for preparing the pharmaceutical composition of the present invention, the method comprising mixing a compound of formula (Ie) or formula (I) as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
[0398] The compounds of the present invention can be administered in various dosage forms, such as tablets, pills, lozenges, aqueous or oily suspensions, solutions, dispersible powders, or granules. The compounds of the present invention can also be administered via infusion techniques or by inhalation or nebulization parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, or transdermally. The compounds can also be administered in suppository form.
[0399] The solid oral form of the pharmaceutical compositions of the present invention may contain, along with the active compound, a diluent such as lactose, dextrose, sucrose, cellulose, corn starch, or potato starch; a lubricant such as silica, talc, stearic acid, magnesium stearate, or calcium stearate and / or polyethylene glycol; a binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; a disintegrant such as starch, alginate, alginate, or sodium glycolate; an effervescent mixture; a dye; a sweetener; a humectant such as lecithin, polysorbate, or lauryl sulfate; and a non-toxic and pharmacologically inactive substance commonly used in pharmaceutical formulations. Such pharmaceutical formulations may be prepared in known ways, for example by mixing, granulation, tableting, sugar coating, or film coating methods.
[0400] Liquid dispersions for oral administration can be syrups, emulsions, and suspensions. Syrups may contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier.
[0401] Suspensions and emulsions may contain carriers such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injection may contain the active compound and pharmaceutically acceptable carriers such as sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride. Other suitable carriers for suspensions include sterile water, hydroxypropyl methylcellulose (HPMC), polysorbate 80, polyvinylpyrrolidone (PVP), aerosol AOT (i.e., sodium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulfonate), pluronic F127, and / or Captisol (i.e., sulfobutyl ether-β-cyclodextrin).
[0402] For example, the compounds of the present invention can be formulated into an aqueous suspension in a carrier selected from:
[0403] (i) 0.5% w / v hydroxypropyl methylcellulose (HPMC) / 0.1% w / v polysorbate 80;
[0404] (ii) 0.67% w / v polyvinylpyrrolidone (PVP) / 0.33% w / v aerosol AOT (sodium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulfonate);
[0405] (iii) 1% w / v Prolactin F 127; and
[0406] (iv) 0.5% w / v polysorbate 80.
[0407] The carrier can be prepared by standard methods known to those skilled in the art. For example, each of carriers (i) to (iv) can be prepared by weighing the desired amount of excipient into a suitable container, adding about 80% of the final volume of water, and magnetically stirring until a solution is formed. The carrier is then brought to the final volume with water. An aqueous suspension of a compound of formula (Ie) or formula I can be prepared by weighing the desired amount of compound of formula I into a suitable container, adding 100% of the desired volume of carrier, and magnetically stirring.
[0408] Solutions intended for injection or infusion may contain, for example, sterile water as a carrier, or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
[0409] The compounds of the present invention can also be administered in combination with other compounds used to treat viral infections. Therefore, the present invention also relates to combination therapies, wherein the compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions or formulations comprising the compounds of the present invention, are administered simultaneously or sequentially with one or more other therapeutic agents or as a combination formulation for the treatment or prevention of viral infections, particularly RSV infection.
[0410] In this application, the term "combination" is understood to mean simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. In the case of sequential or separate application, the delay in applying the second component should not be so delayed that the beneficial effects of the combination are lost.
[0411] Suitable therapeutic agents for combination therapy include:
[0412] (i) RSV fusion inhibitor;
[0413] (ii) Other RSV nucleoshell (N) protein inhibitors;
[0414] (iii) Other RSV protein inhibitors, such as those that inhibit phosphoprotein (P) protein and large (L) protein;
[0415] (iv) Nucleoside or polymerase inhibitors that inhibit L protein;
[0416] (v) Anti-RSV monoclonal antibodies, such as F protein antibodies;
[0417] (vi) Immunomodulatory Toll-like receptor compounds;
[0418] (vii) Other respiratory virus antiviral agents, such as anti-influenza and anti-rhinovirus compounds; and / or
[0419] (viii) Anti-inflammatory compounds.
[0420] RSV nucleocapsid (N) proteins play a crucial role in viral transcription and replication, mediating the interaction between genomic RNA and virus-encoded RNA-dependent RNA polymerase. RSV P- and L proteins are components of the RSV-encoded RNA-dependent RNA polymerase.
[0421] According to another aspect of the invention, a combination of a compound of formula (Ie) or formula (I) as defined above, or a pharmaceutically acceptable salt thereof, with one or more therapeutic agents listed above (i) to (vi) is provided for the treatment of RSV.
[0422] The following examples are provided 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 invention in any way. Example
[0423] Reagents were obtained from commercial sources and used without further purification. Anhydrous solvents were purchased from commercial suppliers, used as supplied, and stored under N2. Unless otherwise specified, reactions were carried out under N2. 2 The experiment was conducted using anhydrous solvents under an atmosphere. All temperatures are in °C. TLC was performed on aluminum-backed silica gel plates with a fluorescent indicator at 254 nm (median pore size). Rapid column chromatography was performed using a Biotage Isolera One system with KP-Sil or Ultra silica gel columns, or Isco CombiFlash Rf with FlashPure or RediSep Rf / RediSep Rf Gold silica gel columns. Reversed-phase column chromatography was performed using a Teledyne ISCO RediSep Rf C18 column on an ISCO CombiFlash Rf. Ion-exchange chromatography was performed on an Isolute SCX-2: silica-propylsulfonic acid solid-phase extraction column, with washings using appropriate solvents selected from water, MeCN, and MeOH.
[0424] NMR spectra were recorded on a 400, 500, 600, or 700 MHz spectrometer at the ambient probe temperature (nominal 298 K). Chemical shifts (δ) are given in ppm and calibrated using residual peaks of the solvent as internal standards (CDCl3, δ = 7.26 ppm; DMSO-d6, δ = 2.50 ppm). Coupling constants are given in Hertz (Hz). 0.5H is equivalent to 1 The 1H peak of the diastereomer is specified in the 1H NMR. Advion Plate Express expression is used with an APCI or ESI ion source. L The compact mass spectrometer records LRMS, switching between positive and negative ion modes.
[0425] LC-MS analysis was performed using a Waters Acquity UPLC system with a CSH C18 or BEH C18 column (2.1 × 30 mm) at 40 °C with a linear 5–95% acetonitrile gradient suitable for the lipophilicity of the compound, at a rate of 0.77 mL / min over 1, 3, 4, or 10 min. 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 between 210 and 400 nm using a Waters Acquity photodiode array detector. Mass spectra were recorded using a Waters Acquity QDa detector, with the ES switching between positive and negative ion modes.
[0426] Method A: 3 min acidic
[0427] Method B: 3 min alkaline
[0428] Method C: 10 min acidic
[0429] Method D: 10 min alkaline
[0430] Method E: 1 min acidic
[0431] Method F: 4 min acidic
[0432] Preparative HPLC was performed at ambient column temperature using the following methods: HPLC Method 1: Gemini NX (30 mm × 150 mm, 5 μm) column, 42 mL / min, with UV detection at 210 nm. HPLC Method 2: Luna Phenomenex C18 (150 × 30 mm, 5 μm) column, 42 mL / min, with UV detection at 210 nm. HPLC Method 3: Waters X-Bridge BEH C18 (30 mm × 100 mm, 5 μm) column, 40 mL / min mobile phase, with full-wavelength UV detection using a PDA. HPLC Method 4: XSelect CSH C18 column (30 mm × 150 mm, 5 μm), 42 mL / min, with UV detection at 220 nm. Preparative chiral HPLC was also performed using the following methods. Preparative chiral HPLC method 1: Chiralpak IC (20 × 250 mm; 5 μm), ambient column temperature, flow rate 20 mL / min, UV detection at 220 nm. Preparative chiral HPLC method 2: Lux IC5 (21.2 mm × 250 mm, 5 μm), ambient column temperature, flow rate 21 mL / min, UV detection at 210 nm. Analytical chiral HPLC was performed at ambient column temperature using the following method: Analytical chiral HPLC method 1A: Chiralpak IC-3 column (2.1 × 150 mm, 3 μm), 1.0 mL / min.
[0433] Preparative chiral SFC was performed using the following methods: SFC Method 1: Torus Diol (19 mm × 150 mm, 5 μm), column temperature 40 °C, flow rate 68 mL / min, pressure 100 bar, detector wavelength 237 nm. SFC Method 2: Torus Diol (19 mm × 150 mm, 5 μm), column temperature 40 °C, flow rate 68 mL / min, pressure 150 bar, detector wavelength 210 nm. Preparative chiral SFC was also performed using the following methods: Preparative chiral SFC Method 1: Chiralpak IA (250 × 10 mm, 5 μm), column temperature 40 °C, flow rate 15 mL / min, pressure 120 bar, detector wavelength 210–400 nm. Preparative chiral SFC Method 2: Lux CL (21.2 mm x 250 mm, 5 μm), column temperature 40 °C, flow rate 50 mL / min, pressure 100 bar, detector wavelength 210 nm. Preparative chiral SFC method 3: Lux C4 (21.2 mm × 250 mm, 5 μm), column temperature 40 °C, flow rate 50 mL / min, 125 bar pressure, detector wavelength 210 nm. Analytical chiral SFC was performed using 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, detector wavelength 210-400 nm, 125 bar back pressure. Analytical chiral SFC method 2A: Lux CL (4.6 mm × 250 mm, 5 μm), column temperature 40 °C, flow rate 4 mL / min, detector wavelength 210-400 nm, 125 bar 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, detector wavelength 210-400 nm, 125 bar back pressure.
[0434] Intermediates 3-bromo-6-ethyl-2-methylpyridine, 5-bromo-6-methyl-N-propyl-2-pyridin-2-amine, 1-(5-bromopyridin-2-yl)-2-methylprop-2-ol, and 5-bromo-4-methyl-N-propyl-2-pyridin-2-amine were prepared according to the method described in WO / 2021 / 032992. Example (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepine was prepared using the methods described in WO / 2004 / 026843, WO / 2005 / 090319, and WO / 2017 / 015449. -2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-one.
[0435] Examples of which the stereocenter is not clearly defined were prepared and tested as mixtures of diastereomers, unless otherwise stated.
[0436] abbreviation
[0437]
[0438]
[0439] Preparation Examples
[0440] 1A ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate
[0441]
[0442] A solution of ethyl 1H-pyrazole-4-carboxylate (5.5 g, 39.3 mmol) in EtOH (60 mL) was cooled to 0 °C, and then a solution of 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 rt for one weekend. A saturated aqueous solution of Na₂S₂O₃ (100 mL) and EtOAc (50 mL) were added to separate the phases, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases (100 mL) were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by rapid chromatography (0–40% MTBE in isohexane solution) to give a white solid (10.3 g, 84%). LCMS (Method A) 297.3 / 299.4 / 301.4 [M+H] + At 1.10 min. 1 H NMR (500MHz, DMSO-d6) δ14.53 (s, 1H), 4.25 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H).
[0443] 2A methanesulfonic acid [(3R)-3-hydroxybutyl] ester
[0444]
[0445] NEt3 (1.1 mL, 7.89 mmol) and then MsCl (0.3 mL, 3.88 mmol) were added to a solution of (3R)-butane-1,3-diol (1.00 g, 11.1 mmol) in CH2Cl2 (10 mL) at 0 °C, and stirred for 10 min at 0 °C. The reaction system was allowed to reach rt, quenched with saturated NaHCO3 aqueous solution (10 mL) and CH2Cl2 (10 mL), and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), the combined organic phases were washed with 50% brine (20 mL), dried (MgSO4), and concentrated under reduced pressure. Purification was achieved by rapid chromatography (0-50% EtOAc in isohexane solution) to give a colorless oil (310 mg, 16%). 1 H NMR (500MHz, CDCl3) δ4.49-4.41 (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=4.8Hz, 1H), 1.26 (d, J=6.3Hz, 3H).
[0446] 2B methanesulfonic acid [(3S)-3-hydroxybutyl] ester
[0447]
[0448] Prepared by a method similar to that described for intermediate 2A. 1 H NMR (500MHz, CDCl3) δ4.49-4.41(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=4.9Hz, 1H), 1.26 (d, J=6.2Hz, 3H).
[0449] 2C Methanesulfonate (3-hydroxy-3-methylbutyl) ester
[0450]
[0451] Prepared by a method similar to that described for intermediate 2A. 1 H NMR (700MHz, CDCl3) δ4.41 (t, J=6.9Hz, 2H), 3.01 (s, 3H), 1.95 (t, J=6.9Hz, 2H), 1.28 (d, J=0.5Hz, 6H).
[0452] 2D-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate
[0453]
[0454] MsCl (1.53 mL, 19.750 mmol) was added dropwise to a cooled (0 °C) solution of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanol (2 mL, 14.11 mmol) and NEt3 (5.11 mL, 36.68 mmol) in CH2Cl2 (40 mL). The mixture was then heated to Rt and stirred for 3 h. The reaction system was quenched with 1 M HCl aqueous solution, the organic layer was washed with brine, and the solvent was removed under reduced pressure by passing the solution through a phase separation column to give a colorless oil (2.81 g, 80% yield). 1 H NMR (500MHz, CDCl3) δ4.46-4.32(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).
[0455] 3A 4-Methylbenzenesulfonic acid [3-(hydroxymethyl)oxetane-3-yl]methyl ester
[0456]
[0457] NEt3 (3.1 mL, 22.2 mmol) and then TsCl (2.12 g, 11.1 mmol) were added to a cooled (0 °C) solution of [3-(hydroxymethyl)oxetane-3-yl]methanol (1.31 g, 11.1 mmol) in CH2Cl2 (10 mL), and stirred at 0 °C for 10 min. The reaction system was allowed to reach rt, quenched with saturated NaHCO3 aqueous solution (10 mL) and CH2Cl2 (10 mL), and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), the combined organic phases were washed with 50% brine (20 mL), dried (MgSO4), and concentrated under reduced pressure. Purification was performed by rapid chromatography (0-50% EtOAc in isohexane solution) to give a colorless oil (826 mg, 26%). 1 H NMR (500MHz, CDCl3) δ7.84-7.78(m, 2H), 7.41-7.35(m, 2H), 4.43(d, J=6.7Hz, 2H), 4.36( d, J=6.6Hz, 2H), 4.31 (s, 2H), 3.91 (d, J=5.5Hz, 2H), 2.47 (s, 3H), 1.86 (t, J=5.4Hz, 1H).
[0458] 3B 4-Methylbenzenesulfonic acid (3R)-3-hydroxybutyl ester
[0459]
[0460] A solution of TsCl (11.02 g, 57.81 mmol) in CH₂Cl₂ (25 mL) was added dropwise to a cooled (0 °C) solution of (R)-(-)-1,3-butanediol (4.99 mL, 55.59 mmol) and NEt₃ (11.62 mL, 83.39 mmol) in CH₂Cl₂ (40 mL) over 30 minutes. The reaction mixture was then heated to Rt and stirred for 16 h. 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. The solution was purified by rapid chromatography (5-60% EtOAc:heptane) to give a pale yellow oil (9.04 g, 67%). 1 H NMR (400MHz, DMSO-d6) δ7.83-7.71 (m, 2H), 7.48 (d, J=8.0Hz, 2H), 4.56 (d, J=5.0Hz, 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=6.2Hz, 3H). LRMS m / z(APCI+)245.0[M+H] + .
[0461] The following intermediate compounds were prepared in a manner similar to that described for intermediate 3B. 4-Dimethylaminopyridine (0.1 eq.) was used in the preparation of intermediate 3D.
[0462] Table 1 - Preparation examples of preparation by toluenesulfonation.
[0463]
[0464]
[0465] 4A 1-(2-bromoethyl)cyclopropane-1-ol
[0466]
[0467] Titanium isopropoxide (IV) (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 Et MgBr (3.0 M Et₂O solution; 8.78 mL, 26.4 mmol) was slowly added. The reaction mixture was stirred at rt for one weekend. The reaction mixture was quenched with saturated NH₄Cl aqueous solution (50 mL), stirred for 10 min, and then 1 M HCl aqueous solution (50 mL) was added, and the mixture was stirred at rt for 2 h. The resulting solution was extracted with EtOAc (3 × 50 mL), the combined organic extracts were washed with brine (50 mL), dried (MgSO₄), and concentrated under reduced pressure to give an orange oil (1.52 g, 77%). 1 H NMR (700MHz, CDCl3) δ3.61 (t, J=7.3Hz, 2H), 2.12 (t, J=7.6, 2H), 0.84-0.75 (m, 2H), 0.65-0.53 (m, 2H).
[0468] 5A Thioacetic Acid S-(3-Bromopropyl) Ester
[0469]
[0470] Potassium thioacetate (563 mg, 4.93 mmol) was added in portions to a solution of 1,3-dibromopropane (0.5 mL, 4.93 mmol) in DMF (10 mL), and the mixture was stirred at rt for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with MTBE (3 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The extract was purified by rapid chromatography (0–30% MTBE in isohexane solution) to give a colorless oil (516 mg, 53%). 1 H NMR (500MHz, CDCl3) δ3.47 (t, J=6.5Hz, 2H), 3.03 (t, J=7.0Hz, 2H), 2.36 (s, 3H), 2.15 (p, J=6.7Hz, 2H).
[0471] 6A ethyl 3,5-dibromo-1-(3-hydroxypropyl)pyrazole-4-carboxylate
[0472]
[0473] A solution of intermediate 1A (500 mg, 1.68 mmol), K₂CO₃ (465 mg, 3.30 mmol), and 3-bromoprop-1-ol (0.16 mL, 1.77 mmol) in MeCN (6 mL) was heated at 80 °C for 3 h. The reaction mixture was cooled to rt, filtered, and washed with MeCN (3 × 20 mL). The filtrate was concentrated under reduced pressure, and the crude product (0-50% EtOAc in isohexane solution) was purified by rapid chromatography to give a colorless oil (561 mg, 89%). LCMS (Method A) 355.1 / 357.1 / 359.1 [M+H] + At 1.11 min. 1 H NMR (500MHz, CDCl3) δ4.40-4.32 (m, 4H), 3.67 (q, J=5.7Hz, 2H), 2.12-2.04 (m, 2H), 1.75 (t, J=5.4Hz, 1H), 1.39 (t, J=7.1Hz, 3H).
[0474] The following intermediate compounds were prepared from intermediate 1A and the reagents / intermediates shown, in a manner similar to that described for intermediate 6A.
[0475] Table 2 - Preparation examples prepared by the general N-alkylation method described in 6A
[0476]
[0477]
[0478]
[0479]
[0480] 7A 1-(3-acetylthiopropyl)-3,5-dibromopyrazole-4-carboxylic acid ethyl ester
[0481]
[0482] 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 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated to give an orange oil (937 mg, 79%), which was used without further purification. LCMS (Method E): m / z 413.1 / 415.1 / 417.1 [M+H] + At 0.70 min.
[0483] 8A ethyl 3,5-dibromo-1-[2-(hydroxymethyl)butyl]pyrazole-4-carboxylate
[0484]
[0485] Imidazole (654 mg, 9.6 mmol) and PPh3 (2.52 g, 9.6 mmol) were added to a solution of 2-ethylprop-1,3-diol (1.0 g, 9.6 mmol) in THF (30 mL), and the mixture was stirred for 1 min. Then, I2 (3.17 g, 12.5 mmol) was added. The reaction mixture was stirred at rt for 1 h, then quenched with a saturated aqueous solution of Na2S2O3 (25 mL) and diluted with CH2Cl2 (25 mL). The separated aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and the combined organic extracts were washed with brine (25 mL), dried (Na2SO4), and the solvent was removed under reduced pressure to give a colorless oil (4.00 g), which was used directly in the next step without further purification. A solution of intermediate 1A (1.00 g, 3.36 mmol), crude 2-(iodomethyl)but-1-ol (4.00 g, 9.60 mmol), and Cs₂CO₃ (1.43 g, 4.36 mmol) in MeCN (15 mL) was heated at 80 °C for 3 h, followed by stirring at rt for 16 h. The reaction mixture was cooled to rt, filtered, and washed with MeCN (2 × 15 mL). The filtrate was concentrated under reduced pressure and purified by rapid chromatography (10–40% EtOAc:heptane) to give a colorless oil (740 mg, 57%). 1 H NMR (400MHz, DMSO-d6) δ4.65 (t, J=5.0Hz, 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=7.5Hz, 3H). LRMS(APCI+)m / z 383.0 / 385.0 / 387.0[M+H] + .
[0486] The following intermediates were prepared in a manner similar to that described for intermediate 8A.
[0487] Table 3 - Preparation Examples of Intermediate 8A Prepared by the General N-alkylation Method Described as Explained
[0488]
[0489]
[0490]
[0491] 9A 2-Bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0492]
[0493] NaH (60% dispersion in mineral oil, 225 mg, 5.63 mmol) was added to a cooled (0 °C) solution of intermediate 6A (1.00 g, 2.81 mmol) in THF (150 mL). The reaction mixture was stirred at rt for approximately 48 h, quenched with water (20 mL), and diluted with EtOAc (20 mL). The separated aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated under reduced pressure. Purification was achieved by rapid chromatography (0–80% EtOAc in isohexane solution) to give a white solid (655 mg, 85%). LCMS (Method A) 275.2 / 277.2 [M+H] + At 0.97 min. 1 H NMR (500MHz, DMSO-d6) δ4.45-4.39 (m, 2H), 4.16 (q, J=7.1Hz, 2H), 4.05 (t, J=6.1Hz, 2H), 2.24-2.16 (m, 2H), 1.23 (t, J=7.1Hz, 3H).
[0494] The following intermediate compounds were prepared in a manner similar to that described for intermediate 9A.
[0495] Table 4 - Preparation examples prepared by general cyclization methods.
[0496]
[0497]
[0498]
[0499]
[0500] 9N(6R)-2-bromo-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0501]
[0502] The method described for intermediate 9A was followed by preparation using intermediate 6F (2.33 g, 6.31 mmol) to give ethyl 2-bromo-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate (1.71 g, 94%). Separation was achieved by chiral SFC method 3 with an isocratic mixture of 30:70EtOH:CO2 (0.2% v / v NH3); the second elution of the enantiomer yielded the title compound as a white solid (670 mg, 40%). 1 H NMR (700MHz, DMSO-d6) δ4.44 (ddd, J=10.7, 3.6, 1.3Hz, 1H), 4.22-4.11 (m, 3H), 4.07 (dd, J=10.7, 9.3H z, 1H), 3.70 (dd, J=12.0, 8.9Hz, 1H), 2.46-2.37 (m, 1H), 1.24 (t, J=7.1Hz, 3H), 1.01 (d, J=6.9Hz, 3H). LRMS(APCI+)m / z289.0 / 291.0[M+H] + .
[0503] The following intermediate compounds were prepared in a manner similar to that described for intermediate 9A. Intermediates 9Q, 9R, and 9T were prepared with 1 eq., 1.05 eq., and 1.1 eq. of NaH, respectively.
[0504] Table 5 - Preparation examples prepared by general cyclization methods.
[0505]
[0506]
[0507] 10A 2-Bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylic acid ethyl ester
[0508]
[0509] 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 h. Volatile substances were removed under reduced pressure, and water (50 mL) and EtOAc (50 mL) were added. The separated aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO₄), and concentrated under reduced pressure to give a colorless oil (644 mg, 98%), which was used without further purification. LCMS (Method E): m / z 291.7 / 293.6 [M+H] +At 0.59 min.
[0510] 11A 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester
[0511]
[0512] K₂CO₃ (1.98 g, 14.3 mmol) and then 1,2-dibromoethane (0.4 mL, 3.90 mmol) were added to a solution of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (550 mg, 3.52 mmol) in MeCN (25 mL). The reaction mixture was heated overnight at 80 °C. The mixture was cooled to rt, filtered, washed with MeCN (2 × 20 mL), and the filtrate was concentrated under reduced pressure. Purification was performed by rapid chromatography (40–100% EtOAc in isohexane solution) to give a white solid (690 mg, 99%). LCMS (Method A) 169.2 (M-OEt). + At 0.86 min. 1 H NMR (500MHz, CDCl3) δ6.02 (s, 1H), 4.38 (q, J=7.1Hz, 2H), 4.34-4.28 (m, 2H), 4.25 (t, J=6.3Hz, 2H), 2.32-2.24 (m, 2H), 1.38 (t, J=7.1Hz, 3H).
[0513] 11B 2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-6-carboxylic acid ethyl ester
[0514]
[0515] Prepared using 1,3-dibromoethane by a method similar to that described for intermediate 11A. LCMS (Method A) 155.1 (M-OEt) + At 0.78 min. 1 H NMR (500MHz, DMSO-d6) δ5.87 (s, 1H), 5.11 (dd, J=8.6, 7.6Hz, 2H), 4.35 (dd, J=8.6, 7.6Hz, 2H), 4.23 (q, J=7.1Hz, 2H), 1.26 (t, J=7.1Hz, 3H).
[0516] 12A 3-Bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester
[0517]
[0518] N-bromosuccinimide (650 mg, 3.65 mmol) was added to a cooled (0 °C) MeCN solution (6 mL) of intermediate 11A, and the reaction mixture was stirred at rt for 2 h. A saturated NaHCO3 aqueous solution (20 mL) and EtOAc (20 mL) were added, and the separated aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO4), and the solvent was removed under reduced pressure. Purification was performed by rapid chromatography (30–80%, isohexane solution of EtOAc) to give a colorless resin (888 mg, 96%). LCMS (Method A) 229.1 / 231.1 (M-OEt) + At 1.07 min. 1 H NMR (500MHz, CDCl3)δ
[0519] 4.46-4.36 (m, 4H), 4.25 (t, J=6.2Hz, 2H), 2.37-2.26 (m, 2H), 1.40 (t, J=7.1Hz, 3H).
[0520] 12B 7-bromo-2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carboxylic acid ethyl ester
[0521]
[0522] Prepared by a method similar to that described for intermediate 12A. 1 H NMR (500MHz, CDCl3) δ 5.16-5.13 (m, 2H), 4.47-4.36 (m, 4H), 1.41 (t, J = 7.1Hz, 3H).
[0523] 13A 2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0524]
[0525] 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), followed by the addition of 1,4-dioxane:water (2:1; 3 mL). The mixture was purged with N2 and heated to 100 °C for 16 h. The reaction mixture was cooled to rt, and Pd(PPh3)4 (74 mg, 0.060 mmol) and 2-fluorophenylboronic acid (240 mg, 1.72 mmol) were added. The mixture was purged with N2 and heated to 100 °C for 4 h. The reaction system was partitioned between EtOAc (10 mL) and water (10 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by rapid chromatography (0-80% EtOAc in isohexane solution) to give a brown oil (208 mg, 63%). LCMS (Method A) 290.9 [M+H] + At 1.14 min. 1 H NMR (500MHz, DMSO-d6) δ7.48-7.40 (m, 1H), 7.39 (ddd, J=7.6, 1.9Hz, 1H), 7.25-7.17 (m, 2H), 4.48 -4.42 (m, 2H), 4.14 (t, J=6.1Hz, 2H), 4.05-3.96 (m, 2H), 2.29-2.21 (m, 2H), 1.03 (t, J=7.1Hz, 3H).
[0526] 14A 2-(2-fluoro-5-methylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester (Suzuki-Miyaura Method A)
[0527]
[0528] Intermediate 9A (140 mg, 0.510 mmol), (2-fluoro-5-methylpyridin-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(crotonyl)Cl; 18 mg, 0.030 mmol) were added to the reaction vessel. The reaction vessel was evacuated and purged with N2, and then THF (4 mL) and water (1 mL) were added. The reaction mixture was purged with N2 and heated overnight at 65 °C. The cooled reaction mixture was diluted with CH2Cl2 (25 mL), washed with brine (3 × 25 mL), dried over a dry organic phase (Na2SO4), and concentrated under reduced pressure. Purification was performed by rapid chromatography (0-100% EtOAc in isohexane solution) to give a white solid (130 mg, 78%). LCMS (Method A) 306.6 [M+H] + At 1.03 min. 1 H NMR (500MHz, DMSO-d6) δ8.11-8.04 (m, 1H), 7.76 (dd, J=9.1, 2.5Hz, 1H), 4.50-4.39 (m, 2H), 4.15 (t, J=6.1Hz, 2H), 4.02 (q, J=7.1Hz, 2H), 2.32 (s, 3H), 2.30-2.17 (m, 2H), 1.04 (t, J=7.1Hz, 3H).
[0529] The following intermediate compounds were prepared in a manner similar to that described for intermediate 14A. This method can be carried out at temperatures varying from 60 to 70 °C, with the stoichiometric amount of K₃PO₄ used varying between 1.2 and 2.0 eq. Intermediates 16C, 16E, and 16F were prepared from the corresponding pinacol esters. Intermediates 16D, 16E, and 16F were prepared using Pd-170 (10 mol%), XPhos (20 mol%), and 4 eq. of K₃PO₄.
[0530] Table 6 - Preparation examples prepared by Suzuki-Miyaura method A.
[0531]
[0532]
[0533]
[0534]
[0535]
[0536] 21A 2-(6-Fluoropyridin-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester (Suzuki-Miyaura Method B)
[0537]
[0538] 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-safe vial, sealed, evacuated, and purged with N2 (3×). K3PO4 (2 M aqueous solution; 1.09 mL, 2.18 mmol) and THF (3 mL) were added, and the mixture was degassed with N2 and heated at 80 °C for 0.5 h via MWI. The cooled mixture was concentrated under reduced pressure, and the residue was purified by rapid chromatography (50–100% EtOAc in heptane solution) to give a yellow-white solid (270 mg, 85%). 1 HNMR (400MHz, DMSO-d6) δ8.48-8.33 (m, 1H), 8.15 (td, J=8.3, 2.5Hz, 1H), 7.22 (ddd, J=8.6, 2. 9, 0.7Hz, 1H), 4.55-4.37 (m, 2H), 4.22-3.99 (m, 4H), 2.31-2.19 (m, 2H), 1.14 (t, J=7.1Hz, 3H). LRMS(APCI+)m / z 292.4[M+H] + .
[0539] The following intermediate compounds were prepared in a manner similar to that described for intermediate 21A. Reaction times varied between 30 min and 1 h 30 min, and heating was performed by MWI or conventional heating.
[0540] Table 7 - Preparation examples prepared by Suzuki-Miyaura method B.
[0541]
[0542]
[0543]
[0544]
[0545]
[0546]
[0547] 26A 2-(2,4-difluorophenyl)-4,4-dioxo-6,7-dihydro-5H-pyrazolo[5,1-
[0548] b][1,3]Thiazine-3-carboxylic acid ethyl ester
[0549]
[0550] mCPBA (125 mg, 0.510 mmol) was added to a cooled (0 °C) solution of intermediate 20B (65.5 mg, 0.2 mmol) in CH₂Cl₂ (5 mL), and the mixture was stirred at rt for 18 h. The reaction mixture was diluted with CH₂Cl₂ (50 mL) and quenched with 10% w / v Na₂S₂O₃ aqueous solution (100 mL). The separated organic phase was washed with saturated NaHCO₃ aqueous solution (100 mL) and brine (100 mL), passed through a phase separation column, and concentrated under vacuum to give a white solid (60 mg, 83%), which was used without further purification. LCMS (Method E): m / z 357.2 [M+H] + At 0.59 min.
[0551] 26B 2-(2-fluorophenyl)-4,4-dioxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylic acid ethyl ester
[0552]
[0553] Prepared by a method similar to that described for intermediate 26A. LCMS (Method E): m / z 339.2 [M+H] + At 0.57 min.
[0554] 27A 3-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester
[0555]
[0556] Add 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) to a vial. Evacuate the vial, purge with N2, add THF (2 mL), purge with N2, and heat overnight at 70 °C. Partition the reaction mixture between EtOAc (20 mL) and 1:1 aqueous saline solution (20 mL). Extract the aqueous phase with EtOAc (2 × 10 mL), wash the combined organic phases with saline solution (20 mL), dry (MgSO4), and concentrate under reduced pressure. Purify by rapid chromatography (0–80%, isohexane solution of EtOAc) to give a white solid (154 mg, 87%). LCMS (Method A) 245.2 [M-OEt] + At 1.25 min. 1 H NMR (500MHz, CDCl3) δ7.38-7.32(m, 1H), 7.32-7.25(m, 1H), 7.18-7.12(m, 1H), 7.12-7.0 5 (m, 1H), 4.36-4.33 (m, 2H), 4.33-4.27 (m, 4H), 2.37-2.25 (m, 2H), 1.25 (t, J=7.1Hz, 3H).
[0557] 27B 3-(2,6-difluoropyridin-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester
[0558]
[0559] Prepared by a method similar to that described for intermediate 27A. LCMS (Method A) 264.3 [M-OEt] + At 1.19 min. 1 H NMR (500MHz, CDCl3) δ7.93-7.84 (m, 1H), 6.84 (dd, J=8.1, 2.9Hz, 1H), 4.38-4.35 (m, 2H), 4.34-4.30 (m, 4H), 2.39-2.24 (m, 2H), 1.29 (t, J=7.1Hz, 3H).
[0560] 28A 7-(2-fluorophenyl)-2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carboxylic acid ethyl ester
[0561]
[0562] Prepared by a method similar to that described for intermediate 27A. LCMS (Method A) 250.2 [M-OEt] + At 1.16 min. 1 H NMR (500MHz, CDCl3) δ7.42-7.35(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=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H).
[0563] 29A 2-[6-(ethylamino)-2-fluoropyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0564]
[0565] Ethylamine (1.46 mL, 2.91 mmol, 2 M MeOH solution) 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 h. The reaction mixture was cooled to rt, diluted with water (10 mL) and brine (10 mL), extracted with EtOAc (3 × 10 mL), dried (Na₂SO₄), and the combined organic fractions were concentrated under reduced pressure. The mixture was purified by rapid chromatography (50–100% EtOAc in heptane solution) to give a white solid (79 mg, 41%). 1 H NMR (400MHz, DMSO-d6) δ7.45 (dd, J=10.0, 8.2Hz, 1H), 7.02 (t, J=5.5Hz, 1H), 6.32 (dd, J=8.3, 1.9Hz, 1H), 4.42 (dd, J=6.0, 4.4Hz, 2H ), 4.10 (t, J=6.1Hz, 2H), 4.03 (q, J=7.1Hz, 2H), 3.25-3.18 (m, 2H), 2.26-2.18 (m, 2H), 1.13 (t, J=7.2Hz, 3H), 1.09 (t, J=7.1Hz, 3H). LRMS(APCI+)m / z 334.9[M+H] + .
[0566] The following intermediate compounds were prepared in a manner similar to that of intermediate 29A. The stoichiometric amounts of the amine reactants could be varied between 5 and 10 eq. Preparation Examples 29C and 33A were heated overnight at 50°C. Preparation Example 30A was heated overnight at 130°C. Preparation Examples 30B and 30C were heated at 130°C for approximately 48 hours.
[0567] Table 8 - Through general S N Preparation examples prepared by the Ar method
[0568]
[0569]
[0570]
[0571] 34A 2-(2-fluorophenyl)-5,5-dimethyl-6,7-dihydropyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (ester hydrolysis method A)
[0572]
[0573] NaOH (2.5 M aqueous solution, 0.88 mL, 2.18 mmol) was added to a 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 pH ≈ 2 with 1 M HCl (aqueous solution; 2.62 mL). The precipitate was filtered, washed with water, and dried under reduced pressure to give a white solid (109 mg, 86%), which was used without further purification. 1 H NMR (700MHz, DMSO-d6) δ 11.65 (s, 1H), 7.44-7.36 (m, 2H), 7.25-7.17 (m, 2H), 4.15 (t, J=6.4Hz, 2H), 2.17 (t, J=6.4Hz, 2H), 1.45 (s, 6H). LRMS(APCI+)m / z 291.2[M+H] + .
[0574] The following intermediate compounds were prepared by a method similar to that described for intermediate 34A. This method can be carried out at temperatures varying between 50 and 70°C, depending on the specific reaction substrate. This method can be modified by replacing 2.5M NaOH aqueous solution (5 eq.) with 5M NaOH aqueous solution (8 eq.).
[0575] Table 9 - Preparation examples of ester hydrolysis method A
[0576]
[0577]
[0578]
[0579] 43A(5R)-2-(2-fluorophenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0580]
[0581] LiOH (1.5 M aqueous solution; 2.52 mL, 3.78 mmol) was added to a stirred solution of intermediate 16A (115 mg, 0.380 mmol) in THF:MeOH (1:1; 6 mL), and the mixture was heated overnight at 40 °C. The cooled reaction mixture was washed with MTBE (3 × 10 mL), and the aqueous phase was acidified with 1 M HCl aqueous solution to pH ≈ 1. Extraction was performed using CHCl3:iPrOH (3:1; 3 × 10 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and given a white solid (92 mg, 78%). LCMS (Method A) 277.6 [M + H2] + At 0.86 min. 1 H NMR (500MHz, DMSO-d6) δ11.70 (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=7.0Hz, 1H), 1.44 (d, J=6.3Hz, 3H).
[0582] The following intermediate compounds were prepared by a method similar to that described for intermediate 43A.
[0583]
[0584] 46A 2-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0585]
[0586] A solution of intermediate 21B (115 mg, 0.4 mmol) and LiOH (1 M aq; 3.21 mL, 3.21 mmol) in MeOH:THF (1:1; 10 mL) was heated at 35 °C for 48 h. Then, LiOH (1 M aqueous solution; 3.21 mL, 3.21 mmol) was added, and the reaction mixture was heated at 60 °C overnight. Volatile substances were removed under reduced pressure, and the residue was acidified to pH ≈ 2 with 1 M HCl aqueous solution. Extraction was performed with EtOAc (3 × 10 mL). The combined organic extracts were washed with 10 mL of water and 10 mL of brine, dried (MgSO4), and the solvent was removed under reduced pressure to give an orange solid (78 mg, 75%). f =0.15 (2:1 EtOAc:heptane). LRMS(APCI+) m / z 258.8 [M+H] + .
[0587] 47A(5R)-2-[2-fluoro-6-(propyl-2-ylamino)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (ester hydrolysis method B)
[0588]
[0589] A solution of intermediate 31A (46 mg, 0.13 mmol) and LiOH (25 mg, 1.04 mmol) in a 1:1:1 MeOH:THF:water (3 mL) solution was heated to 50 °C for 2 h. The reaction mixture was cooled to rt, and 5 mL of 1 M HCl aqueous solution was added. The mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic fractions were passed through a phase separator containing brine, and the solvent was removed under reduced pressure to give a white solid (38 mg, 89%). LCMS (Method A) 335.7 [M + H] + At 0.96 min. 1 H NMR (500MHz, DMSO-d6) δ11.63 (s, 1H), 7.41 (dd, J=9.9, 8.2Hz, 1H), 6.86 (d, J=7.6Hz, 1H), 6.30 (dd, J=8.2, 1.8Hz, 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=6.3Hz, 3H), 1.14 (d, J=6.4Hz, 6H).
[0590] The following intermediate compounds were prepared by the ester hydrolysis method described for intermediate 47A. This method can be modified by varying the stoichiometric amount of LiOH from 4 to 8 eq., depending on the reaction substrate.
[0591] Table 10 - Preparation examples of ester hydrolysis method B
[0592]
[0593]
[0594] 52A 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0595]
[0596] 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 h. Volatile substances were removed under reduced pressure, and the residue was acidified to pH ≈ 1 M HCl aqueous solution.
[0597] 2. Extract with EtOAc (3 × 10 mL). Wash the combined organic extracts with water (10 mL) and brine (10 mL), dry (Na2SO4), concentrate under reduced pressure to give a light brown solid (36 mg, 88%). 1 H NMR (700MHz, DMSO-d6) δ11.80 (s, 1H), 7.42 (td, J=8.4, 6.6Hz, 1H), 7.25 (ddd, J=10.2, 9.4, 2.6H z, 1H), 7.17-7.01 (m, 1H), 4.48-4.37 (m, 2H), 4.13 (t, J=6.1Hz, 2H), 2.23 (tt, J=6.0, 2.9Hz, 2H). LRMS(APCI+)m / z281.0[M+H] + .
[0598] The following compounds were prepared in a manner similar to that used for intermediate 52A. This method can be carried out at temperatures varying between 50°C and 55°C.
[0599]
[0600] 53A 2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carboxylic acid
[0601]
[0602] LiOH (98 mg, 4.08 mmol) was added to a solution of intermediate 20A (63 mg, 0.2 mmol) in THF:water:MeOH (1:1:1; 12 mL), and the mixture was heated at 70 °C for 72 h. The reaction mixture was cooled to rt, acidified with 1 M HCl aqueous solution (10 mL), and concentrated under vacuum to give a white solid (57 mg, 95%), which was used without further purification. LCMS (Method E): m / z 279.2 [M+H] + At 0.50 min.
[0603] The following compounds were prepared in a manner similar to that of intermediate 53A. This method can be carried out at temperatures varying between 60°C and 70°C, depending on the specific substrate. The stoichiometric amounts of LiOH can be varied between 8 eq. and 20 eq.
[0604]
[0605] 55A 2-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0606]
[0607] LiOH (1.5 M 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 for one weekend. The reaction mixture was cooled to rt, acidified with 1 M HCl aqueous solution (1.9 mL), and concentrated under vacuum to give a white solid (57 mg, 95%), which was used without further purification. LCMS (Method E): m / z 319.6 [M+H] + At 0.83 min.
[0608] The following intermediate compounds were prepared by a method similar to that described for intermediate 55A.
[0609]
[0610] 59A ethyl 3,5-dibromo-1-(3,4-dihydro-xy-butyl)pyrazole-4-carboxylate
[0611]
[0612] A solution of intermediate 6J (2.91 g, 6.83 mmol) in AcOH (20 mL) and water (10 mL) was stirred at 110 °C for 2 h, followed by vacuum concentration. The resulting oil was dissolved in CH₂Cl₂ (100 mL), washed with saturated NaHCO₃ aqueous solution (100 mL) and brine (100 mL), and then passed through a phase separation column to remove the solvent under reduced pressure, yielding a colorless oil (2.80 g, 85%), which was used without further purification. LCMS (Method A) 387.1 [M+H] + At 0.99 min. 1 H NMR (500MHz, CDCl3) δ4.50-4.30 (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).
[0613] 60A ethyl 3,5-dibromo-1-[3-hydroxy-2-(hydroxymethyl)propyl]pyrazole-4-carboxylate
[0614]
[0615] 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 rt for 2 h. The mixture was concentrated to dryness and purified by rapid chromatography using (30-70% EtOAc:heptane) to give a colorless oil (9.39 g, 86%). 1 H NMR (400MHz, DMSO-d6) δ4.61 (t, J=5.0Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 4.20 (d , J=7.2Hz, 2H), 3.45-3.35 (m, 4H), 2.19-2.05 (m, 1H), 1.29 (t, J=7.1Hz, 3H). LRMS m / z(APCI+)385.6 / 387.6 / 389.6[M+H] + .
[0616] 61A ethyl 5-benzyl-3-bromo-1H-pyrazole-4-carboxylate
[0617]
[0618] 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 in an ice bath, and Br2 (0.22 mL, 4.34 mmol) was added over 5 minutes. After 30 minutes, the ice bath was removed. EtOH (7 mL) was then added, and the mixture was stirred for 4 hours. A saturated aqueous solution of Na2S2O3 (20 mL) and EtOAc (15 mL) were added to separate the layers. The aqueous layer was extracted with EtOAc (2 × 15 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The solution was purified by rapid column chromatography (10-50% EtOAc: heptane) to give a white solid (385 mg, 57%). LRMS m / z(APCI+)309.3 / 311.3[M+H] + TLCR f =0.63 (1:1 EtOAc:heptane).
[0619] 62A(5R)-2-benzyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0620]
[0621] A solution 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) was heated at 60 °C for 17 h. The reaction system was cooled to rt, filtered, washed with MeCN (3 × 10 mL), and the filtrate was concentrated under reduced pressure. A mixture (480 mg) of ethyl 3-benzyl-5-bromo-1-[(2R)-4-hydroxybut-2-yl]pyrazole-4-carboxylate and ethyl 5-benzyl-3-bromo-1-[(2S)-4-hydroxybut-2-yl]pyrazole-4-carboxylate 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 system was brought to rt and stirred for 24 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated under reduced pressure. The solution was purified by rapid chromatography (1:1 EtOAc:heptane) to give a white solid (138 mg, 39%). 1H NMR (400MHz, DMSO-d6) δ7.29-7.05 (m, 5H), 4.56-4.47 (m, 1H), 4.11-3.99 (m, 5H), 2.2 1 (d, J=14.4Hz, 1H), 2.02-1.89 (m, 1H), 1.39 (d, J=6.3Hz, 3H), 1.15 (t, J=7.1Hz, 3H). LRMS m / z(APCI+)301.4[M+H] + .
[0622] 63A 5-Bromo-2-ethylpyrimidine
[0623]
[0624] Pd(PPh3)4 (304 mg, 0.260 mmol) was added to a cooled (0 °C) solution of 5-bromo-2-iodopyrimidine (1.5 g, 5.27 mmol) in anhydrous THF (15 mL) under a nitrogen atmosphere. Diethylzinc (1 M hexane solution; 6.84 mL, 6.84 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h, then at rt for 3 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (25 mL) and diluted with EtOAc (10 mL). The separated aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers (Na2SO4) were dried and the solvent removed under reduced pressure. Purification was achieved by rapid chromatography (0–10% EtOAc in isohexane solution) to give a colorless oil (560 mg, 55%). LCMS (Method E) 187.6 / 189.6 [M+H] + At 0.51 min. 1 H NMR (500MHz, CDCl3) δ8.69 (s, 2H), 2.94 (q, J=7.6Hz, 2H), 1.34 (t, J=7.6Hz, 3H).
[0625] 64A 1-(5-bromopyridin-2-yl)prop-2-ol
[0626]
[0627] Diisopropylaminolithium (2.5 mL, 5.0 mmol) was added dropwise to a solution of 5-bromo-2-methylpyridine (1.4 mL, 3.49 mmol) in 10 mL of THF under stirring at -78 °C. The solution was stirred at -78 °C for 20 min, followed by the addition of acetaldehyde (0.6 mL, 10.7 mmol). The reaction mixture was stirred at -78 °C for 1 h, then allowed to reach settling temperature and stirred for 1 h. The reaction was quenched with 10 mL of saturated NH4Cl aqueous solution, extracted with CH2Cl2 (3 × 20 mL), and the organic layer extracts were combined, dried (Na2SO4), and concentrated under reduced pressure. The solution was purified by rapid chromatography (0–30% EtOAc in CH2Cl2 solution) followed by continuous purification (0–40% MeOH in CH2Cl2 solution) to give a yellow oil (285 mg, 36%). LCMS (Method F) 216.1 / 218.1 [M+H] + At 0.66 min. 1 H NMR (500MHz, DMSO-d6) δ8.58 (d, J=2.5Hz, 1H), 7.92 (dd, J=8.3, 2.5Hz, 1H), 7.25 (d, J=8.3Hz, 1H), 4.63 (d, J=4. 9Hz, 1H), 4.03-3.94 (m, 1H), 2.78 (dd, J=13.3, 7.3Hz, 1H), 2.71 (dd, J=13.3, 5.6Hz, 1H), 1.07 (d, J=6.2Hz, 3H).
[0628] 65A(5R)-2-(2-methoxypyridin-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester (Suzuki-Miyaura method C)
[0629]
[0630] 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 purged with N2 and heated to 100 °C overnight. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL), and the separated aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification was achieved by rapid chromatography (30–100% EtOAc in isohexane solution) to give a white solid (186 mg, 90%). LCMS (Method A) 318.6 [M+H] + At 1.12 min. 1 H NMR (500MHz, DMSO-d6) δ8.16 (dd, J=5.3, 0.8Hz, 1H), 7.18 (dd, J=5.3, 1.4Hz, 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=6.3Hz, 3H), 1.16 (t, J=7.1Hz, 3H).
[0631] The following intermediate compounds were prepared in a similar manner to intermediate 65A. Intermediates 65C and 66A were prepared from the corresponding pinacol esters.
[0632] Table 11 - Examples of preparations using Suzuki-Miyaura method C
[0633]
[0634]
[0635]
[0636]
[0637]
[0638] 68A(5R)-2-(6-ethyl-2-methylpyridin-3-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0639]
[0640] KOAc (981 mg, 10 mmol) and bis(pinacol)diboron (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 purged with N2 for 10 min, and Pd(dppf)Cl2 (91 mg, 0.12 mmol) was added. The mixture was heated at 85 °C for 16 h. The reaction mixture was cooled to rt, diluted with MTBE (10 mL), filtered through diatomaceous earth (Celite), and washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to give a brown oily substance (600 mg). 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 system was purged with N2, and Pd-170 (42 mg, 0.06 mmol) was added. The reaction system was heated at 70 °C for 1 h. The reaction system was diluted with EtOAc (10 mL), washed with brine (20 mL), and the organic layer was passed through a phase separation column to remove the solvent under reduced pressure. Purification was performed by rapid chromatography (0-5% MeOH in CH2Cl2 solution) to give a brown oil (125 mg, 56%). LCMS (Method E) m / z 330.3
[0641] [M+H] + At 0.27 min. 1 H NMR (500MHz, DMSO-d6) 7.43 (d, J=7.8Hz, 1H), 7.08 (d, J=7.8Hz, 1H), 4.72-4.53 (m, 1H), 4.24-4.08 (m, 2H), 3.96 (q, J=7.1Hz, 2H), 2.73 ( q, J=7.6Hz, 2H), 2.30-2.26 (m, 1H), 2.28 (s, 3H), 2.14-1.99 (m, 1H), 1.45 (d, J=6.3Hz, 3H), 1.23 (t, J=7.6Hz, 3H), 0.99 (t, J=7.1Hz, 3H).
[0642] The following intermediate compounds were prepared in a manner similar to that of intermediate 68A.
[0643]
[0644]
[0645] 69A(5R)-2-[6-(2-hydroxypropyl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0646]
[0647] KOAc (367 mg, 3.74 mmol) and bis(pinacol)diboron (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 purged with N2, and Pd(dppf)Cl2 (69 mg, 0.09 mmol) was added. The mixture was heated overnight at 100 °C. The reaction system was cooled to rt, filtered through diatomaceous earth, and washed with MeOH. The filtrate was concentrated under reduced pressure to give 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 system was purged with N2 and heated at 100 °C for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL), and the separated aqueous phase was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (30 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by rapid chromatography (0–6% MeOH in CH₂Cl₂ solution) to give a brown solid (221 mg, 84%). LCMS (Method E) m / z 346.3 [M+H] + (ES+) at 0.70 min. 1 H NMR (500MHz, DMSO-d6) 8.62 (dd, J=2.3, 0.8Hz, 1H), 7.84 (dd, J=8.0, 2.3Hz, 1H), 7.26 (d , J=8.0, 0.9Hz, 1H), 4.69 (d, J=4.8Hz, 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, 7.0Hz, 1H), 2.75 (dd, J=13.3, 5.9Hz, 1H), 2.31-2.23 (m, 1H), 2.07-1.97 (m, 1H), 1.44 (d, J=6.3Hz, 3H), 1.13 (t, J=7.1Hz, 3H), 1.10-1.05 (m, 3H).
[0648] The following intermediate compounds were prepared in a similar manner to intermediate 69A. Intermediates 69E, 69F, and 69G were prepared using 30 mol% XPhos PdG2 and 3 eq. K3PO4.
[0649]
[0650]
[0651]
[0652] 72A(5R)-2-anilino-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0653]
[0654] XPhos (50 mg, 0.10 mmol) and tris(dibenzylacetone)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 purged with N₂ and stirred overnight at 100 °C. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL), and the separated aqueous phase was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (30 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by column chromatography (0–50% EtOAc in isohexane solution) to give a creamy solid (164 mg, 96%). LCMS (Method F) m / z 302.2 [M+H] + At 2.30 min. 1 HNMR (500MHz, DMSO-d6) δ8.30 (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=7.1Hz, 2H), 4.01-3.96 (m, 2H), 2.28-2.21 (m, 1H), 2.05-1.96 (m, 1H), 1.42 (d, J=6.3Hz, 3H), 1.26 (t, J=7.1Hz, 3H).
[0655] 72B(5R)-2-(4-fluoroanilino)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0656]
[0657] Prepared in a similar manner to intermediate 72A, with subsequent purification by ion-exchange chromatography (2 g SCX column, eluted with 0.7 M NH3 MeOH solution). LCMS (Method A) 320.0 [M+H] + At 1.55 min. 1 H NMR (500MHz, DMSO-d6) δ8.28 (s, 1H), 7.62-7.55 (m, 2H), 7.13-7.04 (m, 2H), 4.60-4.51 (m, 1H), 4.20 (q, J=7.1H z, 2H), 4.01-3.95 (m, 2H), 2.29-2.20 (m, 1H), 2.06-1.94 (m, 1H), 1.42 (d, J=6.3Hz, 3H), 1.26 (t, J=7.1Hz, 3H).
[0658] 73A(5R)-2-(5-cyclopropyl-2-fluoropyridin-3-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0659]
[0660] Potassium cyclopropyltrifluoroborate (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 purged with nitrogen, and the mixture was heated to 70 °C for 16 h. The reaction system was cooled to rt and partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (40 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by column chromatography (0–80% EtOAc in isohexane solution) to give a white solid (37 mg, 25%). LCMS (Method A) m / z 346.0 [M+H] + At 1.29 min. 1HNMR (500MHz, DMSO-d6) δ8.07 (dd, J=2.5, 1.1Hz, 1H), 7.56 (dd, J=8.9, 2.5Hz, 1H), 4.67-4.59 (m, 1H), 4.23-4.12 (m, 2H), 4.02 (q, J=7.1Hz, 2H), 2.33-2.27 (m, 1H), 2.10-1.99 (m, 2H), 1.46 (d, J=6.3Hz, 3H), 1.08-0.98 (m, 5H), 0.78-0.74 (m, 2H).
[0661] 74A 2-(2,6-difluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0662]
[0663] 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 purged with N2 (3×). 1,4-Dioxane (4.5 mL) and water (2.25 mL), which had been purged with N2, were added, and the reaction mixture was heated at 100 °C for 17 h. The reaction mixture was cooled to rt, and then 1,4-Dioxane was removed under reduced pressure. Water (15 mL) was added, and the mixture was extracted with EtOAc (3× 15 mL). The organic extract was washed with water and brine (15 mL each), dried (Na2SO4), and concentrated under reduced pressure. The residue (70-100% EtOAc:heptane) was purified by rapid chromatography to give a colorless oil (180 mg, 41%). 1 HNMR (400MHz, DMSO-d6) δ7.58-7.42 (m, 1H), 7.22-7.04 (m, 2H), 5.16 (t, J=5.6Hz, 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=7.1Hz, 3H). LRMS m / z(APCI+)339.1[M+H] + .
[0664] The following intermediate compounds were prepared by a method similar to that described for intermediate 74A. Both used a catalytic loading of 10 mol% XPhos PdG2.
[0665] Table 12 - Preparation Examples
[0666]
[0667] 76A 2-(2,6-difluorophenyl)-6-(hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0668]
[0669] 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-safe vial, capped, evacuated, and purged with N2 (3×). Water (0.9 mL) and 1,4-dioxane (1.8 mL), degassed with N2, were added, and the vial was heated at 100 °C for 16 h. The reaction mixture was cooled to rt, and XPhos Pd G2 (37 mg, 0.05 mmol) was added. The vial was sealed and heated for another 18 h. Post-treatment and purification were performed similarly to those described for intermediate 74A to give a yellow oil (59 mg, 38%). TLC R f =0.61(EtOAc)LRMS m / z(APCI+)339.4[M+H] + .
[0670] 77A 1-Bromo-4-ethylsulfonyl-2-fluorobenzene
[0671]
[0672] Hydrazine monohydrate (12.4 mL, 255 mmol) was added dropwise to a cooled (0 °C) solution of 4-bromo-3-fluorobenzenesulfonyl chloride (20.0 g, 73.1 mmol) in THF (200 mL). The reaction mixture was brought to rt and stirred for 1 h. Heptane (1000 mL) was added, and the precipitate was collected by filtration. The white precipitate was dissolved in anhydrous EtOH (400 mL), and then NaOAc (36.0 g, 439 mmol) and EtI (29.4 mL, 366 mmol) were added. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. Water (600 mL) was added, and the mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (600 mL), dried (Na₂SO₄), and volatiles were removed under reduced pressure. Purification by column chromatography (15-40% EtOAc in heptane solution) yielded a white solid (12.1 g, 62%). 1H NMR (400MHz, CDCl3) δ7.78 (dd, J=8.3, 6.4Hz, 1H), 7.64 (dd, J=7.5, 2.0Hz, 1H), 7.57 (ddd, J=8.3, 2.0, 0.8Hz, 1H), 3.12 (q, J=7.4Hz, 2H), 1.28 (t, J=7.4Hz, 3H). TLC R f =0.57(EtOAc).
[0673] 78A 2-Bromo-1-fluoro-4-methylsulfonylbenzene
[0674]
[0675] N-bromosuccinimide (8.22 g, 46.2 mmol) was added to a solution of 4-fluorophenylmethyl sulfone (8.05 g, 46.2 mmol) in concentrated H₂SO₄ (80 mL), and the reaction mixture was heated at 50 °C for 3.5 h. The reaction mixture was cooled to rt, and the mixture was poured into ice water (270 mL). The resulting mixture was stirred until cooled (≈10 °C), and the precipitate was collected by filtration. The solid was washed with water, dried on filter paper, and then dried under reduced pressure overnight to give a white solid (10.3 g, 88%). 1 H NMR (400MHz, DMSO-d6) δ 8.26 (dd, J=6.4, 2.3Hz, 1H), 7.99 (ddd, J=8.7, 4.6, 2.3Hz, 1H), 7.65 (t, J=8.6Hz, 1H), 3.30 (s, 3H). TLC R f =0.57(EtOAc).
[0676] 79A 4-Bromo-3-fluoro-N,N-dimethylbenzenesulfonamide
[0677]
[0678] The 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. Dimethylamine (33% ethanol solution; 13.7 mL, 76.8 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 10 min. The reaction mixture was washed with 1 M HCl aqueous solution (350 mL) and brine (215 mL). The organic phase was separated, dried (MgSO₄), filtered, and volatiles were removed under reduced pressure to give a white solid (10.7 g, quantitative), which was used without further purification. 1H NMR (400MHz, CDCl3) δ7.75 (dd, J=8.3, 6.5Hz, 1H), 7.51 (dd, J=7.7, 2.0Hz, 1H), 7.44 (ddd, J=8.3, 2.1, 0.8Hz, 1H), 2.73 (s, 6H). TLC R f =0.59(EtOAc).
[0679] 80A 2-(4-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane
[0680]
[0681] The solution of intermediate 77A (11.6 g, 43.4 mmol), bis(pinacol)diboron (13.2 g, 52.0 mmol), and KOAc (8.50 g, 86.7 mmol) in 1,4-dioxane (120 mL) was purged with N2 for approximately 20 min. Pd(dppf)Cl2·CH2Cl2 (0.952 g, 1.30 mmol, 3 mol%) was added, and the reaction mixture was heated to 85–90 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc (200 mL), filtered through diatomaceous earth, and washed with EtOAc. The filtrate was washed with H2O (100 mL) and brine (100 mL), dried (Na2SO4), and volatiles were removed under reduced pressure. The residue was purified by column chromatography (0–100% EtOAc / 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 rt for 1 h. The solid was collected by filtration under reduced pressure, washed with heptane, and dried under reduced pressure to give a white solid (11.0 g, 80%). 1 HNMR (400MHz, CDCl3) δ7.94 (dd, J=7.7, 5.5Hz, 1H), 7.66 (dd, J=7.7, 1.6Hz, 1H), 7.5 7 (dd, J=8.1, 1.5Hz, 1H), 3.11 (q, J=7.4Hz, 2H), 1.37 (s, 12H), 1.27 (t, J=7.4Hz, 3H). TLC R f =0.43(EtOAc).
[0682] The following intermediate compounds were prepared in a manner similar to that of intermediate 80A.
[0683] Table 13 - Preparation Examples
[0684]
[0685] The following intermediate compounds were prepared in a manner similar to that of intermediate 21A. Reaction times varied from 30 min to 3 h, with heating carried out either by MWI or by conventional heating. Intermediate 88T-88W was heated overnight at 85 °C by conventional heating. Catalyst loading varied between 5-10 mol% XPos PdG2. Intermediates 81J-81W, 84B, and 85A were prepared from the corresponding pinacol esters. Analysis was performed using a 400 MHz spectrometer in DMSO-d6. 1 H NMR, unless otherwise stated.
[0686] Table 14 - Examples of preparations using Suzuki-Miyaura Method B
[0687]
[0688]
[0689]
[0690]
[0691]
[0692]
[0693]
[0694]
[0695]
[0696]
[0697]
[0698] 90A(5R)-2-[6-(3-methoxyazacyclobutane-1-yl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0699]
[0700] A solution of intermediate 81A (200 mg, 0.66 mmol), 3-methoxyazacyclobutane hydrochloride (324 mg, 2.62 mmol), and DIPEA (913 μL, 5.24 mmol) in anhydrous DMSO (3 mL) was heated overnight at 130 °C. The reaction mixture was cooled to rt and partitioned between brine and EtOAc (10 mL each). The aqueous layer was extracted with EtOAc (4 × 15 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification was performed by rapid chromatography [10–36% (EtOH:CH₂Cl₂:NH₄OH; 50:8:1) CH₂Cl₂ solution] to give a light brown solid (191 mg, 78%). 1 H NMR (400MHz, DMSO-d6) δ8.25 (dd, J=2.3, 0.8Hz, 1H), 7.70 (dd, J=8.6, 2.3Hz, 1H), 6.39 (dd, J=8.7, 0.8Hz, 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=6.3Hz, 3H), 1.15 (t, J=7.1Hz, 3H). LRMS m / z(APCI+)373.6[M+H] + .
[0701] The following preparation example intermediates were prepared using a method similar to that used for intermediate 90A.
[0702]
[0703]
[0704] 90D(5R)-5-methyl-2-[6-(trideuterated methylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0705]
[0706] DIPEA (571 μL, 3.28 mmol) and methyl-d3-amine hydrochloride (144 mg, 2.05 mmol) were added to a solution of intermediate 81A (125 mg, 0.409 mmol) in DMSO (3 mL), and the mixture was heated at 140 °C for 6 h by MWI. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The mixture was purified by ion-exchange chromatography (2 g SCX-2 column, eluted with 2N NH3 in MeOH solution) to give an orange solid (61 mg, 47%).
[0707] LCMS (Method B) m / z 385.4 [M+H] + At 0.67 min. LCMS (Method A) m / z 320.3 [M+H] + At 0.62 min. 1 H NMR (500MHz, DMSO-d6) δ8.18 (d, J=2.4Hz, 1H), 7.57 (dd, J=8.6, 2.4Hz, 1H), 6.56 (s, 1H), 6.41 (d, J=8.7Hz, 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=6.3Hz, 3H), 1.16 (t, J=7.1Hz, 3H).
[0708] 90E(5R)-5-methyl-2-[6-(propyl-2-ylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0709]
[0710] 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 the mixture was heated overnight at 60 °C. Then, isopropylamine (312 μL, 3.64 mmol) was added, and the reaction mixture was heated to 100 °C overnight, followed by heating at 100 °C for 16 h via MWI. The reaction mixture was partitioned between CH₂Cl₂ (10 mL) and a saturated aqueous solution of 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 (Na₂SO₄), and concentrated under reduced pressure. Purification was achieved by rapid chromatography (50–100% EtOAc in isohexane solution) to give a pink solid (56 mg, 35%). LCMS (Method B) m / z 345.4 [M+H] + At 1.16 min. 1 H NMR (500MHz, DMSO-d6)δ
[0711] 8.16 (d, J=2.4Hz, 1H), 7.53 (dd, J=8.7, 2.4Hz, 1H), 6.45 (d, J=7.6Hz, 1H), 6.41 (d, J=8.7Hz, 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=6.3Hz, 3H), 1.19-1.13 (m, 9H).
[0712] 90F(5R)-5-methyl-2-(6-morpholin-4-ylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0713]
[0714] Morpholine (158 μL, 1.81 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 the mixture was heated overnight at 60 °C. Morpholine (158 μL, 1.81 mmol) was then added, and the reaction mixture was heated to 100 °C overnight. Post-treatment and purification were performed similarly to those for intermediate 90E to give a pink solid (130 mg, 77%). LCMS (Method B) m / z 373.5 [M+H] + At 1.09 min. 1HNMR (500MHz, DMSO-d6) δ8.33 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.8, 2.4Hz, 1H), 6.83 (d, J=8.9Hz, 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=6.3Hz, 3H), 1.17 (t, J=7.1Hz, 3H).
[0715] 90G(5R)-5-methyl-2-[6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0716]
[0717] (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 a solution of intermediate 81A (130 mg, 0.426 mmol) in DMSO (3 mL), and the mixture was heated at 130 °C for 4 h by MWI. Then, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (115 mg, 0.85 mmol) was added, and the reaction mixture was heated at 130 °C for 8 h by MWI. Post-treatment and purification were performed similarly to those for intermediate 29A to give a pink solid (58 mg, 35%). LCMS (Method B) m / z 385.4 [M+H] + At 0.67 min. 1H NMR (500MHz, DMSO-d6) δ8.26 (dd, J=2.4, 0.8Hz, 1H), 7.69 (dd, J=8.7, 2.3Hz, 1H), 6.52 (d, J=8.7Hz, 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, 1.5Hz, 1 H), 3.65 (d, J=7.3Hz, 1H), 3.47 (dd, J=10.1, 1.5Hz, 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, 2.3Hz, 1H), 1.89-1.82 (m, 1H), 1.43 (d, J=6.3Hz, 3H), 1.16 (t, J=7.1Hz, 3H).
[0718] 90H(5R)-5-methyl-2-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0719]
[0720] Prepared by a method similar to that described for intermediate 90G. LCMS (Method B) m / z 385.4 [M+H]+ at 0.67 min. 1 H NMR (500MHz, DMSO-d6) δ8.26 (d, J=2.3Hz, 1H), 7.69 (dd, J=8.7, 2.4Hz, 1H), 6.52 (d, J=8.7Hz, 1H), 4.87 (s, 1H), 4.66 (d, J=2.5Hz, 1H), 4.61-4.53 (m, 1H), 4.16-4.03 (m, 4H), 3.78 (dd, J=7.3, 1.5Hz, 1H), 3.65 (d, J=7.3Hz, 1H), 3.47 (dd, J=10.1, 1.5Hz, 1H), 3.25 (d, J=10.0Hz, 1H), 2.30-2.23 (m, 1H), 2.10-1.95 ( m, 1H), 1.92 (dd, J=9.9, 2.3Hz, 1H), 1.85 (d, J=9.5Hz, 1H), 1.43 (d, J=6.3Hz, 3H), 1.16 (t, J=7.1Hz, 3H).
[0721] 90I(5R)-2-[6-(ethylamino)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0722]
[0723] Prepared by a method similar to that of intermediate 29A, wherein heating at 100 °C for 30 min via MWI followed by heating at 130 °C for 7.5 h. LCMS (Method B) m / z 331.4 [M+H]+ at 1.05 min. 1 H NMR (500MHz, DMSO-d6) δ8.16 (d, J=2.3Hz, 1H), 7.55 (dd, J=8.6, 2.4Hz, 1H), 6.59 (t, J=5.5Hz, 1H), 6.41 (dd, J=8.7, 0.8Hz, 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=6.3Hz, 3H), 1.16 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H).
[0724] 91A(5S)-5-methyl-2-[6-(propyl-2-ylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0725]
[0726] Prepared using a method similar to that used for intermediate 29A, wherein heating at 130 °C for 6 h was performed via MWI. LCMS (Method A) 345.4 [M+H] + At 0.70 min. 1 H NMR (500MHz, DMSO-d6) δ 8.18-8.13 (m, 1H), 7.53 (dd, J = 8.6, 2.4Hz, 1H), 6.46 (d, J = 7.6Hz, 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=6.3Hz, 3H), 1.19-1.12 (m, 9H).
[0727] 91B(5S)-5-methyl-2-[6-[-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0728]
[0729] Prepared using a method similar to that described for intermediate 90G. LCMS (Method A) m / z 385.5 [M+H] + At 0.66 min. 1 H NMR (500MHz, DMSO-d6) δ (DMSO-d6) 8.29-8.25 (m, 1H), 7.70 (dd, J=8.7, 2.4Hz, 1H), 6.53 (d, J=8 .7Hz, 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=7.2Hz, 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=6.3Hz, 3H), 1.17 (t, J=7.1Hz, 3H).
[0730] 92A 2-[6-(propyl-2-ylamino)pyridin-3-yl]spiro[5,7-dihydropyrazolo[5,1-b][1,3]oxazine-6,1'-cyclopropane]-3-carboxylic acid ethyl ester
[0731]
[0732] Isopropylamine (839 μL, 9.77 mmol) and DIPEA (340 μL, 1.95 mmol) were added to a solution of intermediate 84A (310 mg, 0.98 mmol) in DMSO (6 mL), and the mixture was heated at 140 °C for 48 h. Similar post-treatment and purification were performed as with intermediate 29A to give an orange solid (225 mg, 65%). 1H NMR (500MHz, DMSO-d6) δ8.15 (d, J=2.3Hz, 1H), 7.53 (dd, J=8.7, 2.4Hz, 1H), 6.47 (d, J=7.6Hz, 1H), 6.41 (d, J=8.7Hz, 1H), 4.21 (s, 2H), 4.10 (q, J=7.1Hz, 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] +
[0733] 93A 2-(2-fluorophenyl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0734]
[0735] NaH (60% dispersion in mineral oil, 17 mg, 0.43 mmol) was added to a solution of intermediate 87A (55 mg, 0.17 mmol) in THF (6 mL), and the mixture was stirred at rt for 15 min. MeI (53 μL, 0.86 mmol) was added, and the reaction mixture was stirred at rt for 1.5 h. The mixture was then quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (20 mL), passed through a phase separation column, and concentrated under vacuum. Purification was performed by rapid chromatography (0–100% MTBE in isohexane solution, then 10% MeOH in MTBE solution) to give a colorless oil (34 mg, 59%). LCMS (Method A) m / z 335.2
[0736] [M+H] + At 1.21 min.
[0737] 93B 2-(2-fluorophenyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0738]
[0739] Prepared using a method similar to that described for intermediate 93A. LRMS(APCI+) m / z 335.7 [M+H] + TLC R f =0.84 (2:1EtOAc:heptane).
[0740] 94A 2-(2-fluorophenyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0741]
[0742] Prepared by a method similar to that described for intermediate 93A. LRMS(APCI+)m / z 321.2[M+H] + TLC R f =0.31(EtOAc).
[0743] 95A 2-(2-fluorophenyl)-6-[methyl-[(2-methylprop-2-yl)oxycarbonyl]amino]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0744]
[0745] NaH (60% dispersion in mineral oil, 24.7 mg, 0.62 mmol) was added to a solution of intermediate 89A (100 mg, 0.25 mmol) in DMF (1 mL), and the mixture was stirred at rt for 0.5 h. MeI (0.04 mL, 0.62 mmol) was added, and the mixture was stirred at rt for 1.5 h. Post-treatment and purification were performed similarly to those described for intermediate 93A to give a colorless oil (94 mg, 91%). LRMS m / z (APCI+) 420.4 [M+H] + TLC R f =0.52 (1:1 EtOAc:heptane).
[0746] 96A 2-(2-fluorophenyl)-6-[(4-methylphenyl)sulfonyloxymethyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0747]
[0748] A solution of TsCl (1.34 g, 7.02 mmol) in CH₂Cl₂ (5 mL) was added dropwise to a cooled (0 °C) solution of 88A (900 mg, 2.81 mmol) and NET₃ (0.98 mL, 7.02 mmol) in CH₂Cl₂ (5 mL) over 5 minutes. The reaction system was stirred at 0 °C for 30 min, and then stirred at rt for 19 h. Water (20 mL) was added, the organic layer was separated, washed with water and brine (10 mL each), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by rapid chromatography (30-60% EtOAc:heptane) to give a colorless oil (1.25 g, 94%). 1 H NMR (400MHz, DMSO-d6) δ7.88-7.77(m, 2H), 7.52-7.32(m, 4H), 7.28-7.15(m, 2H), 4.48(dd, J=10.9, 3.2Hz, 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, 7.0Hz, 1H), 2.81 (s, 1H), 2.40 (s, 3H), 1.02 (t, J=7.1Hz, 3H). LRMS(APCI+)m / z 334.9[M+H] + .
[0749] 96B 2-(2-fluorophenyl)-5-[(4-methylphenyl)sulfonyloxymethyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0750]
[0751] Prepared by a method similar to that described for intermediate 96A. 1 H NMR (400MHz, DMSO-d6) δ7.92-7.82 (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, 2.6Hz, 1 H), 4.31 (dd, J=11.2, 6.3Hz, 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=7.1Hz, 3H). LRMS(APCI+)m / z
[0752] 475.6 [M+H] + .
[0753] 97A 6-[(dimethylamino)methyl]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0754]
[0755] A solution of intermediate 96A (104 mg, 0.22 mmol) and dimethylamine (2 M THF solution; 0.76 mL, 1.52 mmol) in 1,4-dioxane (1.5 mL) was heated at 120 °C for 24 h. The reaction system was cooled to rt, and volatile substances were removed under reduced pressure. The residue was purified by column chromatography [0-30% (50:8:1 CH2Cl2:EtOH:NH4OH) CH2Cl2 solution] to give an orange oil (103 mg, 78%). 1 H NMR (400MHz, DMSO-d6) δ7.51-7.35 (m, 1H), 7.29-7.12 (m, 1H), 4.50 (dd, J=10.8, 3.3Hz, 1H), 4.31-4.13 (m, 1H), 4.08- 3.96 (m, 1H), 3.88 (dd, J=12.3, 7.9Hz, 1H), 2.71-2.60 (m, 1H), 2.32-2.23 (m, 1H), 2.18 (s, 3H), 1.03 (t, J=7.1Hz, 1H). LRMS(APCI+)m / z 348.4[M+H] + .
[0756] The following intermediate compounds were prepared in a manner similar to that described for intermediate 97A. The method was carried out at temperatures ranging from 110°C to 140°C.
[0757] Table 15 - Preparation Examples
[0758]
[0759]
[0760]
[0761]
[0762]
[0763] 99A 2-(2-fluorophenyl)-6-(methylthioalkylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0764]
[0765] Sodium methyl sulfate (49.6 mg, 0.71 mmol) was added to a cooled (0 °C) solution of intermediate 96A (280 mg, 0.59 mmol) in EtOH (4 mL). After 1 h, the ice bath was removed, and the mixture was stirred at rt for 16 h. The reaction system was filtered, the filtrate was concentrated, and the residue was purified by rapid chromatography (0-50% EtOAc:heptane) to give a colorless oil (129 mg, 62%). 1 HNMR (400MHz, DMSO-d6) δ7.54-7.37 (m, 2H), 7.28-7.10 (m, 2H), 4.56 (dd, J=10.7, 2.6Hz, 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=7.1Hz, 3H). LRMS(APCI+)m / z 351.1[M+H] + .
[0766] 100A 2-(2-fluorophenyl)-6-(methylsulfonylmethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0767]
[0768] A solution of mCPBA (240 mg, 1.07 mmol) in CH₂Cl₂ (5 mL) was added to a cooled (0 °C) solution of intermediate 99A (125 mg, 0.36 mmol) in CH₂Cl₂ (5 mL). After 1 h, the ice bath was removed, and the mixture was stirred at rt for 3 h. The mixture was washed with saturated NaHCO₃ aqueous solution (2 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was performed by rapid chromatography (20–100% EtOAc:heptane) to give a colorless oil (101 mg, 74%). 1 H NMR (400MHz, DMSO-d6) δ7.49-7.36 (m, 2H), 7.29-7.13 (m, 2H), 4.58 (dd, J=10.7, 3.2Hz, 1H), 4.47-4.27 (m, 2 H), 4.11 (dd, J=12.4, 7.3Hz, 1H), 4.08-3.94 (m, 2H), 3.49-3.34 (m, 3H), 3.12 (s, 3H), 1.05 (t, J=7.0Hz, 3H). LRMS(APCI+)m / z 383.1[M+H] + .
[0769] 101A(5R)-2-cyclohexyl-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0770]
[0771] Palladium on carbon (10% wt. loading; 25 mg, 0.24 mmol) was added to a solution of intermediate 81R (230 mg, 0.79 mmol) in EtOH (6 mL) in a pressure test tube. The vessel was purged continuously with N2 (5×) and hydrogen (5×), and then stirred at 40 psi for 96 h under a hydrogen atmosphere. The mixture was filtered through a glass microfiber sieve, washed with EtOH (3× 10 mL), and the solvent was removed under reduced pressure to give a light brown solid (198 mg, 86%). LRMS (APCI+) m / z
[0772] 293.5 [M+H] + TLC R f =0.5 (2:1 EtOAc:heptane)
[0773] 101B(5R)-5-methyl-2-piperidin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0774]
[0775] It was prepared by a method similar to that described for intermediate 101A, and then purified by rapid chromatography (50:8:1CH2Cl2:EtOH:NH4OH). 1 H NMR (700MHz, DMSO-d6) δ4.53-4.45 (m, 1H), 4.11 (q, J=7.1Hz, 2H), 4.07-3.95 (m, 2H), 3.12-3.02 (m, 1H), 2.96 (d, J=11.9Hz, 2 H), 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=6.4Hz, 3H), 1.22 (t, J=7.1Hz, 3H). LRMS(APCI+)m / z 294.4[M+H] + .
[0776] 102A(5R)-5-methyl-2-(1-methylsulfonylpiperidin-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0777]
[0778] MsCl (70 μL, 0.89 mmol) was added to a cooled (0 °C) solution 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 rt for 21 h. Volatile substances were removed under reduced pressure, and the residue was purified by rapid chromatography [10-30% (50:8:1 CH2Cl2:EtOH:NH4OH) CH2Cl2 solution] to give a white solid (203 mg, 92%). 1 H NMR (400MHz, DMSO-d6) δ4.58-4.43 (m, 1H), 4.13 (q, J=7.1Hz, 2H), 4.09-3.97 (m, 2H), 3.62 (d, J=11.7Hz, 2H), 3.17-3.06 (m, 1H), 2.87 (s, 3H), 2.77 (td, J=12.1, 2.6Hz, 2H), 2.26-2.16 (m, 1H), 2.03-1.87 (m, 3H), 1.71-1.55 (m, 2H), 1.39 (d, J=6.3Hz, 3H), 1.23 (t, J=7.1Hz, 3H). LRMS(APCI+)m / z 372.4.
[0779] 102B(5R)-2-(1-ethylsulfonylpiperidin-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0780]
[0781] Prepared using ethanesulfonyl chloride via a method similar to that described for intermediate 102A. LRMS APCI(+)386.3[M+H + TLC R f =0.53(200:8:1CH2Cl2:EtOH:NH3)
[0782] The following intermediate compounds were prepared by a method similar to that described for intermediate 43A.
[0783] Table 16 - Preparation Examples of Ester Hydrolysis
[0784]
[0785]
[0786] The following intermediate compounds were prepared using a method similar to that described for intermediate 34A, with 5M NaOH aqueous solution (8 eq.). This method can be carried out at temperatures of 50-70 °C. Intermediate 113B was prepared with 5M NaOH aqueous solution (16 eq.). The preparation was performed using a 400 MHz spectrometer in DMSO-d6. 1 H NMR, unless otherwise stated.
[0787] Table 17 - Preparation examples of preparations using ester hydrolysis method A.
[0788]
[0789]
[0790]
[0791]
[0792]
[0793]
[0794]
[0795]
[0796]
[0797]
[0798]
[0799]
[0800]
[0801]
[0802]
[0803] 113U(5R)-5-methyl-2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0804]
[0805] NaOH (0.3 mL, 1.49 mmol, 5 M aqueous solution) was added to a mixture of intermediate 81F (66 mg, 0.19 mmol) and EtOH (5 mL). The mixture was heated at 60 °C for 19 h. Volatile substances were removed under reduced pressure, and the mixture was acidified with 1 M HCl aqueous solution (pH ≈ 4). The mixture was extracted with CHCl3:iPrOH (3:1; 3 × 10 mL), the organic layer was washed with water and brine (10 mL each), dried (Na2SO4), and concentrated under reduced pressure to give a white solid (43 mg, 93%). 1 H NMR (400MHz, DMSO-d6) δ12.30 (s, 2H), 8.05 (dd, J=8.9, 5.0Hz, 2H), 4.52 (ddd, J=8.7, 6.5, 2.3Hz, 1H), 4.15-4.03 ( m, 2H), 3.16 (d, J=4.9Hz, 2H), 2.23 (d, J=14.4Hz, 1H), 1.98 (ddd, J=16.7, 13.1, 8.4Hz, 1H), 1.42 (d, J=6.3Hz, 3H). LRMS(APCI+)m / z 249.2[M+H] + .
[0806] 113V(5R)-5-methyl-2-(1-methylsulfonylpiperidin-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0807]
[0808] Add NaOH (5M aq. 0.8 mL, 3.98 mmol) to a suspension (20 mL) of intermediate 102A in EtOH. Heat the mixture at 60 °C for 3 h. Add NaOH (5M aq. 0.8 mL, 3.98 mmol) and heat the mixture at 70 °C for 2 h. Add NaOH (5M aq. 1.59 mL, 7.97 mmol) and heat the mixture at 80 °C for 18 h. Remove EtOH under reduced pressure, acidify the mixture with 1M HCl aqueous solution to pH≈2, and extract with CHCl3:iPrOH (3:1; 3 × 20 mL). Wash the organic layer with water and brine (20 mL each), dry (MgSO4), and concentrate under reduced pressure to give a white solid (151 mg, 88%). 1HNMR (400MHz, DMSO-d6) δ11.79 (s, 1H), 4.55-4.43 (m, 1H), 4.10-3.95 (m, 2H), 3.60 (d, J=11.7Hz, 2H), 3.21-3.08 (m, 1H), 2 .87 (s, 3H), 2.77 (td, J=12.1, 2.6Hz, 2H), 2.25-2.12 (m, 1H), 2.04-1.83 (m, 3H), 1.70-1.52 (m, 2H), 1.39 (d, J=6.3Hz, 3H). LRMS(APCI+)m / z 344.5[M+H] + .
[0809] 113W(5R)-2-(1-ethylsulfonylpiperidin-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0810]
[0811] Prepared by a method similar to that described for intermediate 113V. 1 H NMR (700MHz, DMSO-d6) δ11.76 (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=7.4Hz, 2H), 2.86 (t d, J=12.3, 2.6Hz, 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=6.3Hz, 3H), 1.21 (t, J=7.4Hz, 3H). LRMS(APCI+) 358.1 m / z [M+H] + .
[0812] 114A 6-[ethyl-[(2-methylprop-2-yl)oxycarbonyl]amino]-2-(2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0813]
[0814] NaH (60% dispersion in mineral oil, 18.5 mg, 0.46 mmol) was added to a solution of intermediate 89A (75 mg, 0.19 mmol) in DMF (1 mL), and the mixture was stirred at rt for 0.5 h. EtI (40 μL, 0.46 mmol) was added, and the mixture was stirred at rt for 1.5 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with water (2 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Purification was achieved by rapid chromatography (10–35% EtOAc:heptane) to give a colorless oil (140 mg), which 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 rt for 16 hours. Volatile substances were removed under reduced pressure, and the residue was acidified with 1M HCl aqueous solution (pH≈4). The mixture was extracted with EtOAc (3 × 10 mL), the organic layer was washed with water and brine (10 mL each), dried (MgSO4), and concentrated under reduced pressure. The residue was ground together with heptane (3 × 5 mL), dried under reduced pressure, and a yellow-white solid (59 mg, 79%) was given. 1 HNMR (400MHz, DMSO-d6) δ11.88 (s, 1H), 7.52-7.28 (m, 2H), 7.28-7.14 (m, 2H), 4.62-4.3 9 (m, 3H), 4.39-4.19 (m, 2H), 3.21 (q, J=7.0Hz, 2H), 1.43 (s, 8H), 1.04 (t, J=6.9Hz, 3H). LRMS(APCI+)m / z 406.5[M+H] + .
[0815] 115A 2-Bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid benzyl ester
[0816]
[0817] 1,8-diazabicyclo[5.4.0]undec-7-ene (270 μL, 1.79 mmol) was added to a solution of intermediate 104A (340 mg, 1.38 mmol) in DMSO (7 mL). After 5 min, benzyl bromide (0.16 mL, 1.38 mmol) in DMSO (7 mL) was added, and the reaction mixture was stirred at rt for 16 h. Water (30 mL) and brine (30 mL) were added, and the mixture was extracted with EtOAc (3 × 25 mL). The organic layer was washed with brine (2 × 25 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification was performed by rapid chromatography (10-80% EtOAc:heptane) to give a colorless oil (356 mg, 77%). 1 H NMR (400MHz, DMSO-d6) δ7.45-7.25 (m, 5H), 5.23 (s, 2H), 4.49-4.37 (m, 2H), 4.06 (t, J = 6.1Hz, 2H), 2.27-2.15 (m, 2H). LRMS m / z(APCI+)337.1 / 339.1[M+H] + .
[0818] The following intermediate compounds were prepared in a manner similar to that of intermediate 21A. Reaction times varied between 45 min and 1 h 20 min, with heating performed either by MWI or by conventional heating. Intermediate 116D was prepared from the corresponding pinacol ester.
[0819] Table 18 - Preparation examples prepared by Suzuki-Miyaura method B.
[0820]
[0821]
[0822] 117A 2-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid benzyl ester
[0823]
[0824] 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 rt for 1 h, then sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added, and the mixture was stirred at rt for 69 h. The mixture was diluted with CH2Cl2 (10 mL), washed with saturated Na2CO3 aqueous solution (2 × 10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue [EtOAc, then 0-40% (50:8:1 CH2Cl2:EtOH:NH4OH) in CH2Cl2 solution] was purified by rapid chromatography to give a yellow oil (171 mg, 72%). 1 H NMR (400MHz, DMSO-d6) δ7.39-7.22 (m, 4H), 7.18-7.11 (m, 3H), 7.06 (dd, J=11.0, 1.5Hz, 1H), 5.07 (s, 2H), 4.4 9-4.42 (m, 2H), 4.14 (t, J=6.1Hz, 2H), 3.61-3.54 (m, 4H), 3.48 (s, 2H), 2.38-2.30 (m, 4H), 2.31-2.20 (m, 2H). LRMS m / z(APCI+)452.4[M+H] + .
[0825] The following intermediate compounds were prepared by a method similar to that described for intermediate 117A.
[0826] Table 19 - Preparation examples of preparations by reductive amination.
[0827]
[0828]
[0829] 119A 2-(2-fluoro-4-methylsulfinylphenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid benzyl ester
[0830]
[0831] A solution of mCPBA (124 mg, 0.55 mmol) in CH2Cl2 (10 mL) was added dropwise to a cooled (0 °C) solution of intermediate 116C (200 mg, 0.5 mmol) in CH2Cl2 (10 mL). After 1 h, the ice bath was removed, and the mixture was stirred at rt for 0.5 h. The mixture was washed with saturated NaHCO3 aqueous solution (2 × 5 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification was performed by rapid chromatography [10–30% (50:8:1 CH2Cl2:EtOH:NH4OH) CH2Cl2 solution] to give a colorless oil (159 mg, 76%). 1 H NMR (400MHz, DMSO-d6) δ7.59 (dd, J=7.9, 6.8Hz, 1H), 7.52 (dd, J=7.9, 1.6Hz, 1H), 7.47 (dd, J=9.4, 1.6Hz, 1H), 7.32-7.25 ( m, 3H), 7.18-7.13 (m, 2H), 5.08 (s, 2H), 4.48 (dd, J=5.8, 4.5Hz, 2H), 4.17 (t, J=6.1Hz, 2H), 2.78 (s, 3H), 2.30-2.21 (m, 2H). LRMS(APCI+)m / z 415.1[M+H] + .
[0832] 120A 2-[2-fluoro-4-(methyliminosulfonyl)phenyl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid benzyl ester
[0833]
[0834] (Diacetoxyiodine)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 rt for 1.5 h. Volatile substances were removed under reduced pressure, and the residue was purified by rapid chromatography [0-30% (50:8:1 CH2Cl2:EtOH:NH4OH) CH2Cl2 solution] to give a colorless oil (185 mg, 86%). 1H NMR (400MHz, DMSO-d6) δ7.76 (dd, J=8.0, 1.7Hz, 1H), 7.71-7.55 (m, 2H), 7.37-7.25 (m, 3H), 7.25-7.16 (m, 2H), 5.10 (s, 2 H), 4.49 (dd, J=5.9, 4.4Hz, 2H), 4.40 (d, J=1.4Hz, 1H), 4.17 (t, J=6.1Hz, 2H), 3.11 (d, J=1.1Hz, 3H), 2.31-2.22 (m, 2H). LRMS(APCI+)m / z 430.1[M+H] + .
[0835] 121A ethyl 2-(2-fluorophenyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylate
[0836]
[0837] Palladium hydroxide on carbon (20 wt.% loading, 50% water; 35 mg, 0.22 mmol) was added to a solution of intermediate 86A (650 mg, 1.64 mmol) in EtOH (15 mL) in a pressure test tube. The vessel was continuously purged with N2 (5×) and hydrogen (5×), and then stirred for 21 h at 40 psi and 60 °C under a hydrogen atmosphere. The reaction system was filtered through a glass microfiber sieve, washed with EtOH (3 × 10 mL) and CH2Cl2 (3 × 10 mL), and the solvent was removed under reduced pressure to give a white solid (390 mg, 78%). 1 HNMR (500MHz, DMSO-d6) δ7.50-7.31 (m, 2H), 7.31-7.07 (m, 2H), 5.69 (d, J=2.8Hz, 1H), 4.43-4.23 (m, 4H), 4.10-3.81 (m, 3H), 1.04 (t, J=7.0Hz, 3H). LRMS(APCI+)m / z 307.4[M+H] + .
[0838] 122A 2-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid
[0839]
[0840] Palladium hydroxide on carbon (20 wt.% loading, 50% water; 15 mg, 0.09 mmol) was added to a solution of 116D (117 mg, 0.31 mmol) in EtOH (6 mL) in a pressure test tube. The container was continuously purged with N2 (5×) and hydrogen (5×), and then stirred at 40 psi for 3 h under a hydrogen atmosphere. The reaction system was filtered through a glass microfiber sieve, washed with EtOH (3×5 mL) and CH2Cl2 (3×5 mL), and the solvent was removed under reduced pressure to give a yellow-white solid (80 mg, 90%). 1 H NMR (400MHz, DMSO-d6) δ11.61 (s, 1H), 7.89 (dd, J=9.8, 1.5Hz, 1H), 7.72 (dd, J=7.9, 1.6Hz, 1 H), 7.66-7.53 (m, 1H), 4.44 (dd, J=6.0, 4.3Hz, 2H), 4.15 (t, J=6.1Hz, 2H), 2.28-2.18 (m, 2H). LRMS(APCI+)m / z 288.2[M+H] + .
[0841] The following intermediate compounds were prepared in a manner similar to that of intermediate 122A.
[0842]
[0843]
[0844] 123A(5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0845] 123B(5R)-2-[6-fluoro-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-5-methyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0846]
[0847] 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 a solution of intermediate 16B (200 mg, 0.62 mmol) in DMSO (3 mL), and heated at 130 °C for 7 h by MWI. Post-treatment was performed similarly to that of intermediate 90E, followed by purification by rapid chromatography [0-70% EtOAc (10% MeOH) in isohexane solution], according to... 1 ¹H NMR yielded a ~6:4 mixture of 123A:123B regioisomers, which could not be separated by silica gel column chromatography and were used without further purification (212 mg). LCMS (Method A) m / z 403.3 [M+H] + At 1.12 (primary) and 1.17 (minor).
[0848] 124A(5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0849] 124B(5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-3-yl]-5-methyl-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0850]
[0851] Prepared by a method similar to that described for intermediate 123A, according to 1 ¹H NMR yielded a mixture of 124A:124B regioisomers at a ratio of ~64:36, which could not be separated by silica gel column chromatography and was used without further purification (200 mg). LCMS (Method A) m / z 403.7 [M+H] + At 1.11 min (primary) and 1.16 min (secondary).
[0852] 125A(5R)-2-[2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0853] 125B(5R)-2-[6-fluoro-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-3-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester
[0854]
[0855] Prepared by a method similar to that described for intermediate 123A. Purified by column chromatography (0-6% MeOH in DCM solution), according to... 1 ¹H NMR yielded a mixture of 125A:125B regioisomers at a ratio of ~62:38, which could not be separated by silica gel column chromatography and was used without further purification (118 mg). LCMS (Method A) m / z 403.8 [M+H] + At 1.07 min (primary) and 1.10 min (secondary).
[0856] Example
[0857] 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
[0858]
[0859] 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-benzodiazepines were administered. -2-one (16.1 mg, 0.064 mmol) was added to a solution of intermediate 52A (18 mg, 0.064 mmol) in DMF (1 mL), and the mixture was stirred at rt for 16 h. Water and brine (1:1; 20 mL) were added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The solution was purified by rapid chromatography (100% EtOAc) to give a white solid (27 mg, 82%). 1H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 7.87 (d, J=7.8Hz, 1H), 7.63 (ddd, J=8.6, 6.9, 1.8Hz, 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=7.8Hz, 1H), 4.66 (t, J=5.2Hz, 2H), 4.21 (t, J=6.0Hz, 2H), 2.38-2.31 (m, 2H). LRMS(APCI+)m / z 513.9[M+H] + .
[0860] The amide coupling method described in Example 1 was employed, using (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepines... -2-keto or (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine The following compounds of the present invention were prepared by 2-one.
[0861] Table 20 - Compounds from Examples Prepared by Amide Coupling Method A
[0862]
[0863]
[0864]
[0865] 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-3-carboxamide
[0866]
[0867] DIPEA (63 μL, 0.362 mmol) was added to (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) were mixed in DMF (1.2 mL) and stirred for 3 min. Then, HATU (76 mg, 0.199 mmol) was added, and the reaction mixture was stirred at rt for 16 h. The reaction was quenched with water (10 mL), and the precipitate was collected by filtration and washed with water (3 × 5 mL). The precipitate was dissolved in EtOAc (20 mL), the solvent was removed under reduced pressure, and the precipitate was purified by rapid chromatography (60-100% EtOAc in heptane solution) to give a white solid (70 mg, 71%). 1 HNMR (700MHz, DMSO-d6) δ10.93 (s, 1H), 8.19 (d, J=7.3Hz, 1H), 7.58 (ddd, J =10.0, 8.3, 1.3Hz, 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, 4.9Hz, 1H), 7.22-7.08 (m, 3H), 5.33 (d, J=7.3Hz, 1H ), 4.24 (dq, J=10.1, 6.6Hz, 2H), 2.35-2.23 (m, 2H), 1.58 (d, J=11.6Hz, 6H). LRMS(APCI+) m / z 542.4 [M+H] + .
[0868] The following compounds were prepared by the amide coupling method described for the compounds of Example 5. Additional purification of Example 14 was performed by preparative HPLC (Method 1), with a step gradient of 30-100% aqueous CH3CN (0.2% v / v NH3).
[0869] Table 21 - Compounds from Examples Prepared by Amide Coupling Method B
[0870]
[0871]
[0872]
[0873]
[0874]
[0875] 15.2-[6-(cyclopropylamino)pyridin-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
[0876]
[0877] A solution of intermediate 30C (47 mg, 0.14 mmol) and LiOH (1.0 M aqueous solution; 2.29 mL, 2.29 mmol) in THF:MeOH (1:1; 6 mL) was heated at 50 °C for 24 h. The reaction mixture was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 2, 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 rt for 10 min. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine was added. -2-one (34.1 mg, 0.13 mmol) was reacted with the mixture stirred at rt for 16 h. The mixture was diluted with water and brine (10 mL each) and extracted with EtOAc (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. The solution was purified by rapid chromatography [0-100% (EtOH:CH2Cl2:NH4OH; 50:8:1) CH2Cl2 solution] to give a white solid (27 mg, 34%). 1 H NMR (700MHz, DMSO-d6) δ10.94 (s, 1H), 8.29 (s, 1H), 8.07 (d, J=7.5Hz, 1H), 7.76 (s, 1H), 7.59 (d dd, J=10.3, 8.2, 1.3Hz, 1H), 7.57-7.41 (m, 5H), 7.31 (td, J=8.1, 5.0Hz, 1H), 7.15 (dd, J=8.0, 1. 1Hz, 1H), 6.88 (s, 1H), 6.56 (d, J=8.6Hz, 1H), 5.42 (d, J=7.5Hz, 1H), 4.66-4.59 (m, 2H), 4.17 (t , J=6.2Hz, 2H), 2.37-2.24 (m, 2H), 1.32-1.18 (m, 1H), 0.78-0.57 (m, 2H), 0.42 (d, J=4.2Hz, 2H). LRMS(APCI+)m / z 551.6[M+H] +
[0878] The following compounds were prepared by the amide coupling method described with the compound of Example 15. This method can be modified by replacing DIPEA with NET3.
[0879] Table 22 - Compounds prepared by amide coupling method C.
[0880]
[0881]
[0882]
[0883] 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
[0884]
[0885] 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-benzodiazepines were added. -2-one (55 mg, 0.21 mmol) was added to a solution of intermediate 45B (54 mg, 0.21 mmol) in DMF (1.5 mL), and stirred at 40 °C for 1 h. The reaction was quenched with water, and the resulting precipitate was filtered and washed with water (100 mL). The precipitate was dissolved in CH2Cl2, dried under vacuum, and purified by rapid chromatography (0-5% MeOH in CH2Cl2 solution) to give a white solid (81 mg, 76%). LCMS (Method C) m / z 514.4 [M+H] + At 3.76 min. 1 H NMR (500MHz, DMSO-d6) δ10.93 (s, 1H), 7.89 (d, J=7.7Hz, 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, 1.1Hz, 1H), 7.15-7.10 (m, 2H), 5.37 (d, J=7.7Hz, 1H), 4.68-4.63 (m, 2H), 4.23-4.19 (m, 2H), 2.39-2.31 (m, 2H).
[0886] The following compounds were prepared by the amide coupling method described in Example 21. This method can be carried out at 40°C for ≥1 hour, or overnight at rt.
[0887] Table 23 - Compounds prepared by amide coupling method D.
[0888]
[0889]
[0890]
[0891]
[0892]
[0893]
[0894]
[0895]
[0896]
[0897]
[0898]
[0899] 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
[0900]
[0901] NEt3 (47 μL, 0.34 mmol), HATU (63 mg, 0.17 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepines were added. -2-one (40 mg, 0.16 mmol) was added to a solution of crude intermediate 43A (44 mg, 0.16 mmol) in DMF (1.5 mL), and stirred at 40 °C for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with brine (5 × 20 mL), dried over Na₂SO₄, concentrated under reduced pressure, and purified by rapid chromatography (0-5% MeOH in CH₂Cl₂ solution) to give a white solid (61 mg, 74%). LCMS (Method C) m / z 510.4 [M+H] + At 3.91 min. 1H NMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.05 (d, J=7.6Hz, 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=7.6Hz, 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=6.3Hz, 3H).
[0902] The following compounds were prepared by the amide coupling method described in Example 24.
[0903] Table 24 - Compounds prepared by amide coupling method E.
[0904]
[0905]
[0906] 42.2-(2-fluoro-5-methylpyridin-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
[0907]
[0908] NEt3 (54 μL, 0.39 mmol), HATU (71 mg, 0.19 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepines were added. -2-one (46 mg, 0.19 mmol) was 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 h. Then HATU (71 mg, 0.19 mmol) was added, and the reaction mixture was stirred at rt for one weekend. The reaction was quenched with water, and the precipitate was filtered, dissolved in EtOAc (30 mL), washed with brine (3 × 20 mL), concentrated under reduced pressure, and purified by rapid chromatography (0-5% MeOH in CH2Cl2 solution) to give a white solid (14 mg, 13%). LCMS (Method C) m / z 511.4 [M+H] + At 3.47 min. 1H NMR (500MHz, DMSO-d6) δ10.99 (s, 1H), 8.01-7.99 (m, 1H), 7.89 (d, J=7.8Hz, 1H), 7.71 (dd, J=8.9, 2.4Hz, 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=7.8Hz, 1H), 4.67( t, J=5.3Hz, 2H), 4.22 (t, J=6.1Hz, 2H), 2.42-2.32 (m, 2H), 2.28 (s, 3H).
[0909] 43.2-(2-fluoro-5-methylpyridin-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
[0910]
[0911] Prepared using a method similar to that described in Example 42. LCMS (Method C) m / z 529.4 [M+H] + At 3.51 min. 1 H NMR (500MHz, DMSO-d6) δ10.95 (s, 1H), 8.02-7.99 (m, 1H), 7.91 (d, J=7.7Hz, 1H), 7.71 (dd, J=9.0, 2.5Hz, 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=7.7Hz, 1H), 4 .67 (t, J=5.3Hz, 2H), 4.22 (t, J=6.1Hz, 2H), 2.39-2.32 (m, 2H), 2.28 (s, 3H).
[0912] 44.2-[6-(cyclopropylamino)-2-fluoropyridin-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
[0913]
[0914] NEt3 (84 μL, 0.60 mmol), HATU (110 mg, 0.29 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepines were added. -2-one (72 mg, 0.29 mmol) was 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 h. Then, NEt3 (84 μL, 0.60 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. Then, HATU (110 mg, 0.29 mmol) was added, and the reaction mixture was stirred at rt for a weekend. Post-treatment and purification were performed similarly to those described for the compound of Example 21, yielding a yellow-white solid (89 mg, 54%). LCMS (Method C) m / z 552.4 [M+H] + At 3.72 min. 1 H NMR (500MHz, DMSO-d6) δ10.97 (s, 1H), 7.86 (d, J=7.8Hz, 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=7.8Hz, 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).
[0915] 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
[0916]
[0917] 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-benzodiazepines were administered. -2-one (36 mg, 0.14 mmol) was 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 h. Then, HATU (26 mg, 0.07 mmol) and NET3 (39 μL, 0.28 mmol) were added, and the reaction mixture was stirred at rt overnight. Post-treatment and purification were performed similarly to those described for the compound of Example 1, yielding a white solid (37 mg, 57%). LCMS (Method C) m / z 460.4 [M+H] + At 3.35 min. 1 H NMR (500MHz, DMSO-d6) δ10.95 (s, 1H), 7.86 (d, J=7.7Hz, 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=7.9Hz, 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).
[0918] 48.(5R)-2-(2-methoxypyridin-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
[0919]
[0920] A solution of intermediate 65A (178 mg, 0.56 mmol) and 1.5 M LiOH aqueous solution (1.87 mL, 2.8 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 50 °C. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 7, and the solvent was removed under reduced pressure to give an orange oil (162 mg, quantitative). 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) was reacted and stirred at 40 °C for 1 h. The reaction was quenched with water (15 mL), and the precipitate was separated by filtration and washed with water (100 mL). Purification was performed by column chromatography (0-6% MeOH in CH₂Cl₂ solution) to give a white solid (115 mg, 73%). LCMS (Method C) m / z 541.4 [M+H] + At 3.69 min. 1 H NMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.40 (d, J=7.2H, 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), 7.1 6 (d, J=7.9Hz, 1H), 5.39 (d, J=7.2Hz, 1H), 4.84-4.76 (m, 1H), 4.29-4.15 (m, 2 H), 3.84 (s, 3H), 2.40-2.33 (m, 1H), 2.21-2.07 (m, 1H), 1.56 (d, J=6.3Hz, 3H).
[0921] The following compounds were prepared by the amide coupling method described for the compound of Example 48. This method can be carried out at 40°C for ≥1 hour, or at rt.
[0922] Table 25 - Examples of compounds prepared by amide coupling method F
[0923]
[0924]
[0925]
[0926]
[0927]
[0928]
[0929]
[0930]
[0931]
[0932]
[0933]
[0934]
[0935] The following compounds were prepared by the amide coupling method described for the compound of Example 48, and then purified by HPLC / SFC as shown.
[0936] Table 26 - Examples of compounds prepared by amide coupling method F
[0937]
[0938]
[0939]
[0940] 77.(5R)-5-methyl-2-(6-methylpyridin-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
[0941]
[0942] A solution of intermediate 16C (171 mg, 0.56 mmol) and 1.5 M LiOH aqueous solution (2 mL, 3 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 40 °C. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution (3.2 mL, 3.2 mmol) to pH ≈ 7, 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) was reacted with the mixture at 40 °C for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The solution was purified by column chromatography (0-5% MeOH in CH2Cl2 solution) to give a white solid (140 mg, 45%). LCMS (Method C) m / z 525.4 [M+H] + At 2.10 min. 1H NMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.68 (dd, J=2.3, 0.9Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 7.9 5(dd, J=8.0, 2.3Hz, 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=8.1Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 5.39 (d, J=7.1Hz, 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=6.3Hz, 3H).
[0943] The following compounds were prepared by a method similar to that described for the compound of Example 77. Example 80 was further purified by reversed-phase chromatography [15-50% MeCN (0.1% formic acid) aqueous solution (0.1% formic acid)]. For the preparation of Examples 81, 82, and 83, 6 eq. NEt3 was used in the amide coupling step, and further purification was performed by reversed-phase chromatography [15-50% MeCN (0.1% formic acid) aqueous solution (0.1% formic acid)].
[0944] Table 27 - Examples of compounds prepared by amide coupling method G
[0945]
[0946]
[0947]
[0948] 84.(5R)-2-(1-ethylpyrazol-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
[0949]
[0950] A solution of intermediate 65 J (88 mg, 0.197 mmol) and 1.5 M LiOH aqueous solution (0.657 mL, 0.985 mmol) in MeOH:THF (1:1; 2 mL) was heated overnight at 50 °C. Then, 0.131 mL, 0.197 mmol of 1.5 M LiOH aqueous solution was added, and the reaction mixture was heated overnight at 50 °C. An additional 0.131 mL, 0.197 mmol of 1.5 M LiOH aqueous solution was added, and the reaction mixture was heated overnight at 50 °C. The reaction mixture was neutralized to pH ≈ 7 with 1 M citric acid aqueous solution 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-benzodiazepines. -2-one (53 mg, 0.197 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h, then stirred overnight at rt. NET3 (62 μL, 0.44 mmol) and HATU (80 mg, 0.21 mmol) were then added, and the reaction mixture was stirred at 40 °C for 1 h. Post-treatment and purification were performed similarly to those in Example 48, followed by purification by chiral SFC method 1 [55% EtOH (0.1% NH3)] to give a white solid (59 mg, 56%). LCMS (Method C) m / z (Method C) 528.4 [M+H] + At 3.48 min. 1 H NMR (500MHz, DMSO-d6) δ10.95 (s, 1H), 8.40 (s, 1H), 8.35 (d, J=7.3Hz, 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=7.2Hz, 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=6.2Hz, 3H), 1.34 (t, J=7.2Hz, 3H).
[0951] 85. (5R)-2-[6-(2-hydroxy-2-methylpropyl)pyridin-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
[0952]
[0953] A solution of intermediate 69D (103 mg, 0.29 mmol) and 1.5 M LiOH aqueous solution (0.96 mL, 1.44 mmol) in MeOH:THF (1:1; 4 mL) was heated overnight at 50 °C. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 7, 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) was reacted and stirred overnight at rt. The reaction was quenched with water (15 mL), and the precipitate was separated by filtration and washed with water (100 mL). The separated solid was purified by column chromatography (0-7% MeOH in CH2Cl2 solution), followed by reversed-phase column chromatography [10-40% MeCN (0.1% formic acid) in water (0.1% formic acid)]. The crude residue was dissolved in CH2Cl2 (10 mL), washed with saturated NaHCO3 aqueous solution (5 mL), and passed through a phase separator to remove the solvent under reduced pressure. The residue was dissolved in MeCN (2 mL) and concentrated under reduced pressure (3×) to give an orange solid (15 mg, 9%). LCMS (Method C) m / z 583.5 [M+H] + At 2.28 min. 1 H NMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.72 (d, J = 2.3Hz, 1H), 8.33 (d, J = 7.2Hz, 1H), 7.97 (dd, J=8.1, 2.3Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.42 (m, 5H), 7.34-7.28 (m, 1H), 7.26 (d, J=8.1Hz , 1H), 7.17-7.14(m, 1H), 5.39(d, J=7.2Hz, 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=6.3Hz, 3H), 1.09 (s, 6H).
[0954] 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]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0955]
[0956] A solution of intermediate 90G (58 mg, 0.151 mmol) and 1.5 M LiOH aqueous solution (1.5 mL, 2.25 mmol) in MeOH:THF (1:1; 3 mL) was heated overnight at 50 °C. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 7, 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) was reacted and stirred overnight at 40 °C. The reaction mixture was diluted with MeOH and purified by ion-exchange chromatography (SCX-2, eluting with MeOH, then eluting the product with a ~2N NH3 MeOH solution), followed by column chromatography [0-5% MeOH (0.7N NH3) in CH2Cl2 solution]. Further purification was achieved by reversed-phase column chromatography [15-70% MeCN (0.1% formic acid) in an aqueous solution (0.1% formic acid)], yielding a white solid (7 mg, 8% yield). LCMS (Method C) m / z 608.4 [M+H] + At 2.23 min. 1HNMR (500MHz, DMSO-d6) δ8.37 (d, J=2.5Hz, 1H), 7.80 (dd, J=8.8, 2.4Hz, 1H), 7.53-7.40 (m, 6H), 7.18 (s, 1H), 7.10 (d , J=7.8Hz, 1H), 6.46 (d, J=8.8Hz, 1H), 5.29-5.20 (m, 1H), 4.84 (s, 1H), 4.79-4.75 (m, 1H), 4.64 (d, J=2.4Hz, 1H), 4.2 1-4.13 (m, 2H), 3.76 (dd, J=7.3, 1.5Hz, 1H), 3.63 (d, J=7.3Hz, 1H), 3.45 (dd, J=10.2, 1.6Hz, 1H), 3.22 (d, J=10.0Hz, 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=6.2Hz, 3H).
[0957] 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]hept-5-yl]pyridin-3-yl]-6,7-
[0958] Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0959]
[0960] Prepared by a method similar to that used for the compound in Example 86, wherein HPLC method 2 (15-100% aqueous solution of MeCN containing 0.1% formic acid) was employed, with purification by HPLC instead of reversed-phase column chromatography. LCMS (Method A) m / z 608.6 [M+H] + At 1.00 min. 1H NMR (500MHz, DMSO-d6) δ8.37 (d, J=2.5Hz, 1H), 7.80 (dd, J=8.8, 2.4Hz, 1H), 7.53-7.40 (m, 6H), 7.18 (s, 1H), 7.10 (d, J=7.8Hz, 1H), 6.46 (d, J=8.8Hz, 1H), 5.29-5.20 (m, 1H), 4.84 (s, 1H), 4.79-4.75 (m, 1H), 4.64 (d, J=2.4Hz, 1H), 4.21 -4.13 (m, 2H), 3.76 (dd, J=7.3, 1.5Hz, 1H), 3.63 (d, J=7.3Hz, 1H), 3.45 (dd, J=10.2, 1.6Hz, 1H), 3.22 (d, J=10.0Hz, 1 H), 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=6.2Hz, 3H).
[0961] 88.(5R)-2-[2-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-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
[0962] 89. (5R)-2-[6-fluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-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
[0963]
[0964] A solution of intermediates 124A / 124B (199 mg, 0.50 mmol) and 1.5 M LiOH aqueous solution (1.7 mL, 2.6 mmol) in MeOH:THF (1:1; 4 mL) was heated at 50 °C for 72 h. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 7, 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) was used, and the reaction system was heated at 40 °C for 1 h. The reaction was quenched with water, and the precipitate was separated by filtration and washed with water (100 mL). Purification was performed by column chromatography (0-6% MeOH in CH2Cl2 solution), followed by HPLC method 2 (33-100% MeCN aqueous solution containing 0.1% NH3, 16 min run time) to obtain Example 88 (first elution isomer) and Example 89 (second elution isomer).
[0965] Example 88: White solid (67 mg, 20%). LCMS (Method C) m / z 626.5
[0966] [M+H] + At 3.6 minutes. 1 H NMR (500MHz, DMSO-d6) 10.92 (s, 1H), 8.09 (d, J=7.5Hz, 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, 5.0Hz, 1H), 7.13 (d, J=7.9Hz, 1H), 6.37 (d, J=8.3Hz, 1H), 5.35 (d, J=7.5Hz, 1H), 4.8 4-4.73 (m, 2H), 4.69-4.62 (m, 1H), 4.24-4.10 (m, 2H), 3.78-3.71 (m, 1H), 3.63 (d, J=7.3Hz, 1H), 3.44-3.40 (m , 1H), 3.21 (d, J=10.1Hz, 1H), 2.40-2.30 (m, 1H), 2.20-2.07 (m, 1H), 1.91-1.80 (m, 2H), 1.55 (d, J=6.3Hz, 3H).
[0967] Example 89: White solid (37 mg, 11%). LCMS (Method C) m / z 626.5 [M+H] +3.78 min. 1 H NMR (500MHz, DMSO-d6) 10.92 (s, 1H), 8.04 (d, J=7.4Hz, 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 = 7.9Hz, 1H), 6.24 (dd, J = 7.9, 3.1Hz, 1H), 5.32 (d, J = 7.3Hz, 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=10.3Hz, 1H ), 2.81 (d, J=10.2Hz, 1H), 2.39-2.30 (m, 1H), 2.19-2.07 (m, 1H), 1.75-1.67 (m, 2H), 1.55 (d, J=6.3Hz, 3H).
[0968] 90. (5R)-2-[2-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyridin-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
[0969]
[0970] Intermediates 123A / 123B (212 mg, 0.53 mmol) were prepared by a method similar to that described for compound 88. Purification by HPLC method 3 (25-100% MeCN aqueous solution containing 0.1% NH3) yielded Example 90 (first elution region isomer) as a white solid (71 mg, 22%). LCMS (Method C) m / z 626.5 [M+H] + 3.63 min. 1H NMR (500MHz, DMSO-d6) δ10.91 (s, 1H), 8.11 (d, J=7.5Hz, 1H), 7.60-7.48 (m, 3H), 7.50-7.40 (m, 4H), 7.27 ( s, 1H), 7.12 (d, J = 7.9Hz, 1H), 6.37 (d, J = 8.3Hz, 1H), 5.31 (d, J = 7.1Hz, 1H), 4.79 (d, J = 12.3Hz, 2H), 4.66 (d , J=2.4Hz, 1H), 4.24-4.10 (m, 2H), 3.76 (d, J=7.4Hz, 1H), 3.64 (d, J=7.4Hz, 1H), 3.42 (d, J=10.1Hz, 1H), 3. 21 (d, J=10.1Hz, 1H), 2.35 (d, J=14.4Hz, 1H), 2.20-2.06 (m, 1H), 1.91-1.81 (m, 2H), 1.55 (d, J=6.3Hz, 3H).
[0971] 91.(5R)-2-[2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-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
[0972]
[0973] Intermediates 125A / 125B (118 mg, 0.29 mmol) were prepared by a method similar to that described for the compound of Example 88. Purification by HPLC method 2 (30-100% MeCN aqueous solution containing 0.1% formic acid) yielded Example 91 (first elution region isomer) as a white solid (18 mg, 10%). LCMS (Method C) m / z 626.5 [M+H] + At 3.53 min. 1H NMR (500MHz, DMSO-d6) 10.92 (s, 1H), 8.07 (d, J=7.5Hz, 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, 5.0Hz, 1H), 7.13 (d, J=7.9Hz, 1H), 6 .21 (dd, J=8.1, 1.7Hz, 1H), 5.33 (d, J=7.4Hz, 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=6.3Hz, 3H).
[0974] 92. (5R)-5-methyl-2-[4-methyl-6-(propyl-2-ylamino)pyridin-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
[0975]
[0976] The intermediate 69E (68 mg, 0.15 mmol) and a solution of 1.5 M LiOH aqueous solution (0.51 mL, 0.77 mmol) in MeOH:THF (1:1; 2 mL) were heated at 50 °C for 90 h. Then, 0.51 mL, 0.77 mmol of 1.5 M LiOH aqueous solution was added, and the reaction mixture was heated at 50 °C for 24 h. The reaction mixture was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 2, 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-benzodiazepines were added. -2-one (32 mg, 0.12 mmol) was added, followed by the addition of HATU (48 mg, 0.13 mmol), and the reaction mixture was stirred at rt for 1.5 h. The reaction was quenched with water (2 mL), acidified with AcOH to pH ≈ 4, and purified by ion exchange chromatography (2 g SCX-2 column, washed with water and methanol, then eluted with 7N NH3 in MeOH solution). The fraction containing the product was concentrated under vacuum and purified by column chromatography (0-5% MeOH in CH2Cl2 solution) to give a white solid (19 mg, 22%). LCMS (Method C) m / z 582.6 [M+H] +At 2.38 min. 1 H NMR (500MHz, DMSO-d6) δ10.90 (s, 1H), 8.06 (d, J=7.4Hz, 1H), 7.70 (s, 1H), 7.62-7.54 (m, 1H), 7.5 6-7.50(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=7.8Hz, 1H), 5.33 (d, J=7.3Hz, 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=6.3Hz, 3H), 1.12 (dd, J=6.5, 1.3Hz, 6H).
[0977] 93. (5R)-5-methyl-2-[2-methyl-6-(propyl-2-ylamino)pyridin-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
[0978]
[0979] Prepared by a method similar to that described for the compound of Example 92. LCMS (Method C) m / z 582.5 [M+H] + At 2.38 min. 1 H NMR (500MHz, DMSO-d6) δ10.91 (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, 2 H), 5.33 (d, J=7.3, 1.2Hz, 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, 1.4Hz, 6H).
[0980] 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]hept-5-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide
[0981]
[0982] The intermediate 91B (116 mg, 0.30 mmol) and a solution of 1.5 M LiOH aqueous solution (2.1 mL, 3.0 mmol) in MeOH:THF (1:1; 3 mL) were heated at 50 °C for 64 h. The reaction system was cooled to rt, acidified with 1 M HCl aqueous solution to pH ≈ 2, 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-benzodiazepines were added. -2-one (71 mg, 0.2 mmol) was added, followed by the addition of HATU (81 mg, 0.2 mmol), and the reaction mixture was stirred at rt for 30 min. The reaction mixture was quenched with water (15 mL), and the precipitate was separated by filtration, washed with water (2 × 10 mL), and then purified by column chromatography (0-6% MeOH in CH2Cl2 solution). The aqueous filtrate was acidified to pH ≈ 4 with AcOH, and then purified by ion exchange chromatography (2 g SCX-2 column, washed with water and methanol, and then eluted with 7N NH3 in MeOH solution). The fraction containing the product was concentrated under vacuum and purified by column chromatography (0-5% MeOH in CH2Cl2 solution) to give a yellow-white solid (47 mg, 39%). LCMS (Method C) m / z 608.5 [M+H] + At 2.31 min. 1HNMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.40-8.36 (m, 1H), 8.32 (d, J=7.2Hz, 1H), 7.81 (dd, J=8.8, 2.3Hz, 1H), 7.59 (t, J=9 .2Hz, 1H), 7.55-7.43(m, 5H), 7.36-7.28(m, 1H), 7.16(d, J=7.9Hz, 1H), 6.48(d, J=8.8Hz, 1H), 5.39(d, J=7.2Hz, 1H), 4.85( s, 1H), 4.77 (t, J=7.6Hz, 1H), 4.65 (s, 1H), 4.25-4.14 (m, 2H), 3.80-3.74 (m, 1H), 3.63 (d, J=7.2Hz, 1H), 3.49-3.42 (m, 1H), 3.23 (d, J=10.0Hz, 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=6.3Hz, 3H).
[0983] 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
[0984]
[0985] A solution of intermediate 72A (150 mg, 0.50 mmol) and 1.5 M LiOH aqueous solution (0.33 mL, 0.50 mmol) in MeOH:THF (1:1; 2 mL) was heated at 50 °C for 3 days. LiOH (1.5 M aqueous solution, 0.33 mL, 0.50 mmol) was then added, and the reaction system was heated again for 24 h. The reaction system was cooled to rt, neutralized with 1 M citric acid aqueous solution to pH≈7, and the solvent was removed under reduced pressure to obtain a brown solid (136 mg, quantitative). 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) was reacted and stirred at 40 °C for 1 h. Post-treatment and purification were performed similarly to those in Example 48, yielding a white solid (31 mg, 19%). LCMS (Method C) m / z 525.3 [M+H] + At 4.96 minutes. 1 H NMR (500MHz, DMSO-d6) δ10.98 (s, 1H), 8.80 (s, 1H), 7.89 (d, J=7.4Hz, 1H), 7.6 3-7.57(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=7.3Hz, 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=6.2Hz, 3H).
[0986] The following compounds were prepared by a method similar to that described for the compound of Example 95. Additional purification of Examples 96 and 97 was performed by reversed-phase chromatography [a solution of 35-65% MeCN (0.1% formic acid) in water (0.1% formic acid)].
[0987] Table 28 - Compounds from Examples
[0988]
[0989] The following compounds were prepared by a method similar to that described for the compounds of Example 1. DIPE was used instead of NEt3.
[0990] Table 29 - Compounds prepared by amide coupling method A
[0991]
[0992]
[0993]
[0994] The following compounds were prepared using a method similar to that described for the compounds of Example 5. Additional purification of Example 107 was performed using SFC method 1 (25:75% MeOH / CO2). The filtration process was carried out using a 400 MHz spectrometer in DMSO-d6. 1 H NMR, unless otherwise specified. LRMS was performed using an APCI ion source, unless otherwise specified.
[0995] Table 30 - Compounds prepared by amide coupling method B.
[0996]
[0997]
[0998]
[0999]
[1000]
[1001]
[1002]
[1003]
[1004]
[1005]
[1006]
[1007]
[1008]
[1009]
[1010]
[1011]
[1012]
[1013]
[1014]
[1015] 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
[1016]
[1017] NaOH (5M aqueous solution, 180 μL, 0.89 mmol) was added to a solution of intermediate 97F (42 mg, 0.11 mmol) in EtOH (4 mL), and the mixture was heated overnight at 60 °C. The reaction mixture was cooled to rt, acidified with 1M HCl aqueous solution to pH ≈ 4, and the solvent was removed under reduced pressure. The crude residue was used directly in the next reaction. The residue was suspended in DMF (2 mL), and DIPEA (39 μL, 0.22 mmol) and HATU (47 mg, 0.12 mmol) were added. The reaction mixture was stirred at rt for 10 min. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine was added. -2-one (39 mg, 0.11 mmol) was reacted and stirred at rt for 16 h. The reaction mixture was then subjected to similar post-treatment and purification as described for the compound of Example 15, yielding a white solid (49 mg, 73%). 1 HNMR (400MHz, DMSO-d6) δ10.96 (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 / z 599.8[M+H] + .
[1018] The following compounds were prepared by a method similar to that described for the compound of 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% aqueous solution of CH3CN containing 0.2% v / v formic acid).
[1019] Table 31 - Compounds from Examples
[1020]
[1021]
[1022]
[1023]
[1024]
[1025] 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
[1026]
[1027] Add NaOH (5M aqueous solution, 370 μL, 1.83 mmol) to a solution of intermediate 97H (100 mg, 0.23 mmol) in EtOH (5 mL), and heat overnight at 60 °C. Cool the reaction system to rt, acidify with 1M HCl aqueous solution to pH≈4, remove the solvent under reduced pressure, and use the crude residue directly in the next step. Suspend the residue in DMF (3 mL), add DIPEA (80 μL, 0.46 mmol) and HATU (96 mg, 0.25 mmol), and stir the reaction mixture at rt for 10 min. Add (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine -2-one (62 mg, 0.23 mmol) was reacted and stirred overnight at rt. The reaction was quenched with water (10 mL), and the 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 rapid chromatography [20-60% (EtOH:CH2Cl2:NH4OH; 50:8:1) CH2Cl2 solution] to give a white solid (58 mg, 38%). 1 H NMR (600MHz, DMSO-d6) δ10.93 (d, J=5.0Hz, 1H), 7.87 (dd, J=7.7, 6.3Hz, 1H), 7.62-7.55 (m, 1 H), 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, 2.9Hz, 1H), 4.72 (dt, J=10.1, 4.3Hz, 1H), 4.42 (dd, J=10.7, 7.8Hz, 1H), 4.28 (dd, J=12.2 , 5.3Hz, 1H), 3.99-3.90 (m, 1H), 3.70-3.57 (m, 2H), 2.78 (s, 1H), 1.00 (td, J=7.0, 5.5Hz, 3H). LRMS(APCI+)m / z 660.7[M+H] + .
[1028] The following compounds were prepared by a method similar to that described for the compound of Example 174. Example 185 underwent additional purification by preparative HPLC method 4 [50:50 MeCN:water (0.1% v / v formic acid)].
[1029] Table 32 - Compounds from Examples
[1030]
[1031]
[1032]
[1033]
[1034]
[1035] The following compounds were prepared as single diastereomers by chiral HPLC or SFC resolution, and isolated as single diastereomers with unknown absolute stereochemistry. Examples 188-1, 188-2, 189-1, and 189-2 were prepared by chiral HPLC / SFC resolution using the amide coupling method described for the compound of Example 5. Examples 190-1, 190-2, 191-1, and 191-2 were prepared by chiral HPLC resolution using the amide coupling method described for the compound of Example 21, with a 1-hour exposure time of 5 eq. NET3, and resolution using the chiral HPLC method described. The stereochemical configurations of these compounds are named R* or S*, where any arbitrarily defined stereocenter is indicated by an asterisk. The retention time of each diastereomer resolved under the analytical conditions shown is given by t. R express.
[1036] Table 33 - Resolution of diastereomers
[1037]
[1038] Table 34 - Examples of preparation as a single diastereomer
[1039]
[1040]
[1041]
[1042]
[1043]
[1044]
[1045] 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
[1046]
[1047] NaOH (5M aq. 0.69 mL, 3.45 mmol) was added to a solution of intermediate 97E (150 mg, 0.43 mmol) in EtOH (8 mL). The mixture was heated at 60 °C for 18 h. Upon cooling, the mixture was acidified to pH ≈ 4 with 1M HCl aqueous solution and then concentrated to dryness. The crude residue was dissolved in DMF (9 mL) and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepines was added. -2-one (349 mg, 1.3 mmol) and DIPEA (150 μL, 0.86 mmol) were added, and the reaction mixture was stirred at rt for 5 min. HATU (181 mg, 0.48 mmol) was added, and the reaction mixture was stirred at rt for 22 h. The mixture was filtered and washed with EtOAc (2 × 5 mL). Water (30 mL) was added to the filtrate, and the filtrate was extracted with EtOAc (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. The solution was purified by rapid chromatography [35-80% (50:8:1 CH₂Cl₂:EtOH:NH₄OH) in CH₂Cl₂ solution] to give a white solid (112 mg, 46%). 1 H NMR (400MHz, DMSO-d6) δ7.90 (t, J=7.7Hz, 1H), 7.63-7.22 (m, 10H), 7.22-7.07 (m, 3H), 5.36 (dd, J=7.7, 3.1Hz, 1H), 4.74 (dd, J=10.7, 2.8Hz, 1H), 4.51-4.38 (m, 1H), 4.29 (dd, J=12.4, 4.8Hz, 1H), 4.01 (dd, J=12.4, 6.9Hz, 1H), 2.74-2.54 (m, 5H), 1.04 (t, J=7.1Hz, 4H). LRMS(APCI+)m / z 571.2[M+H] + .
[1048] 193. 2-(2-fluoro-4-methylthiophenyl)-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
[1049] 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
[1050]
[1051] Palladium hydroxide on carbon (20 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 test tube. The vessel was continuously purged with N2 (5×) and hydrogen (5×), and then stirred at 40 psi for 3 h under a hydrogen atmosphere, followed by stirring at 50 °C for 24 h under a hydrogen atmosphere. The reaction system was filtered through a glass microfiber filter and washed with EtOH (3×5 mL) and CH2Cl2 (3×5 mL) to remove the solvent under reduced pressure. EtOH (8 mL) and NaOH (5 M aq. 0.36 mL, 2.9 mmol) were added, and the mixture was heated at 60 °C for 16 h. EtOH was removed under reduced pressure, and the mixture was acidified to pH ≈ 2 with 1 M HCl aqueous solution and extracted with (3:1 CHCl3:iPrOH; 3×10 mL). The combined organic layers were washed with water and brine (10 mL each), dried (Na₂SO₄), and concentrated under reduced pressure. A mixture (89 mg) 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-methylthiophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid was used without further purification.
[1052] The crude mixture (89 mg) was dissolved in DMF (2 mL), and DIPEA (96 μL, 0.55 mmol) and HATU (115 mg, 0.302 mmol) were added. The reaction mixture was stirred at rt for 10 min. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepines were then added. -2-one (74 mg, 0.28 mmol) was reacted and stirred at rt for 16 h. Post-treatment and purification were performed similarly to those described for the compound of Example 5, followed by rapid chromatography [10-70% (50:8:1 CH2Cl2:EtOH:NH4OH) CH2Cl2 solution], initially yielding Example 193 (30 mg), and subsequently Example 194 (33 mg), as white solids.
[1053] Example 193. 1 H NMR (400MHz, DMSO-d6)δ 1 H NMR (400MHz, DMSO-d6) δ10.96 (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, 2.4Hz, 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] + .
[1054] Example 194. 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.92 (dd, J=7.7, 1.7Hz, 1H), 7.65-7.38 (m, 9H), 7.30 (td, J=8.1, 5.1Hz, 1H), 7. 21-7.07 (m, 1H), 5.37 (d, J=7.7Hz, 1H), 4.67 (t, J=5.2Hz, 2H), 4.23 (t, J=6.1Hz, 2H), 2.79 (s, 3H), 2.42-2.27 (m, 2H). LRMS(APCI+)m / z 576.5[M+H] + .
[1055] 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 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
[1056]
[1057] 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 purged with N2 (3×). 1,4-Dioxane (5 mL) and water (2 mL), both degassed with N2, were added, and the reaction mixture was heated at 100 °C for 18 h. The reaction mixture was cooled to rt, and then 1,4-Dioxane was removed under reduced pressure. Similar post-treatment and purification as 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 gel column chromatography and was used without further purification. This mixture was dissolved in EtOH (5 mL), added to NaOH (5 Maq.soln, 0.59 mL, 2.95 mmol), and then heated at 60 °C for 20 h. Similar post-processing to intermediate 34A yielded a crude mixture (180 mg) 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, which was used without further purification. A portion of the crude 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. The reaction mixture was stirred at rt for 10 min. (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine was added. -2-one (74 mg, 0.28 mmol) was reacted and stirred at rt for 72 h. Post-treatment and purification were performed similarly to those described for the compound of Example 5, followed by rapid chromatography (50-70% EtOAc in heptane solution) to first give Example 195 (36 mg), and then Example 196 (58 mg), as white solids.
[1058] Example 195. 1H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 7.93 (d, J=7.5Hz, 1H), 7.65-7.55 (m, 1H), 7.56-7.40 (m, 5H), 7.33 (td, J=8.1 , 5.0Hz, 1H), 7.21-7.12 (m, 1H), 5.43 (d, J=7.5Hz, 1H), 4.67-4.57 (m, 2H), 4.12 (t, J=6.0Hz, 2H), 2.33-2.26 (m, 2H). LRMS(APCI+)m / z 487.2 / 499.2[M+H] + .
[1059] Example 196. 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 7.87 (d, J=7.8Hz, 1H), 7.64-7.37 (m, 7H), 7.29 (td, J=8.1, 5.1Hz, 1 H), 7.14-6.95 (m, 3H), 5.37 (d, J=7.8Hz, 1H), 4.73-4.63 (m, 2H), 4.23 (t, J=6.0Hz, 2H), 2.40-2.33 (m, 2H). LRMS(APCI+)m / z 531.4[M+H] + .
[1060] 200.(5R)-2-[4-(dimethylaminosulfonyl)-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
[1061]
[1062] DIPEA (91 μL, 0.522 mmol) was added to intermediate 103D (100 mg, 0.261 mmol), (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepine 2-one (74 mg, 0.274 mmol) was added to a solution of DMF (3 mL), and the reaction mixture was stirred at rt for 3 min. HATU (109 mg, 0.287 mmol) was added, and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with H2O (15 mL), and EtOAc (10 mL) was added. The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with H2O (10 mL), dried (Na2SO4), and volatiles were removed under reduced pressure. The residue was purified by column chromatography (0–10% MeOH in CH2Cl2 solution). The separated substance was dissolved in CH2Cl2, washed with 1M HCl aqueous solution (10 mL), dried (Na2SO4), and volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2, washed with saturated NaHCO3 and aqueous solution (20 mL), dried (Na2SO4), and volatile substances were removed under reduced pressure to obtain a white solid (116 mg, 70%). 1 H NMR (400MHz, CDCl3) δ8.23 (d, J=8.0Hz, 1H), 8.01 (s, 1H), 7.65 (dd, J=8.0, 6.8Hz, 1H), 7.56 (dd, J=8.0, 1.6Hz, 1H), 7.53-7.49 (m, 2H), 7.46-7.42 (m, 1H), 7.38-7.34 (m, 2H), 7.32-7.2 7 (m, 1H), 7.16-7.09 (m, 2H), 7.75 (d, J=8.0Hz, 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=6.4Hz, 3H). LRMS(ESI+)m / z 635.0[M+H] + .
[1063] The following compounds were prepared by a method similar to that described for the compounds of Example 200.
[1064] Table 35 - Examples
[1065]
[1066]
[1067]
[1068] The following compounds were prepared by a method similar to that described for the compounds of Example 5.
[1069]
[1070]
[1071] Example 203: Salt Preparation
[1072] Preparation of hydrochloride: Method 1
[1073] Add a 4M HCl solution of 1,4-dioxane (3 eq.) to a solution of the compound in 1,4-dioxane (15-30 vol). Stir the mixture for up to 1 h, or until a precipitate forms. Filter the mixture, wash the precipitate with cold (0°C) diethyl ether, and dry under reduced pressure.
[1074] Preparation of hydrochloride: Method 2
[1075] A solution of 1,4-dioxane in 4M HCl (1 eq.) was added to a solution of the compound in THF (30 vol) at 50 °C. The mixture was cooled to rt 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.
[1076] Preparation of other salts: Method 3
[1077] Examples 106·BSA, 106·H2SO4, 106·MSA, and 106·pTSA were prepared by the following method. A 1M acid solution of THF (1.1 eq.) was added to the solution of Example 106 in THF (30 vol) at 50°C, and the mixture was slowly cooled to rt. For Example 106·H2SO4, a solid precipitate was formed, filtered, washed with cold (0°C) diethyl ether, and dried under reduced pressure. For Example 106·BSA, the mixture was concentrated under reduced pressure, and the residue was ground together with EtOAc (3 × 5 mL) and dried under reduced pressure. For Example 106·MSA, EtOAc was added to an acidic solution to obtain a precipitate, which was filtered, washed with cold (0°C) diethyl ether, and dried under reduced pressure. For Example 106·pTSA, EtOAc (~20 mL) was added, the precipitate was collected, washed with EtOAc, and discarded (~2 mg). The filtrate was concentrated to ~5 mL and cooled to 0°C in an ice bath. The mixture was ground together with EtOAc (3×5mL) and dried under reduced pressure.
[1078]
[1079]
[1080] Example 204: In vitro efficacy
[1081] The RSV etch reduction of the compound was determined according to the following protocol.
[1082] Plaque Reduction Measurement
[1083] Hep-G2 cells (ECACC, 85011430) were passaged in flasks and seeded in 24-well plates in DMEM containing antibiotics and supplemented with 10% FBS. Cells were cultured in DMEM containing 2% FBS during seeding and subsequent incubation. 100 plaque-forming units / well of RSV (RSV A2 ECACC, 0709161V) were mixed with eight serial dilutions of the compound. Subsequently, 100 μL of the virus / compound mixture was added to the confluent Hep-G2 cell monolayer. The cells and virus / compound mixture were incubated at 37°C in a humidified 5% CO2 incubator for 2 h, after which the inoculum was removed and a cover layer of 1 mL containing the compound dilution (DMEM containing 2% FBS and 0.8% CMC) was added. Cells were incubated at 37°C in a humidified 5% CO2 incubator for 2 days.
[1084] Wash cells with PBS, then add 75 / 25% v / v EtOH / MeOH and incubate for 3 min. Remove the fixative and wash the plate with PBS. Add the pre-titered primary antibody to 200 μL PBS / 2% milk powder and incubate the plate at 37°C for 90 min. Wash the plate three times with PBS / 0.05% Tween 20, then add rabbit anti-goat horseradish peroxidase in 200 μL PBS / 2% milk powder and incubate at 37°C for 1 h. After three washes with PBS / 0.05% Tween 20, add 200 μL ready-to-use TrueBlue, incubate the plate at room temperature for 10–15 min, then wash with water. After removing the water, air dry the plate in the dark.
[1085] The plate was scanned and analyzed using an Immunospot S6 Macro analyzer equipped with BioSpot analysis software for counting immunostained plaques (viral spots). Plaque counts were used to calculate the % infection relative to the average plaque count in the RSV control wells. EC was then interpolated using suppression curves. 50 The values were calculated as a 50% reduction in signal strength, and the suppression curve was fitted using a 4-parameter nonlinear regression with a variable slope in Dotmatics. Unless otherwise specified, the EC50 value for the etched spots is... 50 and cytotoxic CC 50 The value is the average of at least two experiments, and the number is rounded to the nearest integer.
[1086] result
[1087]
[1088]
[1089]
[1090]
[1091]
[1092]
[1093]
[1094]
[1095]
[1096] Example 205: In vitro pharmacokinetics
[1097] The compound was subjected to the following tests to investigate liver microsomal stability and hepatocyte stability.
[1098] Microsome incubation: Experimental method
[1099] Mixed liver microsomes were purchased from a reputable commercial supplier and stored at -80°C before use. Microsomes (final protein concentration 0.5 mg / ml), 0.1 M phosphate buffer pH 7.4, and the test compound (final substrate concentration 1 μM; final DMSO concentration 0.25%) were pre-incubated at 37°C, followed by the addition of NADPH (final concentration 1 mM) to initiate the reaction. The final incubation volume was 50 μL. A control incubation was included for each test compound, where 0.1 M phosphate buffer pH 7.4 was added instead of NADPH (subtracted NADPH). Two control compounds were included for each species. Each test compound was incubated individually for 0, 5, 15, 30, and 45 min. Each compound was incubated for 45 min only. The control (subtracted NADPH) was incubated for 45 min only. The reaction was terminated by transferring the incubation to acetonitrile at a 1:3 ratio at the appropriate time point. The stop plate was centrifuged at 3,000 rpm for 20 min at 4°C to precipitate the protein. After protein precipitation, the sample supernatant was combined with a cassette containing up to four compounds, an internal standard was added, and the sample was analyzed by LC-MS / MS. The gradient of the line was determined from the In peak area ratio (compound peak area / internal standard peak area) versus time. Subsequently, the half-life (t) was calculated. 1 / 2 ) and inherent clearance rate (CL) int Compounds exhibiting low clearance (residual >80% at 45 min) under the assay conditions are denoted as t. 1 / 2 >140min.
[1100] Hepatocyte incubation: Experimental method
[1101] Cryopreserved mixed hepatocytes were purchased from a reputable commercial supplier and stored in liquid nitrogen before use. Williams E medium supplemented with 2 mM L-glutamine, 25 mM HEPES, and the test compound (final substrate concentration 3 μM; final DMSO concentration 0.25%) was pre-incubated at 37°C, followed by the addition of the cryopreserved hepatocyte suspension (final cell density 0.5 x 10⁻⁶ cells / mL). 6 Live cells / mL, in Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES, were used to initiate the reaction. The final reaction volume was 500 μL. Two control compounds and appropriate media controls were included for each species. The reaction was terminated by transferring 50 μL of incubator to 100 μL of acetonitrile containing the internal standard at appropriate time points. Samples were collected at 6 time points (0, 5, 15, 30, 45, and 60 min) during the 60 min experiment. The stop plate was centrifuged at 2500 rpm for 30 min at 4 °C to precipitate proteins. After protein precipitation, the sample supernatant was combined in a cassette containing up to 4 compounds and analyzed using general LC-MS / MS conditions. The gradient of the line was determined from the In peak area ratio (compound peak area / internal standard peak area) versus time plot. Subsequently, the half-life (t) was calculated. 1 / 2 ) and inherent clearance rate (CL) int Compounds exhibiting low clearance (residual >80% at 60 min) under the assay conditions are denoted as t. 1 / 2 >186min.
[1102] result
[1103]
[1104] Example 206: In vivo pharmacokinetics
[1105] The pharmacokinetics of the compound were studied in rats at doses of 1 mg / kg (IV) and 10 mg / kg (PO).
[1106] Rat pharmacokinetics
[1107] method
[1108] Male rats prepared by jugular vein cannulation [Sprague Dawley (SD)] were treated with the test compound by intravenous (IV; n = 3; 1 mg / kg) or oral (PO; n = 3; 10 mg / kg). The compound was prepared as a solution in 40:60 dimethylacetamide:saline (IV administration) and in water (80%) in 10% DMSO and 10% cremaphore (PO administration). Animals were observed for any obvious clinical signs or symptoms. Serial blood samples were collected via cannulation at 0.02, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after IV administration of the compound and at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration of the compound. Plasma was prepared by centrifugation and immediately stored at -80°C. The samples were then thawed and prepared for analysis by acetonitrile precipitation of proteins, followed by analysis using tandem LCMS with electrospray ionization and matrix-matched calibration curves. PK parameters were calculated from the obtained data.
[1109] result
[1110]
[1111] Example 207: Aqueous Preparation
[1112] The compound of Example 1 was prepared into a 30% w / v Captisol (i.e., sulfobutyl ether-β-cyclodextrin) solution at pH 4 according to the following method.
[1113] A 30% w / v Captisol (i.e., sulfobutyl ether-β-cyclodextrin) carrier was prepared by weighing the required amount of Captisol into a suitable container, adding approximately 80% of the final volume of water, and magnetically stirring until a solution was formed. The carrier was then brought to the final volume with water.
[1114] An aqueous solution of the compound of Example 1 was prepared by weighing 175 mg of the compound into a suitable container and adding approximately 80% of the required volume of carrier. The pH was adjusted to pH 2 using an aqueous hydrochloric acid solution, and the resulting mixture was magnetically stirred until a solution was formed. The volume of the formulation was then made up with the carrier, and the pH was adjusted to pH 4 using an aqueous sodium hydroxide solution.
[1115] Example 208: Tablet Composition
[1116] The tablets are prepared as follows, each weighing 0.15g and containing 25mg of the compound of the present invention:
[1117] Composition of 10,000 pieces
[1118]
[1119] The compound of the present invention, lactose, and half of the corn starch were mixed. The mixture was then pressed through a sieve with a mesh size of 0.5 mm. 10 g of corn starch was suspended in 90 mL of warm water. The resulting paste was used to granulate the powder. The granules were dried and crushed into small fragments on a sieve with a mesh size of 1.4 mm. The remaining starch, talc, and magnesium stearate were added, carefully mixed, and processed into tablets.
[1120] Example 209: Injection
[1121]
[1122] The compound of the present invention is dissolved in most of the water (35°C-40°C), and the pH is adjusted to 4.0 to 7.0 as appropriate with hydrochloric acid or sodium hydroxide. The batch is then made up to volume with water and filtered through a sterile microporous filter into a sterile 10 mL amber glass vial (Type 1), and sealed with a sterile closure and an outer seal.
[1123] Example 210: Intramuscular Injection
[1124]
[1125]
[1126] The compound of the present invention was dissolved in Glycofurol. Then benzyl alcohol was added and dissolved, and water was added to a final volume of 3 mL. The mixture was then filtered through a sterile microporous filter and sealed in a sterile 3 mL glass vial (Type 1).
[1127] Example 211: Syrup
[1128] #imgpt659#
[1129] The compound of the present invention was dissolved in a mixture of glycerol and mostly pure water. Then, an aqueous solution of sodium benzoate was added to the solution, followed by a sorbitol solution, and finally the flavoring agent. The volume was brought up with pure water and thoroughly mixed.
Claims
1. A compound of formula (Ie′), or a pharmaceutically acceptable salt thereof: in: R 1 It is H or halogen; T represents C, V represents N. , and For valence bonds, and , and It does not exist; X does not exist; W is selected from H, C3-C6 cycloalkyl groups, halogens, and -NHR. 9 Benzyl, phenyl, 4- to 10-membered heterocyclic groups and 4- to 10-membered heteroaryl groups, wherein the phenyl, heterocyclic, and heteroaryl groups are unsubstituted or substituted by one or two substituents selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -OR, -(CH2). m OR, -(CH2) m NR2, -NHR′′, -SO m NR2, -SO m R, -SR, nitro, -CO2R, -CN, -CONR2, -NHCOR, -CH2NR 10 R 11 -NR 10 R 11 And unsubstituted or OR-substituted 4- to 10-membered heterocyclic groups, wherein each R is independently H or C1-C6 alkyl, R′′ is C3-C6 cycloalkyl, and m is 1 or 2; R 9 Selected from phenyl and 4- to 10-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by halogens; R 10 and R 11 Each is independently H or C1-C6 alkyl; or R 10 and R 11 Together with the N atoms to which they are attached, they form (a) a morpholine ring, which is optionally bridged by a -CH2- group connecting two cyclic carbon atoms in para position to each other, or (b) a spiro group of formula (b): (b)； Y and Z form a ring of formula (I-1) with the N and C atoms they are connected to: Where Y is selected from O, S, and SO2, and R 2 To R 7 Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, -OR, -CH2OR, -NR2, -CH2NR 12 R 13 -NRCOOR, -SO m NR2, -SO m R, -CH2SO m R, nitro, -CO2R, -CN, -CONR2, or -NHCOR, where R and m are as defined above, and R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atoms they are attached to, they form unsubstituted 4- to 10-membered heteroaryl groups or unsubstituted or C1-C6 alkyl or halogen-substituted 4- to 10-membered heterocyclic groups, or R 2 To R 7 Any two atoms bonded to the same carbon atom can form a spirocycle, which is selected from C3-C6 cycloalkyl spirocycles and spirooxane heterocyclic butane rings with the following structure: 。 2. The compound according to claim 1, wherein W is selected from H, halogens, cyclopropyl, cyclohexyl, and the following structures:
3. The compound according to claim 1, wherein W is selected from... Wherein R and R′′ are as defined in claim 1.
4. The compound according to claim 1, wherein R 2 To R 7 Each of these is independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -CH2OR, -CH2NR 12 R 13 -NRCOOR, -CH2SO m R or halogen, wherein R and m are as defined in claim 1, and R 12 and R 13 Each is independently H, C1-C6 alkyl, benzyl, 4- to 10-membered heterocyclic group, or R. 12 and R 13 Together with the N atoms they are attached to, they form unsubstituted 4- to 10-membered heteroaryl groups or unsubstituted or C1-C6 alkyl or halogen-substituted 4- to 10-membered heterocyclic groups, or R 2 To R 7 Any two atoms bonded to the same carbon atom can form a spirocyclic ring, which is selected from C3-C6 cycloalkyl groups and spirooxane rings with the following structures: #imgpt48#, and R 2 To R 7 The rest are H.
5. The compound according to claim 1, wherein Y in the ring of formula (I-1) is O.
6. Compounds selected from: 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-fluoropyridin-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-(propyl-2-ylamino)pyridin-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-(propyl-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-(propyl-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)pyridin-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-pyridin-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-pyridin-3-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(6-Cyclopropylpyridin-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-(propyl-2-ylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-[6-(ethylamino)pyridin-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-(propyl-2-ylamino)pyridin-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-(propyl-2-ylamino)pyridin-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]thiazine-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]thiazine-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]thiazine-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]thiazine-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; 3-[6-(cyclopropylamino)-2-fluoropyridin-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-fluoropyridin-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-chloropyridin-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-chloropyridin-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-methylpyridin-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-methylpyridin-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-fluoropyridin-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-methoxypyridin-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-methoxypyridin-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)pyridin-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-fluoropyridin-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-fluoro-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)-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-ethylpyrimidin-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-ethylpyrimidin-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-furanyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(3-furanyl)-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-ethylpyrazol-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-(propyl-2-ylamino)pyridin-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-propyl-2-pyridin-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-(trideuterated methylamino)pyridin-3-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-(2-fluoro-6-methylpyridin-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-methylpyridin-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-ethylpyridin-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-fluoropyridin-4-yl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(6-methylpyridin-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)pyridin-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-methylpyridin-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-fluoropyridin-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-ethylpyrazol-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)pyridin-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]hept-5-yl]pyridin-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]hept-5-yl]pyridin-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]hept-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]hept-5-yl]pyridin-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]hept-5-yl]pyridin-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]hept-6-yl)pyridin-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-(propyl-2-ylamino)pyridin-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-(propyl-2-ylamino)pyridin-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]hept-5-yl]pyridin-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-fluoroaniline)-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-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; 2-(1-Ethylpyrazol-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-(morpholin-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-propyl-2-ylpyrazol-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-methyloxetane-3-yl)methyl]pyrazol-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-ethylpyridin-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; 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 ester; 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]tert-butyl 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)pyrazol-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-propyl-2-pyrazol-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-dimethylpyrazol-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-(oxetane-3-yl)pyrazol-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)pyrazol-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)pyrazol-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)pyrazol-4-yl]-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[1-(difluoromethyl)pyrazol-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-dimethylpyrazol-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)pyrazol-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-(pyrazol-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-pyrazole[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-pyrazole[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(6-ethylpyridin-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-Ethylpyrazol-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-ethylpyridin-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-ethylpyridin-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-Fluoropyridin-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-(methyliminosulfonyl)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-methoxyazacyclobutane-1-yl)pyridin-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-methoxypyrrolidone-1-yl]pyridin-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-methoxypyrrolidone-1-yl]pyridin-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-propyl-2-ylpyrazol-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)pyrazol-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)pyrazol-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)pyrazol-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)pyridin-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)pyrazol-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)pyrazol-4-yl]-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5S)-2-(1-ethylpyrazol-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-pyrazol-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-methylsulfonylpiperidin-4-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-5-methyl-2-(1-methylsulfonylpiperidin-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; 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]pyrazol-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-(morpholin-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(oxane-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(oxetane-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-methylpiperazin-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-(morpholin-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-ethylpyridin-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-ethylpyridin-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-(propyl-2-ylamino)pyridin-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-(propyl-2-ylamino)pyridin-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-ethylpyridin-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-ethylpyridin-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-(pyrrolidone-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-[(propyl-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-difluoropyrrolidone-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-(pyrrolidone-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-methylthiophenyl)-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-aminosulfonylphenyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxamide; (5R)-2-[4-(dimethylaminosulfonyl)-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-Ethylsulfonylpiperidin-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 its pharmaceutically acceptable salts.
7. A pharmaceutical composition comprising a compound as defined in any one of claims 1-6 and a pharmaceutically acceptable carrier or diluent.
8. Use of the compound as defined in any one of claims 1-6 in the preparation of a medicament for treating or preventing RSV infection.
9. Products, which include: (a) the compound as defined in any one of claims 1-6; and (b) One or more other therapeutic agents; It is used, either simultaneously, alone, or sequentially, to treat subjects who have or are susceptible to RSV infection.
10. The product according to claim 9, wherein the additional therapeutic agent is: (i) RSV nucleoshell (N) protein inhibitor; (ii) Protein inhibitors; (iii) Anti-RSV monoclonal antibody; (iv) Immunomodulatory Toll-like receptor compounds; (v) Respiratory antiviral drugs; and / or (vi) Anti-inflammatory compounds.
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