Pharmaceutical Compounds

Abstract

Benzodiazepine derivative compounds of formula (I): JPEG2022545249000206.jpg67104 In the formula: R 1 and R 2 each of is independently H or halo; (i) T is N and Z is C; JPEG2022545249000207.jpg1053 is a bond, and JPEG2022545249000208.jpg1054 is absent; or (ii) T is C and Z is N, JPEG2022545249000209.jpg1054 is a bond, and JPEG2022545249000210.jpg1053 does not exist; R 3 and R 4 each of which is independently halo, -OR 6 , -NR 6 R 7 , -COR 8 , -C(O)OR 8 , -CON(R 8 )2 or -R 6 and;R 5 is H or halo; R 6 and R 7 each independently represents H or C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 a group selected from aryl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, which is unsubstituted or substituted; R 8 is H or C1-C6 alkyl, and each R 8 when present at two, are the same or different; n is 0 or 1; and one of V, W, X, and Y is N or CH, and the other three are CH; and pharmaceutically acceptable salts thereof are inhibitors of RSV and therefore can be used to treat or prevent RSV infection.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to benzodiazepine derivatives and their use in the treatment or prevention of respiratory syncytial virus (RSV) infection. [Background technology]

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

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

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

[0005] RSV occurs seasonally; it is highly predictable and occurs in the winter of both hemispheres, occurring 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 by age 2, and natural immunity is short-lived; many are reinfected annually. Like influenza, in the elderly, RSV causes approximately 10% of winter hospitalizations with a 10% mortality rate.

[0006] Current anti-RSV treatments involve the use of a monoclonal antibody against RSV called palivizumab. Such use of palivizumab is a preventative rather than a therapeutic treatment for RSV. While this antibody is often effective, its use is restricted to premature and high-risk infants. Indeed, its limited availability means that anti-RSV treatment is unavailable to many who need it. Therefore, there is an urgent need for effective alternatives to existing anti-RSV treatments.

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

[0008] There is a need to identify additional compounds with anti-RSV activity, particularly compounds that combine potent antiviral activity with favorable pharmacokinetic properties. Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention It has now been discovered that a novel series of benzodiazepine derivatives possess potent anti-RSV activity in combination with favorable pharmacokinetic and physicochemical properties. Accordingly, the present invention provides compounds that are benzodiazepine derivatives of formula (I):

[0010] [ka]

[0011] During the ceremony: R 1 and R 2 each of is independently H or halo; (i) T is N and Z is C;

[0012] [ka]

[0013] is a bond, and

[0014] [ka]

[0015] is absent; or (ii) T is C and Z is N,

[0016] [ka]

[0017] is a bond, and

[0018] [ka]

[0019] is either not present; R 3 and R 4 each of which is independently halo, -OR 6 , -NR 6 R 7 , -COR 8 , -C(O)OR 8 , -CON(R 8 )2 or -R 6 and; R 5 is H or halo; R 6 and R 7 each independently represents H or C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 a group selected from aryl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, the group being unsubstituted or substituted; R 8 is H or C1-C6 alkyl, and each R 8 If there are two, they may be identical or different; n is 0 or 1; and one of V, W, X and Y is N or CH, and the other three are CH; or a pharmaceutically acceptable salt thereof.

[0020] The compounds of the present invention have two N atoms in the five-membered bicyclic heteroaryl ring attached to the benzodiazepine ring system via an amide group, a structural feature believed to be important to the properties of the compounds as discussed further below.

[0021] Detailed Description of the Invention When any group, ring, substituent or moiety defined herein is substituted, it is typically substituted by Q, as defined below.

[0022] C 1-6 The alkyl group or moiety may be straight or branched. 1-6 The alkyl group is typically C 1-4 Alkyl group or C 4-6 It is an alkyl group. 1-6 Examples of alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl (i.e., 3-methylbut-1-yl), t-pentyl (i.e., 2-methylbut-2-yl), neopentyl (i.e., 2,2-dimethylpropan-1-yl), n-hexyl, i-hexyl (i.e., 4-methylpentan-1-yl), t-hexyl (i.e., 3-methylpentan-3-yl), and neopentyl (i.e., 3,3-dimethylbutan-1-yl). For the avoidance of doubt, when two alkyl moieties are present in a group, the alkyl moieties may be the same or different. C 1-6 Alkyl groups are unsubstituted or typically substituted by one or more groups Q as defined below. For example, C 1-6Alkyl groups are unsubstituted or substituted by one, two or three groups Q as defined below.

[0023] Q is halo, nitro, -CN, OH, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, unsubstituted C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 1-4 Haloalkoxy, -CO2R''', -NR'2, -SR', -S(=O)R', -S(=O)2R', C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl or 4- to 10-membered heteroaryl, where each R' is independently H, C 1-6 Alkyl, C3- 10 Cycloalkyl, 4-10-membered heterocyclyl, C6-C 10 It is selected from aryl and 4- to 10-membered heteroaryl.

[0024] C 1-6 The alkoxy group may be linear or branched. It is typically C 1-4 Alkoxy groups, such as methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy groups. 1-6 Alkoxy groups are unsubstituted or typically substituted by one or more groups Q as defined above.

[0025] C 1-6 The alkylthio group may be linear or branched. It is typically C 1-4 Alkylthio groups, such as methylthio, ethylthio, propylthio, i-propylthio, n-propylthio, n-butylthio, sec-butylthio or tert-butylthio groups. 1-6 Alkylthio groups are unsubstituted or typically substituted by one or more groups Q as defined above.

[0026] The halogen or halo group is F, Cl, Br or I. Preferably, it is F or Cl. C substituted by halogen 1-6 The alkyl group is "C 1-6 haloalkyl" which is a C as defined above in which one or more hydrogens are replaced by halo. 1-6 Similarly, C substituted by halogen 1-6 The alkoxy group is "C 1-6 haloalkoxy" which is a C as defined above in which one or more hydrogens are replaced by halo. 1-6 It means an alkoxy group. Typically, C 1-6 Haloalkyl or C 1-6 Haloalkoxy is substituted by 1, 2 or 3 of said halogen atoms. Haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX and -OCX (where X is a halogen), e.g., -CF-CCl-OCF and -OCCl.

[0027] C 1-6 Hydroxyalkyl groups are C as defined above substituted by one or more OH groups. 1-6 It is an alkyl group. Typically, it is substituted by one, two or three OH groups. Preferably, it is substituted by a single OH group.

[0028] C 1-6 The alkoxyalkyl group is a C as defined above. 1-6 C as defined above substituted by an alkoxy group 1-6 It may be, for example, a methoxyalkyl or ethoxyalkyl, where the alkyl moiety is a C as defined above. 1-6 It is an alkyl group.

[0029] C6-C 10An aryl group is an aromatic carbocyclic group containing 6 to 10 carbon atoms. It may be a monocyclic or a fused bicyclic ring system in which an aromatic ring is fused to another aromatic carbocyclic ring. C6-C 10 Examples of aryl groups include phenyl and naphthyl. When substituted, aryl groups are typically substituted by a group Q as defined above, for example by 1, 2 or 3 groups selected from the groups Q as defined above. More particularly, substituted aryl groups, such as substituted phenyl groups, are substituted with C1-C6 alkyl, halo, -OR 8 and -N(R 8 )2, wherein R 8 is H or C1-C6 alkyl, and each R 8 If there are two of these, they are the same or different.

[0030] C 3-10 A cycloalkyl group is a saturated hydrocarbon ring having 3 to 10 carbon atoms. 3-10 The cycloalkyl group can be a C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typically, it is a C3-C6 cycloalkyl, or a C4-C6 cycloalkyl, such as cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, it is cyclobutyl. 3-10 Cycloalkyl groups are unsubstituted or typically substituted by one or more groups Q as defined above.

[0031] A 4- to 10-membered heteroaryl group or moiety is a 4- to 10-membered aromatic heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, and S. It is monocyclic or bicyclic. Typically, it contains one N atom and 0, 1, 2, or 3 additional heteroatoms selected from O, S, and N. It can be, for example, a 5- to 7-membered heteroaryl group, such as a 5- or 6-membered N-containing heteroaryl group. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, and pyrazolyl groups. Furanyl, thienyl, imidazolyl, pyridyl, and pyrimidyl groups are preferred. Alternatively, it can be a bicyclic heteroaryl group, such as an 8- to 10-membered bicyclic heteroaryl group. Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, imidazopyridazinyl, pyrrolopyridinyl, pyrazolopyrimidinyl and pyrrolopyrimidinyl. When substituted, heteroaryl groups (monocyclic or bicyclic) are typically C 1-4 It is substituted by one or more, for example 1, 2 or 3, groups selected from alkyl and a group Q as defined above.

[0032] A 4- to 10-membered heterocyclyl group is a monocyclic or bicyclic non-aromatic saturated or unsaturated ring system containing 5 to 10 carbon atoms and at least one atom or group selected from N, O, S, SO, SO2 and CO, more typically N or O. When the ring system is bicyclic, one ring can be saturated and one ring can be unsaturated. Typically, it is a C ring in which one, two or three of the carbon atoms in the ring are replaced by an atom or group selected from O, S, SO2, CO and NH. 4-10It is a ring system. More typically, it is a monocyclic ring, preferably a monocyclic C4-C6 ring. Examples of 4- to 10-membered heterocyclyl groups include azetidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl, and tetrahydropyranyl, piperidine-2,6-dionyl, and piperidin-2-onyl moieties. In particular, the 4- to 10-membered heterocyclyl group can be azetidinyl, piperidyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0033] When substituted, heterocyclic groups (monocyclic or bicyclic) typically include unsubstituted C 1-4 It is substituted by one or more, for example, 1, 2, or 3 groups selected from alkyl and the group Q defined above. It can also be substituted by a bridgehead connecting two of the ring atoms, typically two ring carbon atoms. For example, a piperazine group or a morpholine group can be substituted by a carbon bridgehead. The resulting bicyclic structure can be a 2,5-diazabicyclo[2.2.1]heptane or a 2-oxa-5-azabicyclo[2.2.1]heptane group, respectively.

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

[0035] In one embodiment of formula (I) as defined above, R 2 is a halo substituent at the 9-position of the benzodiazepinyl ring system, particularly F. An example of such a compound is a compound of formula (I') below:

[0036] [ka]

[0037] R in the formula 1 is H or halo, and R 2 is H or halo, and the remaining groups and variables are as defined above for formula (I). Typically, R 1 is H or F, and R 2 is H or F. For example, R 1 is H or F, and R 2 is F.

[0038] In one embodiment of Formula (I), T is N and Z is C. In such compounds:

[0039] [ka]

[0040] is a bond, while

[0041] [ka]

[0042] Such compounds have the following formula (Ia):

[0043] [ka]

[0044] wherein all groups and variables are as defined above for formula (I) or (I').

[0045] In another embodiment of Formula (I), T is C and Z is N. In such compounds,

[0046] [ka]

[0047] is a bond, and

[0048] [ka]

[0049] Such compounds have the following formula (Ib):

[0050] [ka]

[0051] wherein all groups and variables are as defined above for formula (I) or (I').

[0052] In the above formulas (I), (I'), (Ia) and (Ib), V is typically N, and each of W, X and Y is CH. Examples of such structures include benzodiazepinylimidazopyridazines of formula (Ia') below and benzodiazepinylpyrazolopyrimidines of formula (Ib') below:

[0053] [ka]

[0054] In formulas (Ia') and (Ib'), R 1 ~R 5 and n are as defined above for formula (I) or (I').

[0055] In one embodiment of the compounds of the present invention having any of the structural formulas (I), (I′), (Ia), (Ib), (Ia′) and (Ib′) defined above, R 1 is H or F, and R 2 is F at ring position 9 of the benzodiazepinyl ring system.

[0056] In one embodiment of the compounds of Formula (Ia') and (Ib'), R 1 and R 2 has the definitions and ring positions as defined for formula (I') above. Such compounds include benzodiazepinylimidazopyridazines of formula (Ia''):

[0057] [ka]

[0058] R in the formula 1 ~R 5 and n are as defined above for formula (I'); and a benzodiazepinylpyrazolopyrimidine of formula (Ib''):

[0059] [ka]

[0060] R in the formula 1 ~R 5 and n are as defined above for formula (I').

[0061] In the compounds of the present invention having any of the structural formulae defined above, R 3 is typically C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 A group selected from aryl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, which is unsubstituted or substituted by one or two groups Q as defined above. For example, R as defined above 3 can be unsubstituted or C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 trifluoroalkyl, halo, -OR 8 , -N(R 8 )2, where R 8 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, and each R8 If there are two, they are the same or different, and -N(R 9 )2, where R 9 together form a ring selected from morpholine, piperidine, piperazine and pyrrolidine, which ring may be unsubstituted or substituted by C1-C6 alkyl.

[0062] In the compounds of the present invention having any of the structural formulae defined above, R 3 is typically a group selected from C1-C6 alkyl, C1-C6 haloalkyl (such as C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl), dihydroindole, phenoxy, and phenyl, which group may be unsubstituted or selected from halo, -OR 8 and -N(R 8 )2, wherein R 8 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, and each R 8 If there are two of these, they are the same or different.

[0063] In one embodiment of the above-defined structural formula, R 3 is a group of formula (II):

[0064] [ka]

[0065] where R'' is H, halo, -OR as defined above. 8 or -N(R 8 )2.

[0066] In another embodiment of the above-defined structural formula, R 3is a 4- to 10-membered heteroaryl group selected from pyridyl, pyrrolopyridyl and indazolyl. The 4- to 10-membered heteroaryl group may be unsubstituted or substituted depending on the group Q defined above, for example, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 trifluoroalkyl, halo, -OR 8 , -N(R 8 )2, where R 8 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, and each R 8 If there are two, they are the same or different, and -N(R 9 )2, where R 9 The groups together form a ring selected from morpholine, piperidine, piperazine and pyrrolidine, which ring is unsubstituted or substituted by a C1-C6 alkyl or by a group selected from substituted by a bridgehead carbon atom connecting two ring atoms.

[0067] R 3 Examples of groups include:

[0068] [ka]

[0069] In the compounds of the present invention having any of the structural formulae defined above, R 4 is attached to any available carbon atom in the six-membered ring. Thus, in fact, in the structural formulae (I), (I'), (Ia), (Ib), (Ia') and (Ib') defined above, the group R 4 When present, replaces one H of the ring CH group represented by any of V, W, X and Y. Therefore, only one CR 4 is present, one of V, W, X and Y is N, CH or CR 4 and the other three are CH or CR 4 is.

[0070] In one embodiment of the compounds of the invention having any of the structural formulas defined above, V is N and one of W, X, and Y is CR 4 and the other two are CH. In another embodiment, V is N, Y is CH, and one of W and X is CR 4 and the others are CH.

[0071] In the compounds of the present invention, R 4 is halo, -OR 6 , -NR 6 R 7 , -COR 8 , -C(O)OR 8 , -CON(R 8 )2 and -R 6 where R 6 and R 7 each independently represents H or C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 is a group selected from aryl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, said group being unsubstituted or substituted, and wherein R 8 is H or C1-C6 alkyl, and each R 8 If there are two of these, they are the same or different.

[0072] In one embodiment, R 4 is halo, -OR 6 , -NR 6 R 7 or C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 R is a group selected from aryl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, and the group is unsubstituted or substituted. When substituted, the group is typically substituted by the group Q defined above. 4 -OR 6 , where R 6 is a substituted C1-C6 alkyl, and when R is a substituted C1-C6 alkoxy, 6 is C1-C6 alkoxyalkyl. R4 -OR 6 , where R 6 is C4-C 10 When R is a heterocyclyl group, the heterocyclyl group can be, for example, azetidinyl, unsubstituted or substituted, for example, by C1-C6 alkyl, such as methyl. 4 -OR 6 , where R 6 is a C1-C6 alkyl, where one or more H atoms in the alkyl group can be replaced by D. For example, R 4 can be a group -OCD3.

[0073] Typically, R 4 is halo (e.g. Cl), -OR 6 , -NR 6 R 7 , C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrimidyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each of which is unsubstituted or substituted by a group Q as defined above. 4 When R is substituted, preferred substituents are halo or C1-C6 alkyl. For example, R 4 When R is a substituted C1-C6 alkyl, it can be a mono-, di-, or trihalo-substituted C1-C6 alkyl group, such as a difluoroalkyl or trifluoroalkyl group. 4 When is a substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, the substituent is typically C1-C6 alkyl. Another preferred substituent for piperidinyl, piperazinyl, and morpholinyl is the bridgehead carbon atom connecting two ring atoms.

[0074] Specific compounds of the present invention include: 2-[4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-[4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[4-(propan-2-ylamino)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(1-methyl-2,3-dihydroindol-6-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-Fluoro-4-methoxyphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-Fluoro-4-propan-2-yloxyphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-[2-Fluoro-4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 6-chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-methylimidazo[1,2-b]pyridazine-3-carboxamide; 6-chloro-2-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-(furan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-Fluoro-5-methylphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-Fluoro-5-methylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(5-chloropyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(5-chloropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Cyclopropylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Cyclopropylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(5-Cyclopropylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-5-methylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,4-Difluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-7-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-5-(morpholin-4-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,3-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,3-Difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,6-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-4-pyrrolidin-1-ylphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 6-Methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(2-Methoxyethyl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethoxypyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethyl-2-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethyl-2-methylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-propan-2-ylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-propan-2-ylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[4-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1-methylindazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(3-methylmorpholin-4-yl)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(3-methylmorpholin-4-yl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-Fluoro-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-morpholin-4-ylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-2-Oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(2-hydroxy-2-methylpropyl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-fluoropyridin-2-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-morpholin-4-ylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-morpholin-4-yl-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Methoxy-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methylimidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide 6-(Azetidin-1-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-pyridin-3-ylimidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-2-(2-methylpyridin-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 2-(3-Fluoropyridin-4-yl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3-fluoropyridin-4-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide 2-(5-Fluoropyridin-3-yl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-fluoropyridin-3-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(5-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-2-(6-morpholin-4-ylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(6-morpholin-4-ylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 6-(Ethylamino)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(1-methylazetidin-3-yl)oximidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-(1-methylazetidin-3-yl)oxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(2-methoxyethoxy)imidazo[1,2-b]pyridazine-3-carboxamide 6-Methoxy-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-2-Oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenyl-6-(trideuteriomethoxy)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenyl-6-(trideuteriomethoxy)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide 6-chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide 6-chloro-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-(5-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3-fluoropyridin-4-yl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-(6-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-6-methoxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 6-Ethoxy-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-6-( 2 H3) Methoxyimidazo[1,2-b]pyridazine-3-carboxamide 2-(6-[(3S * )-3-Methylmorpholin-4-yl]pyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-{6-[(3S * )-3-Methylmorpholin-4-yl]pyridin-3-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1H-indazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide and pharmaceutically acceptable salts thereof.

[0075] The compounds of the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms.All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the present invention.Compounds of formula (I) containing one or more chiral centers can be used in enantiomerically or diastereoisomeric pure form, or in the form of a mixture of isomers.

[0076] The present invention includes all geometric and positional isomers of the compounds of the present invention as defined above. For example, if a compound of the present invention incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures thereof, are encompassed within the scope of the present invention. In addition, both single positional isomers and mixtures of positional isomers are within the scope of the present invention.

[0077] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is meant to encompass both the solvated and unsolvated forms.

[0078] The compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol tautomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0079] The compounds of the invention may be prepared by the synthetic methods described in the examples below or by analogy with such methods using appropriate starting materials and methodology well known to the skilled chemist.

[0080] The benzodiazepine derivative of formula (I) can be converted into its pharmaceutically acceptable salt, and the salt can be converted into the free compound by a conventional method. For example, the benzodiazepine derivative of formula (I) can be contacted with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

[0081] Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, or nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides, and organic bases such as alkylamines, aralkylamines, and heterocyclic amines.

[0082] The compounds of the present invention have been found to be inhibitors of respiratory syncytial virus (RSV) in biological tests. They have a combination of potent anti-RSV activity and favorable bioavailability and physicochemical properties. This combination of properties makes the compounds therapeutically useful and superior as drug candidates compared to many of the compounds disclosed in the prior art documents previously discussed.

[0083] Accordingly, the present invention further provides a compound which is a benzodiazepine derivative of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0084] The present invention also provides the compound of the present invention as defined above for use in a method for treating or preventing RSV infection.Furthermore, the present invention provides the use of the compound of the present invention in the manufacture of a medicament for use in treating or preventing RSV infection.Subjects suffering from or susceptible to RSV infection can therefore be treated by a method comprising administering the compound of the present invention as defined above.The condition of the subject can thereby be improved or ameliorated.

[0085] RSV infection is typically a respiratory infection.RSV infection can be infection in children, for example, children under 10 years old or infants under 2 years old.In one embodiment, the present invention provides the compound of the present invention as defined above for use in treating or preventing RSV infection in pediatric patients.Alternatively, infection can be infection in elderly or geriatric patients, for example, adults over 60 years old, adults over 70 years old, or adults over 80 years old.The present invention further provides a compound for use in treating or preventing RSV infection in geriatric patients.

[0086] The RSV infection can be in an immunocompromised individual or an individual suffering from COPD or CHF. In another embodiment, the RSV infection is in an individual who is not immunocompromised, such as an otherwise healthy individual.

[0087] The compounds of the present invention can be administered orally in various dosage forms, such as tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously.The compounds can therefore be administered by injection, infusion, or by inhalation or spray.The compounds are preferably administered orally.

[0088] The dosage depends on various factors, including the patient's age, weight, and condition, as well as the route of administration. The daily dosage can vary within wide limits and is individually adapted to individual needs. However, typically, when the compound is administered alone to an adult human, the dosage adapted for each route ranges from 0.0001 to 650 mg / kg, most commonly 0.001 to 10 mg / kg, of body weight, e.g., 0.01 to 1 mg / kg. Such dosages can be given, for example, 1 to 5 times daily. For intravenous injection, a suitable daily dose is 0.0001 to 1 mg / kg of body weight, preferably 0.0001 to 0.1 mg / kg of body weight. The daily dosage can be administered as a single dose or according to a divided dosing regimen.

[0089] A unit dosage form such as a tablet or capsule usually contains 1-250 mg of active ingredient. For example, the compound of formula (I) can be administered to a human patient at a dose of 100-250 mg once a day, twice a day, or three times a day. For example, the compound of formula (I) can be administered to a human patient at a dose of 100-250 mg once a day, twice a day, or three times a day.

[0090] The compound of formula (I) and its pharmaceutically acceptable salts can be used as they are. Alternatively, they can be administered in the form of pharmaceutical compositions. The present invention therefore also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinabove, together with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0091] Depending on the mode of administration, the pharmaceutical composition preferably contains 0.05-99% w (weight %), more preferably 0.05-80% w, even more preferably 0.10-70% w, and even more preferably 0.10-50% w of the active ingredient, all weight percentages being based on the total composition.

[0092] The present invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0093] The compound of the present invention can be administered in various dosage forms.Therefore, they can be orally administered, for example, as tablets, troches, drops, aqueous or oily suspensions, solutions, dispersible powders or granules.The compound of the present invention can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, by infusion techniques, or by inhalation or spray.The compound can also be administered as a suppository.

[0094] The solid oral form of pharmaceutical composition of the present invention can contain active compound together with diluent such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricant such as silica, talc, stearic acid, magnesium stearate or calcium stearate, and / or polyethylene glycol; binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; anti-agglomerating agent such as starch, alginic acid, alginate or sodium starch glycolate; effervescent mixture; dye; sweetener; wetting agent such as lecithin, polysorbate, lauryl sulfate; and non-toxic and pharmacologically inactive substance generally used in pharmaceutical formulation.Such pharmaceutical preparations can be prepared by known method, for example, by mixing, granulating, tableting, sugar-coating or film-coating process.

[0095] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerine and / or mannitol and / or sorbitol.

[0096] Suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier.Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride.More suitable carriers for suspensions include sterile water, hydroxypropylmethylcellulose (HPMC), polysorbate 80, polyvinylpyrrolidone (PVP), aerosol AOT (i.e., sodium 1,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate), Pluronic F127, and / or Captisol (i.e., sulfobutylether-beta-cyclodextrin).

[0097] The compounds of the present invention may be formulated, for example, as an aqueous suspension in a carrier selected from the following: (i) 0.5% w / v hydroxypropyl methylcellulose (HPMC) / 0.1% w / v polysorbate 80; (ii) 0.67% w / v polyvinylpyrrolidone (PVP) / 0.33% w / v aerosol AOT (sodium 1,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate); (iii) 1% w / v Pluronic F127; and (iv) 0.5% w / v polysorbate 80.

[0098] The carriers can be prepared by standard procedures known to those skilled in the art. For example, each of the carriers (i) to (iv) can be prepared by weighing the required amount of excipient into a suitable container, adding about 80% of the final volume of water, and magnetically stirring until a solution is formed. The carrier is then made up to the specified volume with water. An aqueous suspension of the compound of formula I can be prepared by weighing the required amount of the compound of formula I into a suitable container, adding 100% of the required volume of the carrier, and magnetically stirring.

[0099] Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0100] The compounds of the present invention can also be administered with other compounds used to treat viral infections. Accordingly, the present invention further relates to combination therapies in which a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing a compound of the present invention, is administered simultaneously, sequentially, or as a combined preparation with another therapeutic agent for the treatment or prevention of a viral infection, particularly infection by RSV.

[0101] In this specification, when the term "combination" is used, it should be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0102] Suitable therapeutic agents for use in combination therapy are (i) RSV fusion inhibitors (ii) Other RSV nucleocapsid (N)-protein inhibitors (iii) other RSV protein inhibitors, such as those that inhibit the phosphoprotein (P) protein and the large (L) protein; iv) nucleoside or polymerase inhibitors that inhibit the L protein; (v) anti-RSV monoclonal antibodies, such as F-protein antibodies; (vi) immunomodulatory toll-like receptor compounds; (vii) other respiratory virus antivirals, such as anti-influenza and anti-rhinovirus compounds; and / or (viii) anti-inflammatory compounds; Includes:

[0103] The RSV nucleocapsid (N) protein plays a crucial role in viral transcription and replication, mediating the interaction between the genomic RNA and the virally encoded RNA-dependent RNA polymerase. The RSV P and L proteins are components of the virally encoded RNA-dependent RNA polymerase of RSV.

[0104] According to a further aspect of the present invention, there is provided a compound of formula (I), as defined hereinabove, or a pharmaceutically acceptable salt thereof, in combination with one or more of the therapeutic agents listed above as (i) to (vi), for use in the treatment of RSV.

[0105] The following examples serve to further illustrate the present invention. The preparative examples relate to the preparation of starting materials and intermediates used to prepare the example compounds. None of the examples or preparative examples limit the present invention in any way.

[0106] Example 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. Reactions were performed using anhydrous solvents under a N2 atmosphere unless otherwise noted. All temperatures are in °C. TLC was performed on aluminum-backed silica gel plates (average pore size 60 Å) at 254 nM with a fluorescent indicator. Flash column chromatography was performed on a Biotage Isolera One system using KP-Sil or Ultra silica gel columns, or on an Isco CombiFlash Rf system using FlashPure or RediSep Rf / RediSep Rf Gold silica gel columns. Reverse-phase column chromatography was performed on an Isco CombiFlash Rf system using a Teledyne Isco RediSep Rf C18 reverse-phase column. Ion-exchange chromatography was performed on an Isolute SCX-2 silica-propylsulfonic acid solid-phase extraction cartridge, washed with the appropriate solvent selected from water, MeCN, and MeOH. Elution of basic compounds was performed with NH3 in MeOH (0.7 N or 7 N depending on the substrate).

[0107] Preparative HPLC was performed at ambient column temperature using the following methods: HPLC Method 1: Gemini NX (30 mm × 150 mm, 5 μm) column at 42 mL / min with UV detection at 210 nm; HPLC Method 2: Waters X-Select CSH C18 (30 × 100 mm, 5 μm) column at 50 mL / min with UV detection at 215 nm; HPLC Method 3: Waters X-select CDH C18 (19 × 50 mm, 5 μm) column at 42 mL / min with UV detection across all wavelengths using a photodiode array; and HPLC Method 4: Waters XSelect CSH C18 (30 × 100 mm, 5 μm) column at 42 mL / min with UV detection across all wavelengths using a photodiode array. Preparative chiral HPLC was performed using a ChiralPAK IC (20 × 250 mm; 5 μm) column at 15 mL / min on a Gilson HPLC system (UV detection at 230 nm) at ambient column temperature. Analytical chiral HPLC was performed using a ChiralPAK IC column (2.1 × 150 mm; 3 μm particle size) at 0.4 mL / min flow rate and 10 min run time on an Agilent 1100 HPLC (UV detection at 260 nm) at ambient column temperature. Preparative chiral SFC was performed using a Waters SFC prep 15 (UV detection by DAD at 210-400 nm; flow rate 15 mL / min; column temperature 40 °C; 120 bar backpressure) and a Phenomenex Lux® Cellulose-4 column (1 × 25 cm; 5 μm). Analytical chiral SFC was performed using a Waters SFC ACQUITY UPC column with a 3 min run time. 2 The analysis was performed on a Phenomenex Lux® Cellulose-4 (1 × 25 cm; 5 μm) column with UV detection by DAD at 220–400 nm; flow rate 1.5 mL / min; column temperature 40° C.; 1750 psi back pressure.

[0108] NMR spectra were recorded on 400 or 500 MHz spectrometers at ambient probe temperature (nominal 298 K). Chemical shifts (δ) are given in ppm and are referenced to the residual peak of the solvent (CDCl3, δ) as an internal reference. = 7.26 ppm; DMSO-d6, δ Coupling constants are given in Hertz (Hz). LRMS was performed using an Advion Plate Express expression spectroscopy system equipped with an APCI ion source. L Recorded using a miniature mass spectrometer.

[0109] LCMS analysis was performed using a Waters Acquity UPLC on either a CSH C18 or BEH C18 column (2.1 × 30 mm) at 40 °C at 0.77 mL / min with a linear 5-95% acetonitrile gradient over 3 or 10 min, appropriate for the lipophilicity of the compound. 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 an electrospray ionization (ESI) detector, switching between positive and negative ion modes. Method A: 3 minutes acidic Method B: 3 minutes basic Method C: 10 minutes acidic Method D: 10 min Basic Method E: 1 min Basic Method F: 1 minute acidic

[0110] Preparation Examples (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one were prepared using the methods described in WO / 2004 / 026843, WO / 2005 / 090319, and WO / 2017 / 015449.

[0111] [Table 1]

[0112] Preparation example 1A Ethyl-5-amino-3-bromo-1H-pyrazole-4-carboxylate

[0113] [ka]

[0114] A solution of N-bromosuccinimide (13.77 g, 77.34 mmol) in MeCN (270 mL) was added dropwise over 25 min to a cooled (0 °C) solution of 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (10.00 g, 64.45 mmol) in THF (250 mL). The reaction was allowed to reach rt and stirred overnight. The reaction mixture was adsorbed onto silica gel, volatiles were removed under reduced pressure, and the residue was purified by column chromatography [10-50% (EtOH:CHCl:NHOH; 50:8:1) in CHCl] to give a beige solid, which was triturated with CHCl (~20 mL) to give a white solid (5.93 g, 39%). LRMS (APCI+) m / z 234.1 / 236.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 6.25 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0115] 2A Ethyl 2-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate

[0116] [ka]

[0117] A solution of Intermediate 1A (2.27 g, 9.70 mmol) and 1,1,3,3-tetramethoxypropane (1.93 mL, 11.64 mmol) in AcOH (33.9 mL) was heated at 70 °C for 68 h. After cooling to rt, the volatiles were removed under reduced pressure, the residue was dissolved in EtOAc (50 mL), and neutralized with sat. aq. NaHCO to pH ≈ 7. The mixture was extracted with CHCl (3 × 50 mL), and the combined organics were dried (NaSO) and concentrated in vacuo. The residue was purified by column chromatography (0–3% MeOH in CHCl) to give a beige solid (2.31 g, 88%). LCMS (Method A): m / z 292.0 [M+Na] at 0.93 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 9.24 (dd, J = 7.0, 1.8 Hz, 1H), 8.86 (dd, J = 4.3, 1.8 Hz, 1H), 7.33 (dd, J = 6.9, 4.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0118] 3A Ethyl 2-bromo-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0119] [ka]

[0120] A solution of Intermediate 1A (877 mg, 3.750 mmol) and 4,4-dimethoxybutan-2-one (0.99 mL, 7.490 mmol) in toluene (6.3 mL) was heated at 100° C. for 19 h. The volatiles were removed under reduced pressure, and the residue was purified by column chromatography (30-57% EtOAc in heptane) to give a white solid (539 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 7.1 Hz, 1H), 4.30 (d, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). LRMS (APCI+) m / z240.2 [M-OCH2CH3] +

[0121] 4A Ethyl 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0122] [ka]

[0123] 5-Amino-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.64 g, 9.69 mmol) and AcOH (8.32 mL, 145.41 mmol) were added to a solution of 2-bromomalonaldehyde (1.50 g, 9.94 mmol) in EtOH (19.4 mL) and heated at 75 °C overnight. The volatiles were removed under reduced pressure, CHCl (75 mL) and sat. aq. NaHCO (50 mL) were added, and the aqueous layer was extracted with CHCl (2 × 50 mL). The combined organic extracts were washed with sat. aq. NaHCO and brine (25 mL each), dried (NaSO), and the solvent was removed under reduced pressure. Purification by column chromatography (18–50% EtOAc in heptane) gave a white solid (1.98 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 2.2 Hz, 1H), 8.85 (d, J = 2.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). LRMS (APCI+) m / z238.1 [M-OCH2CH3] +

[0124] 5A 3-Fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0125] [ka]

[0126] Sodium triacetoxyborohydride (268 mg, 1.27 mmol) was added to a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.27 mmol), formaldehyde (0.1 mL, 1.33 mmol), and AcOH (0.11 mL, 1.90 mmol) in CHCl (6 mL) and stirred at rt for 3 h. Additional AcOH (0.11 mL, 1.90 mmol) and sodium triacetoxyborohydride (268 mg, 1.27 mmol) were added, and the reaction was stirred at rt overnight. The reaction mixture was partitioned between CHCl (10 mL) and water (10 mL), separated, and the organic layer was passed through a hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (0-100% (EtOAc in isohexane) to give a yellow solid (100 mg, 28%). LCMS (Method A) m / z 252.2 [M+H] at 1.48 min + (ES+).

[0127] 6A Ethyl 2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0128] [ka]

[0129] A mixture of Intermediate 2A (300 mg, 1.11 mmol), phenylboronic acid (167 mg, 1.37 mmol), and K2CO3 (464 mg, 3.36 mmol) in 1,4-dioxane:water (2:1, 3.0 mL) was degassed with N2 for 5 min. Pd(PPh3)4 (192 mg, 0.170 mmol) was added, and the reaction mixture was further degassed with N2 for 5 min and then heated to 100 °C overnight. The reaction was cooled to rt, diluted with CHCl2 (10 mL), and the organic layer was washed with brine (3 × 10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (0–80% EtOAc in hexanes) to give a yellow solid (111 mg, 36%). LCMS (Method A) m / z 222 [M+H] at 1.13 min + (ES+). 1 H NMR (500 MHz, CDCl3) δ 8.79 (dd, J = 4.2, 1.8 Hz, 1H), 8.75 (dd, J = 6.9, 1.9 Hz, 1H), 7.79-7.75 (m, 2H), 7.49-7.45 (m, 3H), 7.03 (dd, J = 6.9, 4.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0130] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 6A. Preparations 6M and 6N were prepared from the corresponding boronic acid pinacol esters. Preparation 6O was prepared using 2 eq. of (2,3-difluorophenyl)boronic acid.

[0131] [Table 2-1]

[0132] [Table 2-2]

[0133] [Table 2-3]

[0134] [Table 2-4]

[0135] 6P Ethyl 2-(2-fluorophenyl)-5-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0136] [ka]

[0137] A solution of Intermediate 24C (149 mg, 0.386 mmol), 2-fluorophenylboronic acid (141 mg, 1.00 mmol), and K2CO3 (161 mg, 1.162 mmol) in 1,4-dioxane / water (2:1, 1.9 mL) was sparged with N2 for ~5 min. Pd(PPh3)4 (134 mg, 0.116 mmol) was added, and the reaction was heated at 100 °C overnight. The reaction mixture was diluted with CHCl2 (25 mL) and acidified (pH ≈ 4) with AcOH. The mixture was purified by ion exchange chromatography (2 g SCX-2). The resulting solution was concentrated under reduced pressure to give a brown solid (124 mg, 73%). LCMS (Method A) m / z 396.4 [M+H] at 0.74 min. + (ES+). 1H NMR (500 MHz, CDCl3) 8.33 (d, J = 7.6 Hz, 1H), 7.58-7.50 (m, 1H), 7.46-7.38 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 9.1 Hz, 1H), 6.29-6.18 (m, 1H), 4.28-4.18 (m, 2H), 4.04-3.92 (m, 1H), 3.86-3.73 (m, 1H), 3.62-3.50 (m, 1H), 3.21-3.03 (m, 1H), 2.61 (s, 3H), 2.55-2.46 (m, 1H), 2.26-2.12 (m, 1H), 2.05-1.93 (m, 1H), 1.40-1.31 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H).

[0138] 7A Ethyl 2-(2-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0139] [ka]

[0140] Prepared from Intermediate 3A by a procedure similar to that described for Intermediate 6A. 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 7.1 Hz, 1H), 7.60-7.49 (m, 2H), 7.37-7.28 (m, 2H), 7.22 (d, J = 7.1 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H). LRMS (APCI+) m / z 254.3 [M-OCH2CH3] +

[0141] 8A Ethyl 6-(furan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0142] [ka]

[0143] A solution of intermediate 4A (200 mg, 0.70 mmol), furan-3-boronic acid (118 mg, 1.06 mmol), and K2CO-3 (292 mg, 2.11 mmol) in 1,4-dioxane / water (3:1; 3.52 mL) in a microwave reactor vial was degassed with N2 for ∼10 min. Pd(dppf)Cl2 (39 mg, 0.05 mmol) was added, and the sealed vial was heated at 80 °C for 16 h. The reaction was cooled to rt, diluted with EtOAc, and filtered through a pad of Celite® on a glass microfiber filter paper, washing with EtOAc. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (18–70% EtOAc in heptane). The resulting solid was triturated with cold (0° C.) Et 2 O / heptane (1:1) followed by heptane (2×) and dried under vacuum to give a pink solid (85 mg, 45%). 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J = 2.2 Hz, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.45-8.43 (m, 1H), 7.85 (t, J= 1.7 Hz, 1H), 7.19 (dd, J = LRMS (APCI+) m / z 226.2 [M-OCH2CH3] +

[0144] 9A 2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0145] [ka]

[0146] A solution of intermediate 6B (124 mg, 0.320 mmol) and LiOH (1.5 M aq; 0.9 mL, 1.350 mmol) in 1:1 THF / MeOH (4 mL) was stirred at rt overnight. The reaction mixture was diluted with water (20 mL) and washed with EtOAc (2 × 25 mL). The aqueous layer was acidified to pH ≈ 2 by dropwise addition of 1 M HCl (aq) and then extracted with CHCl3 / iPrOH (3:1; 3 × 25 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to give a yellow solid (48 mg, 56%). LCMS (Method A) m / z 280.4 [M+Na] at 0.82 min + . 1 H NMR (500 MHz, DMSO-d6) 12.19 (br s, 1H), 9.29 (dd, J = 6.9, 1.8 Hz, 1H), 8.84 (dd, J = 4.2, 1.8 Hz, 1H), 7.63-7.49 (m, 2H), 7.36-7.26 (m, 2H).

[0147] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 9A.

[0148] [Table 3-1]

[0149] [Table 3-2]

[0150] 9K 6-Methyl-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxylic acid

[0151] [ka]

[0152] Prepared by a procedure similar to that described for Intermediate 9A, using heating at 40° C. LCMS (Method A) m / z 322.7 [M+H] at 1.03 min + . 1 H NMR (500 MHz, DMSO-d6) 13.48 (s, 1H), 9.30 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.62-8.58 (m, 1H), 8.24 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 9.3 Hz, 1H), 2.62 (s, 3H).

[0153] 10A 2-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0154] [ka]

[0155] A mixture of intermediate 9G (250 mg, 1.03 mmol), 2-chlorobenzeneboronic acid (170 mg, 1.08 mmol), and K2CO3 (432 mg, 3.13 mmol) in 1,4-dioxane:water (2:1, 3.0 mL) was degassed with N2 for 5 min. Pd(PPh3)4 (119 mg, 0.100 mmol) was added, and the reaction mixture was further degassed with N2 for 5 min and then heated to 100 °C overnight. The reaction was cooled to rt and concentrated under reduced pressure. NaOH (2 M aq; 30 mL) was added, and the solution was washed with MTBE (3 × 50 mL). The aqueous solution was acidified (pH ≈ 2) with 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a white solid (105 mg, 30%). LCMS (Method A) m / z 255.99 [M-OCH2CH3] at 0.86 min + .

[0156] 11A 2-(2-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0157] [ka]

[0158] A solution of Intermediate 7A (222 mg, 0.740 mmol) and LiOH (1 M aq, 2.23 mL, 2.230 mmol) in THF / MeOH (3:1; 3.7 mL) was heated at 50 °C for 16 h. Volatiles were removed under reduced pressure, and the residue was triturated with EtO, acidified with HCl (1 M; 2.2 mL) and sat. aq. NH4Cl solution (5 mL), and extracted with MeOH / CHCl2 (1:4; 4 × 15 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4), and the solvent was removed under reduced pressure to give a pale yellow solid (151 mg, 75%). 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (br s, 1H), 9.12 (d, J = 7.1 Hz, 1H), 7.57-7.48 (m, 2H), 7.33-7.27 (m, 2H), 7.19 (d, J = 7.1 Hz, 1H), 2.64 (s, 3H). LRMS (APCI+) m / z 272.2 [M+H] + .

[0159] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 11A.

[0160] [Table 4]

[0161] 11D 2-(2-fluorophenyl)-5-morpholin-4-ylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0162] [ka]

[0163] A solution of Intermediate 26D (192 mg, 0.518 mmol) and LiOH (1 M aq, 2.205 mL, 2.205 mmol) in THF / MeOH (3:1; 2.58 mL) was heated at 50 °C for 19 h. Additional LiOH (1 M aq, 1.036 mL, 1.036 mmol) was added and the reaction was heated for 23 h. Workup similar to that described for Intermediate 11A, followed by trituration with EtO, afforded an off-white solid (158 mg, 58%). 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 7.52-7.44 (m, 2H), 7.29-7.21 (m, 2H), 6.91 (d, J = 7.9 Hz, 1H), 3.82-3.66 (m, 8H). LRMS (APCI+) m / z 343.1 [M+H] + .

[0164] 11E 2-(2-fluorophenyl)-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0165] [ka]

[0166] Prepared by a procedure similar to that described for Intermediate 11D. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.75 (d, J = 7.7 Hz, 1H), 7.54-7.44 (m, 2H), 7.32-7.22 (m, 2H), 6.59 (d, J= 7.8 Hz, 1H), 3.68-3.49 (m, 4H), 2.08-1.89 (m, 4H). LRMS (APCI+) m / z327.2 [M+H] + .

[0167] 12A 6-(furan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0168] [ka]

[0169] A solution of ethyl 6-(furan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate Intermediate 6A and LiOH (1 M aq; 0.94 mL, 0.94 mmol) in THF / MeOH (3:1, 4 mL) was heated at 50 °C for 2 h, then at 40 °C for 48 h. Volatiles were removed under reduced pressure, and the crude material was triturated with EtO, then acidified to pH ≈ 2 with HCl (1 M aq, 0.8 mL) and sat. aq. NH4Cl (5 mL), and extracted with EtOAc / EtOH (∼3:1; 3 × 25 mL). The combined organic extracts were washed with brine (5 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was suspended in water, filtered, washed with water, and the resulting precipitate was dried under reduced pressure to give the crude product as a light brown solid (56 mg, 74%). 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 9.48 (d, J = 2.3 Hz, 1H), 9.08 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 7.85 (s, 1H), 7.19 (s, 1H), 2.60 (s, 3H). LRMS (APCI+) m / z244.2 [M+H] + .

[0170] 13A Ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate

[0171] [ka]

[0172] A solution of ethyl (2-fluorobenzoyl)acetate (0.43 mL, 2.38 mmol) in MTBE (1 mL) was added dropwise to a stirred solution of sulfuryl dichloride (0.21 mL, 2.62 mmol) in MTBE (5 mL) at 0 °C, and the reaction was stirred at rt for 2 h. Additional sulfuryl dichloride (0.08 mL, 0.95 mmol) was added, and the reaction was stirred at rt overnight. The reaction was quenched with sat. aq. NaHCO3 solution (60 mL) and EtOAc (60 mL) and stirred for 30 min. The organic layer was separated, washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give a yellow oil (346 mg, 55%). 1 H NMR (500 MHz, CDCl3) δ 7.95 (td, J= 7.6, 1.9 Hz, 1H), 7.65-7.57 (m, 1H), 7.33-7.26 (m, 1H), 7.24-7.14 (m, 1H), 5.63 (s, 1H), 4.30 (q, J = 7.1 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0173] 14A Ethyl-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxylate

[0174] [ka]

[0175] A solution of pyridazin-3-amine (201 mg, 2.110 mmol) and Intermediate 13A (0.27 mL, 2.640 mmol) in EtOH (4 mL) was heated to 100° C. for 2 h via MWI. The reaction mixture was cooled to rt, evaporated in vacuo, and the residue was purified by column chromatography (0-100% EtOAc in isohexane) to give a yellow solid (70 mg, 9%). LCMS (Method A) m / z 286.01 [M+H] at 1.13 min + . 1H NMR (500 MHz, DMSO-d6) δ 8.77 (dd, J = 4.5, 1.7 Hz, 1H), 8.33 (dd, J = 9.3, 1.7 Hz, 1H), 7.69 (td, J = 7.5, 1.8 Hz, 1H), 7.58-7.48 (m, 2H), 7.38-7.29 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H).

[0176] 15A Ethyl 2-(2-fluorophenyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxylate

[0177] [ka]

[0178] Prepared by a procedure similar to that described for Intermediate 14A. LCMS (Method A) m / z 300.14 [M+H] at 1.21 min + . 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 9.3 Hz, 1H), 7.68 (td, J = 7.5, 1.8 Hz, 1H), 7.56-7.48 (m, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.37-7.27 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H).

[0179] 16A 2-(2-fluorophenyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid

[0180] [ka]

[0181] Prepared from Intermediate 15A by a procedure similar to that described for Intermediate 9A, using heating at 40° C. for ∼18 h. LCMS (Method A) m / z 272.04 [M+H] at 0.86 min + . 1 H NMR (500 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.18 (d, J = 9.3 Hz, 1H), 7.65 (td, J = 7.5, 1.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.34-7.25 (m, 2H), 2.60 (s, 3H).

[0182] 17A 3-Bromo-6-ethyl-2-methylpyridine

[0183] [ka]

[0184] Pd(PPh3)4 (576 mg, 0.50 mmol) was added to a cooled (0 °C) solution of 3,6-dibromo-2-methylpyridine (2.5 g, 9.96 mmol) in THF (40 mL) under nitrogen, followed by the dropwise addition of diethylzinc (1 M in hexanes; 11.96 mL, 11.96 mmol). The reaction was stirred at 0 °C for 1 h and then at rt for 16 h. The reaction was quenched with sat. aq. NH4Cl (25 mL), diluted with EtOAc (10 mL), and the separated aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (0–10% EtOAc in isohexane) gave a colorless oil (1.3 g, 62%). LCMS (Method B): m / z 200.1 / 202.1 [M+H] in 1.35 min + . 1H NMR (500 MHz, CDCl3) 7.71 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.66 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H).

[0185] 18A 5-Bromo-6-methyl-N-propan-2-ylpyridin-2-amine

[0186] [ka]

[0187] A solution of isopropylamine (5.09 mL, 59.2 mmol) and 3-bromo-6-fluoro-2-methylpyridine (2.5 g, 13.2 mmol) in DMSO (6 mL) was heated at 120 °C for 12 h via MWI. The reaction was diluted with water (100 mL) and extracted with CHCl (3 × 15 mL). The combined organics were dried (NaSO), and the solvent was removed under reduced pressure. Purification by column chromatography (5-50% EtOAc in isohexane) gave a colorless oil (2.30 g, 76%). LCMS (Method B): m / z 229.1 / 231.1 [M+H] at 1.54 min + . 1 H NMR (500 MHz, CDCl3) 7.48 (d, J = 8.7 Hz, 1H), 6.11 (d, J = 8.7 Hz, 1H), 4.38 (d, J = 7.6 Hz, 1H), 3.80-3.74 (m, 1H), 2.47 (s, 3H), 1.23 (d, J = 6.4 Hz, 6H).

[0188] 18B 5-Bromo-4-methyl-N-propan-2-ylpyridin-2-amine

[0189] [ka]

[0190] Prepared from 5-bromo-2-fluoro-4-methylpyridine (2 g, 10.5 mmol) and isopropylamine (4.52 mL, 52.6 mmol) by a procedure similar to that described for Intermediate 18A. LCMS (Method B): m / z 229.1 / 231.2 [M+H] at 0.45 min + . 1 H NMR (500 MHz, CDCl3) 8.09 (s, 1H), 6.27 (s, 1H), 4.40-4.22 (m, 1H), 3.84 (m, 1H), 2.30 (s, 3H), 1.23 (d, J = 6.4 Hz, 6H).

[0191] 19A 5-Bromo-2-(2-methoxyethyl)pyridine

[0192] [ka]

[0193] NaH (60% in mineral oil, 109 mg, 2.73 mmol) was added to a cooled (-78 °C) solution of 2-(5-bromopyridin-2-yl)ethanol (500 mg, 2.48 mmol) in THF (10 mL) and stirred at -78 °C for 30 min, followed by the addition of MeI (0.17 mL, 2.73 mmol). The reaction mixture was allowed to reach rt and stirred overnight, then quenched with sat. aq. NH4Cl (5 mL). The separated aqueous layer was extracted with CHCl2 (3 × 10 mL), the combined organics were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (0-30% EtOAc in heptane) afforded a colorless oil (401 mg, 68%). LCMS (Method B): m / z 216.5 / 218.5 [M+H] at 1.00 min + . 1H NMR (500 MHz, DMSO-d6) 8.59 (dd, J = 2.5, 0.7 Hz, 1H), 7.94 (dd, J = 8.3, 2.5 Hz, 1H), 7.29 (dd, J = 8.3, 0.7 Hz, 1H), 3.66 (t, J = 6.6 Hz, 2H), 3.22 (s, 3H), 2.93 (t, J = 6.5 Hz, 2H).

[0194] 20A 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol

[0195] [ka]

[0196] Lithium diisopropylamide (2 M in THF / heptane / ethylbenzene, 4.1 mL, 8.20 mmol) was added dropwise to a cooled (−78 °C) solution of 5-bromo-2-methylpyridine (1 g, 5.81 mmol) in THF (10 mL). The solution was stirred at −78 °C for 20 min, and then acetone (5.8 mL, 17.4 mmol) was added dropwise. The reaction was allowed to reach room temperature and stirred for 3 h, then quenched with sat. aq. NH4Cl (40 mL) and extracted with CHCl2 (2 × 50 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by column chromatography (0–20% EtOAc in CHCl2) to give a colorless oil (435 mg, 32%). LCMS (Method B): m / z 214.1 [M-OH] at 0.95 min + . 1 H NMR (500 MHz, CDCl3) δ 8.59 (dd, J= 2.5, 0.8 Hz, 1H), 7.78 (dd, J = 8.3, 2.5 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 2.90 (s, 2H), 1.24 (s, 6H).

[0197] 21A Ethyl 2-bromo-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0198] [ka]

[0199] A solution of Intermediate 1A (963 mg, 4.11 mmol) and 3-ethoxymethacrolein (0.5 mL, 4.22 mmol) in AcOH (11.8 mL) was heated at 75 °C for 24 h. After cooling to rt, the volatiles were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL), and the separated aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed successively with sat. aq. NaHCO3, water, and brine (50 mL each), dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (30-79% EtOAc in heptane) gave a white solid (936 mg, 80%). LRMS (APCI+) m / z 238.0, 240.0 [M-OCH2CH3] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 1.1 Hz, 1H), 8.76 (d, J = 2.2 Hz, 1H), 4.31 (d, J = 7.1 Hz, 2H), 2.36 (d, J= 1.1 Hz, 3H), 1.32 (t, J = 7.1Hz, 3H).

[0200] 22A Ethyl 2-bromo-5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0201] [ka]

[0202] Ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (7.88 g, 30.4 mmol) was added to a suspension of ethyl 3-ethoxyacrylate (6.58 mL, 45.6 mmol) and CsCO (15.1 g, 46.0 mmol) in DMF (120 mL) at rt, and the resulting mixture was heated at 110 °C for 1.5 h. The reaction was cooled to rt and poured into ice-cold water (~500 mL) containing acetic acid (3.48 mL, 60.8 mmol), and the reaction vessel was further rinsed with water (~100 mL). The resulting precipitate was collected by filtration, washed with water, and then dried under reduced pressure to give an off-white solid (8.09 g, 87%). LCMS (Method A): m / z 240.0 / 242.5 [M-OCHCH] at 0.93 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 6.16 (d, J = 7.9 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H).

[0203] 23A Ethyl 2-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate

[0204] [ka]

[0205] A solution of Intermediate 22A (8.09 g, 26.1 mmol) in POCl3 (25 mL, 268 mmol) was refluxed for 3 h. The reaction was cooled to rt, and the volatiles were removed under reduced pressure. The residue was diluted with CHCl2 (~200 mL) and slowly poured into sat. aq. NaHCO3 (300 mL) (CAUTION: exothermic). The resulting exotherm was controlled by adding ice to the mixture. The phases were separated, and the aqueous layer was extracted with CHCl2 (2 x 200 mL). The combined organics were dried (NaSO4), and the solvent was removed under reduced pressure to give a gray solid (7.94 g, 94%). LCMS (Method A): m / z 326.6 / 328.5 [M+Na] at 1.18 min + . 1 H NMR (500 MHz, DMSO-d6) δ 9.27 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0206] 24A Ethyl 2-bromo-5-morpholin-4-ylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0207] [ka]

[0208] A solution of Intermediate 23A (200 mg, 0.657 mmol), morpholine (75 μL, 0.857 mmol), and DIPEA (232 μL, 1.306 mmol) in DMF (3.28 mL) was heated at 60 °C in a sealed tube for 7 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with sat. aq. NH4Cl (3 × 10 mL). The aqueous washes were neutralized with sat. aq. NaHCO3 (~20 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed successively with water (3 × 30 mL) and brine (30 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (35–100% EtOAc in heptane) afforded a white solid (194 mg, 83%). LRMS (APCI+) m / z 354.9 / 356.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 4.19 (t, J = 7.1 Hz, 2H), 3.80-3.67 (m, 8H), 1.29 (t, J= 7.1 Hz, 3H).

[0209] 24B Ethyl 2-bromo-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0210] [ka]

[0211] A solution of Intermediate 23A (300 mg, 0.985 mmol), pyrrolidine (107 μL, 1.286 mmol), and DIPEA (232 μL, 1.306 mmol) in DMF (4.23 mL) was heated in a sealed vial at 60° C. for 65 h. The reaction was cooled to rt and quenched with water. The resulting precipitate was collected by filtration, washed with water, then dissolved in EtOAc and washed with water (2×15 mL) and brine (15 mL), dried (NaSO), and the solvent removed under reduced pressure. Purification by column chromatography (33-70% EtOAc in heptane) gave a white solid (280 mg, 84%). LRMS (APCI+) m / z 339.0 / 341.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 4.19 (q, J= 7.1 Hz, 2H), 3.59 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H), 2.07-1.87 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H).

[0212] 24C Ethyl 2-bromo-5-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0213] [ka]

[0214] A solution of Intermediate 23A (519 mg, 1.551 mmol), (2R,5R)-1,2,5-trimethylpiperazine-1,4-diium dichloride (390 mg, 1.939 mmol), and DIPEA (1 mL, 5.741 mmol) in DMSO (6.5 mL) was heated at 70 °C for 66 h. The reaction mixture was cooled to rt, diluted with brine (25 mL), extracted with EtOAc (3 × 25 mL), and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and purified by ion exchange chromatography (2 g SCX-2). The aqueous fraction was also purified by ion exchange chromatography (2 g SCX-2). The combined solution was concentrated under reduced pressure to give a brown solid (444 mg, 59%). LCMS (Method A) m / z 380.3 / 382.6 [M+Na] at 0.59 min. + . 1 H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 7.7 Hz, 1H), 6.33-6.00 (m, 1H), 5.27-5.10 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.65 (s, 1H), 3.50-3.34 (m, 1H), 3.21-2.76 (m, 2H), 2.61 (s, 1H), 2.49 (s, 3H), 2.15-2.00 (m, 1H), 1.94-1.78 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H).

[0215] 25A Ethyl 2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0216] [ka]

[0217] A reaction vial was charged with ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (700 mg, 2.990 mmol), 4,4-dimethoxybutan-2-one (0.48 mL, 3.590 mmol), 70% ethanol (9.00 mL), and conc. HCl (0.25 mL, 2.99 mmol) and heated to 140 °C for 30 min via MWI. The reaction mixture was poured into sat. aq. NaHCO (100 mL), stirred for 15 min, and the precipitate was collected by filtration and washed with water. The resulting solid was purified by column chromatography (0-20% CHCl:EtOH:NH [50:8:1] in CHCl) to give a white solid (568 mg, 669%). LRMS m / z [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J= 4.4 Hz, 1H), 7.28 (dd, J = 4.4, 1.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.75 (d, J = 0.8 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0218] 26A Ethyl 2-(2-fluorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

[0219] [ka]

[0220] A solution of Intermediate 21A (264 mg, 0.929 mmol), 2-fluorophenylboronic acid (195 mg, 1.394 mmol), and K2CO3 (389 mg, 2.813 mmol) in 1,4-dioxane / water (2:1, 2.79 mL) was sparged with N2 for ~10 min. Pd(PPh3)4 (149 mg, 0.139 mmol) was added, and the reaction was heated at 100 °C for 18 h. The reaction was cooled to rt, diluted with CHCl2, and filtered through a pad of Celite® on a glass microfiber filter, rinsing with CHCl2. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (30-70% EtOAc in heptane) to give a pale yellow solid (222 mg, 80%). LRMS (APCI+) m / z 254.1 [M-OCH2CH3] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J = 2.1, 1.1 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.36-7.29 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.40 (d, J = 1.1 Hz, 3H), 1.11 (t, J= 7.1 Hz, 3H).

[0221] The following intermediates were prepared in an analogous manner to Intermediate 26A.

[0222] [Table 5]

[0223] 27A Ethyl 2-(5-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0224] [ka]

[0225] A reaction vessel was charged with Intermediate 2A (502 mg, 1.86 mmol), (5-chloropyridin-3-yl)boronic acid (583 mg, 3.70 mmol), KPO (621 mg, 2.92 mmol), XPhos (63 mg, 0.133 mmol), and XPhos Pd(crotyl)Cl (Pd-170; 122 mg, 0.180 mmol) and then sparged with N for 5 min. THF (9 mL) and water (3 mL) were added, and the reaction mixture was sparged with N for 5 min and then heated at 65 °C for 3 h. The reaction was cooled to rt, diluted with CHCl (50 mL), and washed with brine (50 mL). The aqueous layer was extracted with CHCl (2 × 50 mL), and the combined organic layers were dried (NaSO), and the solvent was removed under reduced pressure. Purification by column chromatography (0-3.5% MeOH in CH2Cl2) gave a yellow solid (409 mg, 70%). LCMS (Method A) m / z 303.2 [M+H] at 1.06 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.35 (dd, J = 7.0, 1.8 Hz, 1H), 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.32 (t, J = 2.1 Hz, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0226] The following intermediates were prepared in a manner similar to Intermediate 27A: Preparation 27G was prepared from the corresponding boronic acid pinacol ester.

[0227] [Table 6-1]

[0228] [Table 6-2]

[0229] 28A Ethyl 2-(6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0230] [ka]

[0231] XPhos Pd G2 (59 mg, 0.076 mmol) was added to a suspension of Intermediate 2A (170 mg, 0.504 mmol), (6-methoxypyridin-3-yl)boronic acid (154 mg, 1.008 mmol), and CsF (348 mg, 2.266 mmol) in 1,4-dioxane:water (4:1; 5 mL). The reaction mixture was sparged with N2 and then heated at 100 °C overnight. The reaction was cooled to rt, diluted with water and EtOAc (10 mL each), and the separated aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (0–100% EtOAc in hexanes) afforded a yellow solid (149 mg, 99%). LCMS (Method A) m / z 299.3 [M+H] at 1.00 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.30 (dd, J = 6.9, 1.8 Hz, 1H), 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 8.54 (dd, J = 2.4, 0.8 Hz, 1H), 8.07 (dd, J = 8.6, 2.5 Hz, 1H), 7.32 (dd, J = 6.9, 4.2 Hz, 1H), 6.94 (dd, J = 8.6, 0.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0232] The following intermediates were prepared in a manner similar to Intermediate 28A: Preparations 29C and 29D were prepared from the corresponding boronic acid pinacol esters.

[0233] [Table 7]

[0234] 28E Ethyl 2-(2,6-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0235] [ka]

[0236] Prepared by a procedure similar to that described for Intermediate 28A from Intermediate 2A (76 mg, 0.276 mmol) and 2,6-difluorophenylboronic acid (440 mg, 2.786 mmol) using Xphos Pd G2 (57 mg, 0.072 mmol) and CsF (169 mg, 1.272 mmol) in 1,4-dioxane:water (3:1; 4 mL). White solid (74 mg, 0.244 mmol). LCMS (Method A) m / z 283.0 [M+H] at 0.49 min. + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.35 (dd, J = 7.0, 1.7 Hz, 1H), 8.91 (dd, J = 4.2, 1.8 Hz, 1H), 7.68-7.58 (m, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 7.30-7.22 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H).

[0237] 29A Ethyl 2-(2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0238] [ka]

[0239] XPhos Pd G2 (59 mg, 0.076 mmol) was added to a suspension of Intermediate 2A (170 mg, 0.504 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (221 mg, 1.00 mmol), and CsF (347 mg, 2.266 mmol) in 1,4-dioxane:water (4:1; 5 mL), and the reaction mixture was sparged with N2 and heated at 70 °C overnight. The reaction was cooled to rt and re-treated with XPhos Pd G2 (59 mg, 0.076 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (221 mg, 1.01 mmol), and CsF (347 mg, 2.266 mmol), and the reaction was heated to 70 °C overnight. Workup and purification similar to that described for Intermediate 28A gave a yellow solid (75 mg, 53%). LCMS (Method A) m / z 283.0 [M+H] at 0.49 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.32 (dd, J = 7.0, 1.7 Hz, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.56 (d, J = 5.1 Hz, 1H), 7.61-7.57 (m, 1H), 7.52 (dd, J = 5.1, 1.7 Hz, 1H), 7.36 (dd, J = 7.0, 4.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0240] 30A Ethyl 2-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0241] [ka]

[0242] XPhos Pd G2 (198 mg, 0.25 mmol) was added to a suspension of Intermediate 2A (1 g, 3.59 mmol), 2-fluoropyridine-5-boronic acid (607 mg, 4.31 mmol), and K3PO4 (1.53 g, 7.21 mmol) in 1,4-dioxane:water (4:1; 10 mL), and the reaction mixture was sparged with N2 and heated to 100 °C for 4 h. Workup and purification similar to that described for Intermediate 28A afforded a yellow solid (850 mg, 83%). LCMS (Method A) m / z 287.4 [M+H] at 0.96 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.36-9.31 (m, 1H), 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.35 (td, J = 8.2, 2.5 Hz, 1H), 7.39-7.31 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0243] 31A Ethyl 2-(6-ethylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0244] [ka]

[0245] KOAc (633 mg, 6.45 mmol) was added to a suspension of bis(pinacolato)diboron (600 mg, 2.36 mmol) and 5-bromo-2-ethylpyridine (400 mg, 2.15 mmol) in dioxane (3.3 mL). The mixture was sparged with N, Pd(dppf)Cl (118 mg, 0.161 mmol) was added, and the mixture was heated at 100 °C for 1 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and filtered through Celite, washing with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to give a red oil (501 mg), and the residue was carried on directly to the next reaction. A portion of the crude residue (251 mg, 1.08 mmol) was suspended in 1,4-dioxane:water (4:1; 5 mL) and Intermediate 2A (170 mg, 0.504 mmol) and CsF (347 mg, 2.266 mmol) were added, followed by XPhos Pd G2 (59 mg, 0.076 mmol). The reaction was sparged with N2 for 5 min and then heated at 100 °C for 2 h. Workup and purification similar to that described for Intermediate 28A afforded an orange solid (112 mg, 73%). LCMS (Method A) m / z 297.4 [M+H] at 0.66 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.32 (dd, J = 6.9, 1.8 Hz, 1H), 8.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.79 (dd, J = 2.3, 0.9 Hz, 1H), 8.05 (dd, J = 8.0, 2.3 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 6.9, 4.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.83 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).

[0246] The following intermediates were prepared in a similar manner to Intermediate 31A: Preparations 31F and 31G were subjected to additional purification by ion exchange chromatography (SCX-2). The reaction for 31G was heated at 70°C.

[0247] [Table 8-1]

[0248] [Table 8-2]

[0249] 32A Ethyl 2-(5-cyclopropylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0250] [ka]

[0251] Potassium cyclopropyltrifluoroborate (143 mg, 0.964 mmol), K2CO3 (187 mg, 1.353 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos; 29 mg, 0.063 mmol), and Pd(OAc)2 (7.1 mg, 0.031 mmol) were added to a solution of Intermediate 27A (95 mg, 0.313 mmol) in toluene (1.7 mL) and water (0.2 mL) under N2, and the reaction was heated to 130 °C for 2 h by MWI. The reaction mixture was combined with a second batch prepared using 49 mg of 27A (total input 144 mg, 0.476 mmol). The combined reaction mixture was diluted with C2Cl2 (25 mL) and washed with brine (25 mL). The aqueous layer was extracted with CH2Cl2 (2 x 25 mL), the combined organic extracts were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by column chromatography (0-3% MeOH in CH2Cl2) gave an amber oil (104 mg, 71% combined yield). LCMS (Method A) m / z 309.3 [M+H] at 0.80 min + (ES+). 1 H NMR (500 MHz, CDCl3) 8.88-8.83 (m, 1H), 8.83-8.76 (m, 2H), 8.55-8.50 (m, 1H), 7.86-7.81 (m, 1H), 7.10 (dd, J = 7.0, 4.1 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.07-2.01 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.16-1.07 (m, 2H), 0.91-0.80 (m, 2H).

[0252] 33A Ethyl 2-[6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0253] [ka]

[0254] DIPEA (0.18 mL, 1.04 mmol) and isopropylamine (0.36 mL, 4.22 mmol) were added to a solution of Intermediate 30A (240 mg, 0.84 mmol) in DMSO (2 mL) and heated at 100 °C overnight. The reaction mixture was partitioned between EtOAc (10 mL) and sat. aq. NH4Cl (10 mL). The separated aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (0-100% EtOAc in hexanes) afforded a yellow solid (127 mg, 42%). LCMS (Method B): m / z 326.4 [M+H] at 1.06 min. + . 1 H NMR (500 MHz, DMSO-d6) 9.23 (dd, J = 6.9, 1.8 Hz, 1H), 8.78 (dd, J = 4.2, 1.8 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.7, 2.4 Hz, 1H), 7.25 (dd, J = 6.9, 4.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.51 (dd, J = 8.8, 0.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.14-4.02 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.4 Hz, 6H).

[0255] The following intermediates were prepared in a similar manner to Intermediate 33A: For Intermediate 33C the reaction was heated at 50° C. for 3 h.

[0256] [Table 9]

[0257] 34A Ethyl 2-[6-(ethylamino)-2-fluoropyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0258] [ka]

[0259] DIPEA (99 μL, 0.57 mmol) and ethylamine (2 M in THF; 583 μL, 1.12 mmol) were added to a solution of Intermediate 27E (144 mg, 0.47 mmol) in DMSO (2 mL) and heated at 100° C. for 30 min via MWI. Workup similar to that described for Intermediate 33A, followed by purification by column chromatography (0-2% MeOH in CHCl) afforded a yellow solid (84 mg, 52%). LCMS (Method A): m / z 352.3 [M+Na] at 1.09 min + . 1 H NMR (500 MHz, CDCl3) 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.75 (dd, J = 7.0, 1.8 Hz, 1H), 7.84-7.78 (m, 1H), 7.04 (dd, J = 7.0, 4.2 Hz, 1H), 6.37-6.33 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.40 (q, J = 7.2 Hz, 2H), 1.35-1.29 (m, 6H).

[0260] 35A Ethyl 2-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0261] [ka]

[0262] DIPEA (116 μL, 0.67 mmol) and isopropylamine (117 μL, 1.36 mmol) were added to a solution of Intermediate 27E (168 mg, 0.55 mmol) in DMSO (2 mL) and stirred at rt for 4 h, then heated at 40° C. for 1 h. Workup similar to that described for Intermediate 33A, followed by purification by column chromatography (0-3% MeOH in CHCl) afforded a white solid (89 mg, 46%). LCMS (Method A): m / z 344.2 [M+H] at 1.19 min. + . 1 H NMR (500 MHz, DMSO-d6) 9.24 (dd, J = 7.0, 1.7 Hz, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 7.67 (dd, J = 9.9, 8.3 Hz, 1H), 7.27 (dd, J = 6.9, 4.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.43 (dd, J = 8.2, 1.8 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.01-3.90 (m, 1H), 1.22-1.15 (m, 9H).

[0263] 36A Ethyl 2-[6-(3-methylmorpholin-4-yl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0264] [ka]

[0265] A solution of Intermediate 30A (150 mg, 0.49 mmol), 3-methylmorpholine (39 μL mL, 0.50 mmol), and DIPEA (107 μL, 0.62 mmol) in DMSO (2 mL) was heated at 100° C. overnight. Additional 3-methylmorpholine (330 μL, 2.42 mmol) and DIPEA (600 μL, 3.45 mmol) were added, and the mixture was heated at 145° C. overnight. The reaction mixture was cooled to rt, diluted with EtOAc (25 mL), and washed with sat. aq. NaHCO (3×25 mL). The organic layer was dried (NaSO), the solvent was removed under reduced pressure, and the residue was purified by column chromatography (0-4% MeOH in CHCl) to give a brown oil (140 mg, 65%). LCMS (Method A): m / z 368.4 [M+H] at 0.75 min + . 1 H NMR (500 MHz, CDCl3) 8.81-8.77 (m, 1H), 8.77-8.74 (m, 1H), 8.70-8.66 (m, 1H), 8.04-8.00 (m, 1H), 7.07-7.01 (m, 1H), 6.71-6.67 (m, 1H), 4.49-4.41 (m, 3H), 4.10-4.04 (m, 1H), 4.00-3.96 (m, 1H), 3.88-3.79 (m, 2H), 3.72-3.63 (m, 1H), 3.34-3.30 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.34-1.30 (m, 3H).

[0266] 37A Ethyl 2-(1-methylindazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0267] [ka]

[0268] NaH (60% dispersion in mineral oil, 55 mg, 1.38 mmol) was added to a cooled (0 °C) solution of Intermediate 6N (139 mg, 0.45 mmol) in DMF (2 mL), and the reaction was stirred at 0 °C for 30 min. Methyl iodide (34 μL, 0.54 mmol) was added, and the reaction was stirred at rt for 4 h. The reaction was quenched with water (5 mL), diluted with EtOAc (25 mL), and the organic layer was washed with brine (3 × 25 mL), dried (NaSO), and the solvent was removed under reduced pressure. Purification by column chromatography (0-2% MeOH in CHCl) gave a white solid (47 mg, 32%). LCMS (Method A): m / z 322.7 [M+H] at 1.00 min + . 1 H NMR (500 MHz, CDCl3) 8.81-8.73 (m, 2H), 8.20 (dd, J = 1.6, 1.0 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.48 (dt, J = 8.8, 1.0 Hz, 1H), 7.03 (dd, J = 6.9, 4.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0269] 38A Ethyl 2-(2-fluoro-4-pyrrolidin-1-ylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0270] [ka]

[0271] 1,4-Dibromobutane (67 μL, 0.57 mmol) was added to a solution of Intermediate 6M (170 mg, 0.57 mmol), K2CO3 (156 mg, 1.13 mmol), and KI (45 mg, 1.15 mmol) in MeCN (10 mL), and the reaction was heated to 90 °C for ~3 days. Volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc (10 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (0-100% EtOAc in hexanes) afforded an orange solid (120 mg, 49%). LCMS (Method A): m / z 355.1 [M+H] at 1.43 min. + . 1 H NMR (500 MHz, DMSO-d6) 9.24 (dd, J = 6.9, 1.8 Hz, 1H), 8.78 (dd, J = 4.1, 1.8 Hz, 1H), 7.25 (dd, J = 6.9, 4.2 Hz, 1H), 6.45 (dd, J = 8.6, 2.3 Hz, 1H), 6.39 (dd, J = 13.8, 2.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.31-3.25 (m, 4H), 2.02-1.94 (m, 4H), 1.18 (t, J = 7.1 Hz, 3H).

[0272] 39A Ethyl 6-ethylpyridine-3-carboxylate

[0273] [ka]

[0274] EtMgBr (3.0 M solution in EtO; 41 mL, 123 mmol) was added dropwise to a cooled (−75°C) solution of ethyl 6-chloropyridine-3-carboxylate (15.11 g, 81.41 mmol), iron(III) acetylacetonate (2.99 g, 8.30 mmol), and 1-methylpyrrolidin-2-one (11 mL, 114.3 mmol) in THF (400 mL). The mixture was stirred at −75°C for 1 h, then warmed to 0°C and quenched by the dropwise addition of water (250 mL). The resulting mixture was extracted with EtOAc (3 × 250 mL), and the combined organic layers were concentrated under reduced pressure. The residue was diluted with EtOAc (250 mL), washed with brine (3 × 250 mL), dried (NaSO), and the solvent was removed under reduced pressure. Purification by column chromatography (0-15% EtOAc in isohexane) gave a yellow oil (13.45 g, 90%). LCMS (Method A) m / z 180.3 [M+H] at 0.98 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 8.99 (d, J = 2.3 Hz, 1H), 8.19 (dd, J = 8.1, 2.3 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.83 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H).

[0275] 40A 6-Ethylpyridine-3-carboxylic acid

[0276] [ka]

[0277] A solution of Intermediate 39A (13.45 g, 73.30 mmol) and LiOH (9.22 g, 219.67 mmol) in MeOH:THF:water (1:1:1; 23 mL) was stirred at rt overnight. The reaction mixture was acidified (pH ≈ 4-5) by dropwise addition of 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 250 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. The aqueous phase was acidified (pH ≈ 3-4) by dropwise addition of 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 250 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue from the previous organic extraction was combined to give an off-white solid (8.05 g, 71%). LCMS (Method A) m / z 152.4 [M+H] at 0.26 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 13.23 (s, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.1, 2.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 2.83 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

[0278] 41A Ethyl 3-(5-fluoropyridin-2-yl)-3-oxopropanoate

[0279] [ka]

[0280] CDI (1.21 g, 7.44 mmol) was added to a solution of 5-fluoropyridine-2-carboxylic acid (1 g, 7.09 mmol) in THF (10 mL) and refluxed for 1 h. The reaction was cooled to rt, potassium 3-ethoxy-3-oxopropanoic acid (1.33 g, 7.80 mmol) was added, followed by MgCl (0.81 g, 8.50 mmol), and heated to 60 °C overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between saturated aq. NH Cl (50 mL) and EtOAc (50 mL). The separated aqueous was extracted with EtOAc (50 mL), and the combined organics were dried (Na SO ) and concentrated under reduced pressure. Purification by column chromatography (0-50% EtOAc in isohexane) gave a colorless oil (450 mg, 29%). LCMS (Method A) m / z 166.3 [M-OCH2CH3] at 0.88 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 8.73 (d, J = 2.7 Hz, 1H), 8.11 (dd, J = 8.7, 4.7 Hz, 1H), 7.99-7.91 (m, 1H), 4.16-4.00 (m, 4H), 1.14 (t, J = 7.1 Hz, 3H).

[0281] 42A Ethyl 3-(2-methylpyridin-4-yl)-3-oxopropanoate

[0282] [ka]

[0283] Potassium 3-ethoxy-3-oxopropanoic acid (2.05 g, 12.03 mmol) and NEt (4.57 mL, 32.81 mmol) were added to a cooled (0 °C) suspension of MgCl (1.25 g, 13.13 mmol) in MeCN (25 mL) and stirred at rt for 3 h (vial A). In a separate vial, CDI (1.86 g, 11.48 mmol) was added to a suspension of 2-methylpyridine-4-carboxylic acid (1.5 g, 10.94 mmol) in THF:MeCN (1:1; 20 mL) and stirred at 40 °C for 3 h (vial B). After this time, the contents of vial A were added via pipette to vial B, and the combined reaction mixture was stirred at rt for 18 h. The reaction mixture was poured into ice-water (~10 mL), acidified with conc. HCl to pH ≈ 6, and extracted with EtOAc (2 x 15 mL). The organics were washed with brine (50 mL), dried (MgSO4), and concentrated under reduced pressure to give a yellow oil (2.05 g, 90%), which was used without further purification. LCMS (Method F) m / z 208.3 [M+H] at 0.88 min + (ES+).

[0284] The following intermediates were prepared in an analogous manner to Intermediate 42A.

[0285] [Table 10-1]

[0286] [Table 10-2]

[0287] 43A Ethyl 2-chloro-3-oxo-3-phenylpropanoate

[0288] [ka]

[0289] Sulfuryl dichloride (1.47 mL, 18.19 mmol) was added dropwise to a cooled (0 °C) solution of ethyl 3-oxo-3-phenylpropanoate (3 mL, 17.32 mmol) in CHCl (65 mL) and stirred at rt for 3 h. The reaction was partitioned between CHCl (30 mL) and saturated aqueous NaHCO (50 mL). The separated aqueous layer was extracted with CHCl (2 × 20 mL), and the combined organic layers were washed with brine (50 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give a yellow oil (3.93 g, 80%). 1 H NMR (500 MHz, CDCl3) 8.04-8.00 (m, 2H), 7.68-7.63 (m, 1H), 7.55-7.51 (m, 2H), 5.63 (s, 1H), 4.34-4.29 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0290] 43B Ethyl 2-chloro-3-(2,4-difluorophenyl)-3-oxopropanoate

[0291] [ka]

[0292] Prepared by a procedure similar to that described for Intermediate 43A. 1 H NMR (500 MHz, CDCl3) 8.07-8.00 (m, 1H), 7.08-7.03 (m, 1H), 6.96-6.91 (m, 1H), 5.60 (s, 1H), 4.32 (q, J = 7.2, 0.7 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0293] 44A Ethyl 2-bromo-3-oxo-3-pyridin-3-ylpropanoate

[0294] [ka]

[0295] Bromine (111 μL, 2.17 mmol) was added dropwise to a solution of ethyl 3-oxo-3-(3-pyridyl)propionate (400 mg, 2.07 mmol) in CHCl (10 mL) and stirred at rt for 1 h. The reaction was diluted with CHCl (20 mL), washed with aq. NaSO (10% w / v; 50 mL), sat. aq. NaHCO (50 mL), and brine (50 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give an orange oil (501 mg, 62%), which was used without further purification. LCMS (Method A) m / z 272.2 / 274.2 [M+H] at 1.02 min + (ES+). 1 H NMR (500 MHz, CDCl3) 9.23-9.19 (m, 1H), 8.86-8.80 (m, 1H), 8.32-8.28 (m, 1H), 7.47 (ddt, J = 7.3, 4.7, 1.6 Hz, 2H), 5.59 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0296] The following intermediates were prepared in an analogous manner to Intermediate 44A.

[0297] [Table 11]

[0298] 45A Ethyl 2-phenylimidazo[1,2-b]pyridazine-3-carboxylate

[0299] [ka]

[0300] A suspension of crude Intermediate 43A (0.6 g, 1.85 mmol) and pyridazin-3-amine (0.18 g, 1.85 mmol) in EtOH (4 mL) was heated at 150 °C for 12 h by MWI. The reaction mixture was cooled to rt, evaporated under reduced pressure, and the residue was purified by column chromatography (0-100% EtOAc in isohexane) to give a brown solid (147 mg, 29%). LCMS (Method E) m / z 268.3 [M+H] at 0.55 min + (ES+). 1 H NMR (500 MHz, CDCl3) 8.60 (dd, J = 4.5, 1.7 Hz, 1H), 8.07 (dd, J = 9.1, 1.7 Hz, 1H), 7.86-7.79 (m, 2H), 7.52-7.42 (m, 3H), 7.26 (dd, J = 9.1, 4.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0301] The following intermediates were prepared in a manner similar to Intermediate 45A: Preparations 45G-45K were prepared from the corresponding crude 2-bromoketoester using 1.3 eq. of the corresponding pyridazin-3-amine.

[0302] [Table 12-1]

[0303] [Table 12-2]

[0304] [Table 12-3]

[0305] 46A Ethyl 6-methyl-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxylate

[0306] [ka]

[0307] A solution of bromine (186 μL, 3.63 mmol) in CHCl (5 mL) was added dropwise to a cooled (0 °C) solution of Intermediate 42E (2.7 mL, 3.46 mmol) in CHCl (20 mL) and stirred at rt overnight. The reaction was diluted with CHCl (50 mL), washed with sat. aq. NaHCO (100 mL), dried (NaSO), and concentrated under reduced pressure to give an orange oil (918 mg), which was used directly in the next reaction. The residue was dissolved in EtOH (3 mL), 6-methylpyridazin-3-amine (383 mg, 3.51 mmol) was added, and the mixture was heated to 150 °C for 3 h by MWI. The reaction mixture was cooled to rt, evaporated under reduced pressure, and the residue was purified by column chromatography (0-100% EtOAc in isohexane) to give an off-white solid (185 mg, 20%). LCMS (Method A) m / z 351.3 [M+H] at 1.28 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 9.25 (d, J = 2.0 Hz, 1H), 9.08-9.03 (m, 1H), 8.60-8.55 (m, 1H), 8.25 (d, J = 9.3 Hz, 1H), 7.47 (d, J = 9.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0308] The following intermediates were prepared in a similar manner to Intermediate 46A using heating at 140° C. with MWI.

[0309] [Table 13-1]

[0310] [Table 13-2]

[0311] 47A Ethyl 6-methyl-2-(6-morpholin-4-ylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate

[0312] [ka]

[0313] A solution of bromine (720 μL, 14.02 mmol) in CHCl (10 mL) was added dropwise to a cooled (0 °C) solution of Intermediate 42F (3.04 g, 13.35 mmol) in CHCl (40 mL) and stirred at rt for 2 h. The reaction was diluted with CHCl (50 mL), washed with sat. aq. NaHCO (100 mL) and brine (100 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give a yellow oil (4.15 g), which was used directly in the next reaction. The crude residue was dissolved in EtOH (15 mL), 6-methylpyridazin-3-amine (1.11 g, 10.15 mmol) was added, and the mixture was heated to 140 °C for 2.5 h by MWI. The reaction was cooled to rt, evaporated under reduced pressure, and the residue was purified by column chromatography (0-10% MeOH in CHCl) to give a yellow solid (2.24 g), which was used directly in the next reaction. The crude residue (200 mg) was dissolved in DMSO (6 mL) and treated with morpholine (0.07 mL, 0.85 mmol) followed by DIPEA (0.3 mL, 1.70 mmol) and stirred at rt for 18 h. Additional morpholine (0.07 mL, 0.85 mmol) and DIPEA (0.3 mL, 1.70 mmol) were added, and the mixture was stirred at rt for an additional 4 days. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (3 × 20 mL), dried (MgSO), and the solvent was removed under reduced pressure to give a pale yellow solid (230 mg). LCMS (Method F) m / z 368.3 [M+H] at 0.42 min + (ES+). 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 8.8, 2.4 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 3.87 (t, J = 4.9 Hz, 4H), 3.65-3.60 (m, 4H), 2.70 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0314] 48A Ethyl 6-(azetidin-1-yl)-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxylate

[0315] [ka]

[0316] A solution of Intermediate 45D (72 mg, 0.230 mmol), azetidine (50 μL, 0.680 mmol), and DIPEA (240 μL, 1.350 mmol) in DMSO (3 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (50 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give an orange solid (68 mg, 85%), which was used without further purification. LCMS (Method E) m / z 341.4 [M+H] at 0.62 min + (ES+). 1H NMR (500 MHz, CDCl3) 7.77 (d, J = 9.6 Hz, 1H), 7.66 (td, J = 7.4, 1.8 Hz, 1H), 7.44-7.36 (m, 1H), 7.25 (td, J = 7.5, 1.2 Hz, 1H), 7.16-7.10 (m,1H), 6.57 (d, J = 9.6 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.21 (t, J = 7.5 Hz, 4H), 2.55-2.45 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0317] The following intermediates were prepared in an analogous manner to Intermediate 48A.

[0318] [Table 14]

[0319] 48E Ethyl 2-(2-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylate

[0320] [ka]

[0321] Prepared by a procedure similar to that described for Intermediate 48A using Intermediate 45D (162 mg, 0.42 mmol), 1-methylpiperazine (240 μL, 2.15 mmol) and DIPEA (240 μL, 1.35 mmol) in DMSO (5 mL). LCMS (Method B) m / z 384.4 [M+H] at 1.21 min + (ES+). 1H NMR (500 MHz, CDCl3) 7.81 (d, J = 9.9 Hz, 1H), 7.65 (td, J = 7.4, 1.8 Hz, 1H), 7.43-7.38 (m, 1H), 7.25 (td, J = 7.5, 1.1 Hz, 1H), 7.13 (ddd, J = 9.7, 8.3, 1.2 Hz, 1H), 7.01 (d, J = 9.9 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.67 (t, J = 5.1 Hz, 4H), 2.61-2.55 (m, 4H), 2.39 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0322] 49A Ethyl 6-(ethylamino)-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxylate

[0323] [ka]

[0324] A solution of Intermediate 45D (80 mg, 0.21 mmol), ethylamine (70% w / w in water; 68 μL, 0.85 mmol), and DIPEA (296 μL, 1.70 mmol) in DMSO (6 mL) was heated at 100° C. for 18 h. Additional ethylamine (70% w / w in water; 1 mL, 17.97 mmol) was added, and the reaction mixture was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (2×10 mL). The combined organics were washed with brine (20 mL), dried (MgSO), and the solvent removed under reduced pressure to give an orange solid (74 mg, 85%), which was used without further purification. LCMS (Method B) m / z 329.4 [M+H] at 1.30 min + (ES+).

[0325] 50A Ethyl 6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxylate

[0326] [ka]

[0327] A solution of Intermediate 45C (150 mg, 0.5 mmol), (1R,4R)-2-oxa-5-azoniabicyclo[2.2.1]heptane chloride (81 mg, 0.6 mmol), and DIPEA (296 μL, 1.7 mmol) in DMSO (2 mL) was heated at 100° C. overnight. The reaction mixture was cooled to rt, treated with additional (1R,4R)-2-oxa-5-azoniabicyclo[2.2.1]heptane chloride (40 mg, 0.3 mmol) and DIPEA (113 μL, 0.646 mmol), and heated to 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (3×40 mL), passed through a phase separation cartridge, and concentrated under reduced pressure. Purification by column chromatography (0-100% EtOAc in isohexane) gave an off-white solid (86 mg, 46%). LCMS (Method A) m / z 365.3 [M+H] at 1.22 min + (ES+). 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J= 9.8 Hz, 1H), 7.76 (d, J = 7.3 Hz, 2H), 7.47-7.40 (m, 2H), 7.40-7.35 (m, 1H), 7.14 (d, J = 9.8 Hz, 1H), 4.89 (s, 1H), 4.71 (s, 1H), 4.30 (q, J= 7.1 Hz, 2H), 3.81 (d, J = 7.5 Hz, 1H), 3.75 (d, J = 7.5 Hz, 1H), 3.54 (d, J = 10.2 Hz, 1H), 3.40 (d, J = 10.2 Hz, 1H), 1.98 (d, J = 9.9 Hz, 1H), 1.92 (d, J = 9.9 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H).

[0328] 51A Ethyl 6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxylate

[0329] [ka]

[0330] A solution of Intermediate 45C (175 mg, 0.58 mmol), (2S,5S)-1,2,5-trimethylpiperazine-1,4-diium dibromide (204 mg, 0.70 mmol), and DIPEA (0.61 mL, 3.48 mmol) in DMSO (2 mL) was heated at 70° C. overnight. The reaction mixture was cooled to rt, treated with additional (1R,4R)-2-oxa-5-azoniabicyclo[2.2.1]heptane chloride (200 mg, 0.690 mmol) and DIPEA (0.61 mL, 3.480 mmol), and heated to 70° C. over the weekend. The reaction mixture was cooled to rt, diluted with brine (10 mL), and extracted with EtOAc (4×10 mL). The combined organic extracts were washed with brine (10 mL), passed through a phase separation cartridge, and concentrated under reduced pressure to give an off-white solid (143 mg, 65%). LCMS (Method A) m / z 378.4 [M+H] at 0.74 min + (ES+). 1 H NMR (500 MHz, DMSO-d6) 7.95 (d, J = 9.8 Hz, 1H), 7.79-7.73 (m, 2H), 7.46-7.41 (m, 2H), 7.41-7.35 (m, 1H), 7.10 (d, J = 9.8 Hz, 1H), 4.65 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 5.2 Hz, 1H), 3.62-3.57 (m, 1H), 3.38 (d, J = 10.1 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 2.87 (d, J = 9.6 Hz, 1H), 2.33 (s, 2H), 1.95-1.92 (m, 1H), 1.85-1.79 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H).

[0331] 52A 2-(2-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0332] [ka]

[0333] A solution of Intermediate 26B (190 mg, 0.635 mmol) and 5 M aq. NaOH (0.635 mL, 3.174 mmol) in EtOH / water (3:1, 4 mL) was heated at 75 °C for 1 h. The reaction was cooled to rt, and the EtOH was removed under reduced pressure. The residual aqueous solution was diluted with water (5 mL) and acidified (pH ≈ 1) with 1 M HCl (aq). The resulting precipitate was collected by filtration and purified by column chromatography (0-10% EtOH in EtOAc) to give a pale yellow solid (128 mg, 74%). LRMS (APCI+) m / z 272.3 [M+H] +

[0334] 53A 2-(2,3-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0335] [ka]

[0336] A solution of intermediate 6O (129 mg, 0.425 mmol) and LiOH (1.5 M aq; 2.83 mL, 4.25 mmol) in THF / MeOH (1:1; 4 mL) was stirred at 40 °C overnight. The reaction was cooled to rt and washed with MTBE (3 × 10 mL). The aqueous layer was acidified (pH ≈ 1) with 1 M HCl (aq) and then extracted with CHCl3 / iPrOH (3:1; 3 × 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give an orange solid (135 mg, 97%), which was used without further purification. LCMS (Method A) m / z 258.7 [M-OCH2CH3] at 0.89 min + . 1H NMR (500 MHz, DMSO-d6) 12.39 (s, 1H), 9.31 (dd, J = 7.0, 1.8 Hz, 1H), 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 7.63-7.53 (m, 1H), 7.43-7.36 (m, 1H), 7.37-7.29 (m, 2H).

[0337] The following intermediate compounds were prepared by procedures similar to those described for Intermediate 53A.

[0338] [Table 15]

[0339] 54A 2-(2-fluoro-5-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0340] [ka]

[0341] A solution of intermediate 27F (334 mg, 0.855 mmol) and LiOH (1.5 M aq; 2 mL, 3 mmol) in THF (9 mL) was heated at 40 °C overnight. Additional LiOH (1.5 M aq; 2 mL, 3 mmol) and MeOH (2 mL) were added, and the reaction was heated at 60 °C for 2 h. The reaction mixture was cooled to rt, diluted with water (20 mL), and washed with MTBE (2 × 25 mL). The aqueous layer was acidified (pH ≈ 4) by dropwise addition of 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 25 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed under reduced pressure to give an orange solid (200 mg, 70%). LCMS (Method A) m / z 273.6 [M+H] at 0.74 min + . 1H NMR (500 MHz, CDCl3) 12.27 (s, 1H), 9.30 (dd, J = 7.0, 1.7 Hz, 1H), 8.85 (dd, J = 4.1, 1.8 Hz, 1H), 8.18-8.14 (m, 1H), 7.98-7.92 (m, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 2.37 (s, 3H).

[0342] 55A 2-(2-fluoro-5-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0343] [ka]

[0344] A mixture of Intermediate 2A (250 mg, 0.907 mmol), (2-fluoro-5-methylphenyl)boronic acid (172 mg, 1.117 mmol), and K2CO3 (432 mg, 2.721 mmol) in 1,4-dioxane:water (2:1, 3.0 mL) was sparged with N2 for 5 min. Pd(PPh3)4 (157 mg, 0.136 mmol) was added, and the reaction was degassed with N2 for 5 min and then heated to 100 °C overnight. The reaction was cooled to rt, 2 M aq. NaOH (3.0 mL) was added, and then stirred at rt for 30 h. The mixture was concentrated under reduced pressure to remove 1,4-dioxane, then diluted with water (30 mL), and washed with MTBE (3 × 20 mL). The aqueous solution was acidified (pH ≈ 2) with 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a brown solid (238 mg, 74%). LCMS (Method A) m / z 294.0 [M+Na] at 0.94 min. + . 1H NMR (500 MHz, DMSO-d6) 12.26 (s, 1H), 9.28 (dd, J = 7.0, 1.8 Hz, 1H), 8.83 (dd, J = 4.2, 1.8 Hz, 1H), 7.35 (m, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 2.36 (s, 3H).

[0345] 56A 2-(2-fluorophenyl)-6-(1-methylazetidin-3-yl)oxyimidazo[1,2-b]pyridazine-3-carboxylic acid

[0346] [ka]

[0347] NaH (60% dispersion in mineral oil, 31 mg, 0.774 mmol) was added to a cooled (0 °C) solution of 1-methylazetidin-3-ol hydrochloride (47 mg, 0.378 mmol) in DMF (4 mL) and stirred for 15 min. A solution of Intermediate 45D (55 mg, 0.172 mmol) in DMF (2 mL) was then added, and the reaction was stirred at rt for 1 h. LiOH (103 mg, 4.301 mmol) was added, and the solution was stirred for an additional 1 h. The reaction was acidified with 1 M aq. HCl to pH ∼4, the volatiles were removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (5-65% MeCN in 10 mM (NH4)2CO3 aq. solution) to give an off-white solid (55 mg, 93%). LCMS (Method B) m / z 343.4 [M+H] at 0.47 min + (ES+).

[0348] 56B 2-(2-fluorophenyl)-6-(2-methoxyethoxy)imidazo[1,2-b]pyridazine-3-carboxylic acid

[0349] [ka]

[0350] Prepared by a procedure similar to that described for Intermediate 56A. LCMS (Method B) m / z 332.3 [M+H] at 0.49 min + (ES+).

[0351] 57A 6-(1-methylazetidin-3-yl)oxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid

[0352] [ka]

[0353] NaH (60% dispersion in mineral oil, 89 mg, 2.237 mmol) was added to a cooled (0 °C) solution of 1-methylazetidin-3-ol hydrochloride (135 mg, 1.094 mmol) in DMF (10 mL), and the mixture was stirred for 15 min. A solution of Intermediate 45C (150 mg, 0.497 mmol) in DMF (2 mL) was added, and the reaction mixture was warmed to rt and stirred for 2 h. An additional suspension of NaH (89 mg, 2.237 mmol) and 1-methylazetidin-3-ol hydrochloride (135 mg, 1.094 mmol) in DMF (3 mL) in a separate flask was added and stirred at rt for 45 min, and the reaction was stirred for an additional 1 h. LiOH (298 mg, 12.43 mmol) was added, and the solution was stirred at rt for 72 h. The reaction was acidified with 1 M aq. HCl to pH ∼4, the volatiles were removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (5-65% MeCN in 10 mM (NH)CO aq. solution) to give a yellow solid (87 mg, 53%). LCMS (Method B) m / z 324.6 [M+H] at 0.51 min. + (ES+).

[0354] 58A 2-(6-Ethylpyridin-3-yl)-6-(trideuteriomethoxy)imidazo[1,2-b]pyridazine-3-carboxylic acid

[0355] [ka]

[0356] LiOH (1.5 M aq; 0.49 mL, 0.736 mmol) was added to a solution of Intermediate 46F (52 mg, 0.147 mmol) in methanol-d4 (1.2 mL, 29.5 mmol) and water (2 mL) and heated to 100 °C for 1 h via MWI. The reaction was cooled to rt, acidified with 1 M aq. HCl to pH ∼4, and then concentrated under reduced pressure to give a beige-white solid (40 mg, 86%), which was used without further purification. LCMS (Method A) m / z 301.7 [M+H] at 0.20 min + (ES+).

[0357] Example 1. 2-[4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Procedure A)

[0358] [ka]

[0359] Intermediate 9B (122 mg, 0.450 mmol) was added to a mixture of (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (130 mg, 0.520 mmol), HATU (214 mg, 0.560 mmol), and NEt (0.200 mL, 1.430 mmol) in DMF (3 mL), and the mixture was stirred at rt overnight. The reaction was quenched with water (15 mL), and the resulting precipitate was filtered and washed with water (2 × 15 mL). The precipitate was dried under vacuum, dissolved in CHCl, and purified by column chromatography (0–90% EtOAc in isohexane) to give a yellow solid (95 mg, 40%). LCMS (Method D) 502.29 [M+H] at 3.80 min.+ . 1 H NMR (500 MHz, DMSO-d6) 10.98 (s, 1H), 9.91 (d, J = 7.8 Hz, 1H), 9.31 (dd, J = 6.9, 1.7 Hz, 1H), 8.87 (dd, J = 4.3, 1.7 Hz, 1H), 7.81-7.74 (m, 2H), 7.68-7.42 (m, 6H), 7.37-7.32 (m, 2H), 7.31-7.24 (m, 2H), 6.58-6.51 (m, 2H), 5.98 (q, J = 5.0 Hz, 1H), 5.52 (d, J = 7.8 Hz, 1H), 2.71 (d, J = 5.0 Hz, 3H).

[0360] The following compounds of the invention were prepared by the amide coupling procedure A described for the compound of Example 1 using (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one.

[0361] [Table 16-1]

[0362] [Table 16-2]

[0363] [Table 16-3]

[0364] [Table 16-4]

[0365] [Table 16-5]

[0366] [Table 16-6]

[0367] [Table 16-7]

[0368] 11. 2-(1-methyl-2,3-dihydroindol-6-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Procedure B)

[0369] [ka]

[0370] LiOH (1.5 M aq, 0.447 mL, 0.671 mmol) was added to a solution of Intermediate 6E (12 mg, 0.038 mmol) in THF:MeOH (1:1, 4 mL), and the reaction mixture was stirred at 40 °C overnight. The mixture was cooled to rt, neutralized with HCl (1 M aq, 0.671 mL, 0.671 mmol), and concentrated in vacuo. The crude product was dissolved in DMF (1.5 mL), NEt (11 μL, 0.076 mmol), HATU (22 mg, 0.057 mmol), and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (13 mg, 0.052 mmol) were added, and the reaction mixture was stirred at 40 °C for 2 h. The reaction was quenched with water (10 mL), and the resulting precipitate was filtered and washed with water. The precipitate was purified by column chromatography (0-5% MeOH in CH2Cl2) to give a yellow solid (6 mg, 29%). LCMS (Method C) 528.30 [M+H] at 4.13 min + . 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.91 (d, J = 7.8 Hz, 1H), 9.33 (dd, J = 6.9, 1.7 Hz, 1H), 8.89 (dd, J = 4.3, 1.7 Hz, 1H), 7.72-7.63 (m, 3H), 7.56-7.42 (m, 5H), 7.38-7.23 (m, 4H), 6.52 (d, J = 8.2 Hz, 1H), 5.53 (d, J= 7.8 Hz, 1H), 3.36-3.26 (m, 2H), 2.92 (t, J = 8.3 Hz, 2H), 2.76 (s, 3H).

[0371] The following compounds of the invention were prepared by the amide coupling procedure B described for the compound of Example 11.

[0372] [Table 17-1]

[0373] [Table 17-2]

[0374] [Table 17-3]

[0375] 18. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide

[0376] [ka]

[0377] Prepared from intermediate 14A by amide coupling procedure B described for the compound of Example 11. LCMS (Method C) m / z 509.1 [M+H] at 3.88 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.18 (d, J= 7.6 Hz, 1H), 8.98 (dd, J = 4.6, 1.6 Hz, 1H), 8.45 (dd, J = 9.2, 1.6 Hz, 1H), 7.63-7.49 (m, 6H), 7.49-7.42 (m, 3H), 7.36-7.18 (m, 3H), 7.16 (d, J= 7.9 Hz, 1H), 5.57 (d, J = 7.5 Hz, 1H).

[0378] 19. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide

[0379] [ka]

[0380] Prepared from Intermediate 16A by the amide coupling procedure A described for Example 1, using heating at 0° C. overnight. LCMS (Method C) m / z 523.15 [M+H] at 4.12 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.59 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 9.3 Hz, 1H), 7.63-7.41 (m, 9H), 7.36-7.28 (m, 1H), 7.28-7.20 (m, 2H), 7.20-7.14 (m, 1H), 5.53 (d, J = 7.2 Hz, 1H), 2.75 (s, 3H).

[0381] 20. 6-Chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-methylimidazo[1,2-b]pyridazine-3-carboxamide (Procedure C)

[0382] [ka]

[0383] HATU (205 mg, 0.540 mmol) was added to a solution of (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (121 mg, 0.45 mmol), 6-chloro-2-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (99.8 mg, 0.47 mmol), and DIPEA (172 μL, 0.99 mmol) in anhydrous DMF (2.88 mL) under N2, and the reaction was stirred at rt for 24 h. The reaction was quenched with water, resulting in the formation of an off-white precipitate, which was filtered and washed with water. The precipitate was dissolved in EtOAc, and the solvent was removed under reduced pressure. Purification by column chromatography [10-37% (EtOH:CH2Cl2:NH4OH; 50:8:1) in CH2Cl2] gave a white solid (153 mg, 74%). 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.91 (d, J = 7.1 Hz, 1H), 8.36 (d, J = 9.5 Hz, 1H), 7.69-7.57 (m, 2H), 7.57-7.42 (m, 5H), 7.39-7.30 (m, 1H), 7.21 (d, J = 7.9 Hz, 1H), 5.60 (d, J = 7.2 Hz, 1H), 2.68 (s, 3H). LRMS (APCI+) m / z463.3 [M+H] +

[0384] The following compounds were prepared by the amide coupling procedure C described above for the compound of Example 20. Examples 40 and 41 were prepared with additional purification by HPLC Method 1 (MeCN / water with 0.2% v / v formic acid; 25-100% over 18 min).

[0385] [Table 18-1]

[0386] [Table 18-2]

[0387] [Table 18-3]

[0388] [Table 18-4]

[0389] [Table 18-5]

[0390] [Table 18-6]

[0391] 42. 2-(2,3-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Procedure D)

[0392] [ka]

[0393] NEt3 (59 μL, 0.423 mmol), HATU (79 mg, 0.206 mmol), and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (56 mg, 0.206 mmol) were added to a solution of Intermediate 53A (57 mg, 0.206 mmol) in DMF (2 mL), and the reaction mixture was 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 CHCl2 (30 mL), concentrated under reduced pressure, and purified by column chromatography (0–5% MeOH in CHCl2) to give an off-white solid (44 mg, 40%). LCMS (Method C) m / z 527.3 [M+H] at 4.39 min. + . 1 H NMR (500 MHz, DMSO-d6) 10.97 (s, 1H), 9.61 (d, J = 8.0 Hz, 1H), 9.44 (dd, J = 7.0, 1.7 Hz, 1H), 9.02 (dd, J = 4.3, 1.7 Hz, 1H), 7.61-7.57 (m, 1H), 7.57-7.48 (m, 4H), 7.47-7.42 (m, 3H), 7.39-7.33 (m, 1H), 7.33-7.26 (m, 2H), 7.16-7.13 (m, 1H), 5.54 (d, J = 7.9 Hz, 1H).

[0394] The following compounds of the invention were prepared by the amide coupling procedure D described for the compound of Example 42.

[0395] [Table 19-1]

[0396] [Table 19-2]

[0397] [Table 19-3]

[0398] 48. 2-[6-(Cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Procedure E)

[0399] [ka]

[0400] A solution of Intermediate 33C (70 mg, 0.205 mmol) and LiOH (1.5 M aq; 0.6 mL, 0.9 mmol) in THF / MeOH (1:1; 1 mL) was stirred at 40 °C overnight. The mixture was cooled to rt, neutralized with 1 M aq. HCl (0.92 mL, 0.920 mmol), and concentrated under reduced pressure. The crude residue was dissolved in DMF (1.26 mL), and HATU (78 mg, 0.206 mmol), NEt (57 μL, 0.41 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (41 mg, 0.205 mmol) were added, and the reaction was stirred at 40 °C overnight. Workup and purification similar to that described for Example 42 afforded a yellow solid (39 mg, 35%). LCMS (Method C) m / z547.3 [M+H] in 4.13 min + . 1H NMR (500 MHz, DMSO-d6) 10.99 (s, 1H), 9.61 (d, J = 8.0 Hz, 1H), 9.38 (dd, J = 7.0, 1.7 Hz, 1H), 8.95 (dd, J = 4.3, 1.7 Hz, 1H), 7.75-7.68 (m, 1H), 7.68-7.61 (m, 1H), 7.55-7.50 (m, 1H), 7.50-7.40 (m, 4H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 2H), 7.30-7.23 (m, 1H), 6.51 (d, J = 8.1 Hz, 1H), 5.47 (d, J = 8.0 Hz, 1H), 2.56-2.51 (m, 1H), 0.75-0.66 (m, 2H), 0.48-0.41 (m, 2H).

[0401] The following compounds of the present invention were prepared by a procedure similar to that described for the compound of Example 48 (amide coupling procedure E). The amide coupling procedure may be performed at rt or 40°C, and the stoichiometry of NEt used may vary from 2 to 4 eq. For Examples 69-76, 10 eq. of LiOH (1.5 M aq.) was used in the ester hydrolysis step. Example 75 was subjected to additional purification by reverse-phase column chromatography (15-65% MeCN in water with 1% formic acid).

[0402] [Table 20-1]

[0403] [Table 20-2]

[0404] [Table 20-3]

[0405] [Table 20-4]

[0406]

Table 20-5

[0407]

Table 20-6

[0408]

Table 20-7

[0409]

Table 20-8

[0410]

Table 20-9

[0411]

Table 20-10

[0412]

Table 20-11

[0413]

Table 20-12

[0414]

Table 20-13

[0415]

Table 20-14

[0416] [Table 20-15]

[0417] 77. 2-[6-(2-hydroxy-2-methylpropyl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0418] [ka]

[0419] Prepared by amide coupling procedure E as described for Example 48, with further purification by reverse-phase column chromatography [5-40% MeCN (0.1% formic acid) in water (0.1% formic acid)] followed by preparative HPLC [Method 3: 15-100% MeCN in water (0.1% formic acid)] to give a white solid (9 mg, 5%). LCMS (Method C) m / z 564.4 [M+H] at 2.40 min + . 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.86 (d, J = 7.8 Hz, 1H), 9.43 (dd, J = 7.0, 1.7 Hz, 1H), 8.98 (dd, J = 4.3, 1.7 Hz, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.1, 2.3 Hz, 1H), 7.64-7.56 (m, 1H), 7.56-7.49 (m, 3H), 7.49-7.28 (m, 5H), 7.18 (d, J = 7.9 Hz, 1H), 5.59 (d, J = 7.8 Hz, 1H), 4.72 (s, 1H), 2.88 (s, 2H), 1.12 (s, 6H).

[0420] The following compounds of the present invention were prepared by a procedure similar to that described for the compound of Example 48 (amide coupling procedure E). For Example 79, 10 eq. of LiOH (1.5 M aq.) was used in the ester hydrolysis step. Example 81 was subjected to additional purification by reverse-phase column chromatography [15-70% MeCN in water w / 0.1% (NH)CO].

[0421] [Table 21-1]

[0422] [Table 21-2]

[0423] [Table 21-3]

[0424] 84. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0425] [ka]

[0426] A solution of intermediate 6P (124 mg, 0.282 mmol) and LiOH (1.5 M aq; 0.55 mL, 0.825 mmol) in THF / MeOH (1:1; 2.18 mL) was stirred at rt overnight and then at 40 °C for 86 h. The mixture was cooled to rt, acidified (pH ≈ 1) with 1 M aq. HCl (0.92 mL, 0.920 mmol), and concentrated under reduced pressure. A portion of the crude acid (52 mg, 0.135 mmol) was carried directly to the next reaction and dissolved in DMF (1.5 mL). HATU (51 mg, 0.135 mmol), NEt (75 μL, 0.541 mmol), and then (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (36 mg, 0.135 mmol) were added, and the reaction was stirred at rt for 1 h. The reaction was quenched with water (5 mL), acidified with AcOH (pH ≈ 2), and purified by ion exchange chromatography (2 g SCX-2). The resulting residue was further purified by column chromatography [0-7% (0.7 N NH in MeOH)] in CHCl to give a cream-colored solid (13 mg, 15%) as a mixture of rotamers. 1 In the H NMR assignments, 0.5H corresponds to 1H in the rotamer peak. LCMS (Method C) m / z 619.4 [M+H] at 2.42 min + . 1H NMR (500 MHz, DMSO-d6) δ 11.08-10.89 (m, 1H), 10.02-9.92 (m, 1H), 8.85-8.75 (m, 1H), 7.61-7.54 (m, 1H), 7.54-7.39 (m, 6H), 7.34-7.25 (m, 1H), 7.24-7.10 (m, 3H), 6.85 (d, J = 7.8 Hz, 0.5H), 6.54 (d, J = 7.8 Hz, 0.5H), 5.49-5.43 (m, 1H), 5.40 (d, J = 7.3 Hz, 0.5H), 4.82 (s, 0.5H), 4.16-4.09 (m, 0.5H), 3.68-3.60 (m, 0.5H), 3.58 (s, 0.5H), 3.52-3.43 (m, 1.5H), 2.95-2.87 (m, 0.5H), 2.84-2.77 (m, 0.5H), 2.70-2.63 (m, 0.5H), 2.37-2.27 (m, 3H), 2.01-1.94 (m, 0.5H), 1.93-1.79 (m, 2H), 1.75 (s, 1H).

[0427] 85. 2-(2-Fluoro-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0428] [ka]

[0429] 86. 2-(2-Methoxy-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0430] [ka]

[0431] A solution of intermediate 27B (227 mg, 0.717 mmol) and LiOH (1.5 M aq; 4.78 mL, 7.17 mmol) in THF / MeOH (1:1; 6 mL) was heated at 40 °C for 48 h. The reaction mixture was cooled to rt, diluted with water (20 mL), and washed with MTBE (3 × 10 mL). The aqueous layer was acidified (pH ≈ 1) with 1 M aq. HCl and extracted with CHCl3 / iPrOH (3:1; 3 × 10 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed under reduced pressure to give a white solid (151 mg), which was used without further purification. The residue was dissolved in DMF (1.5 mL), HATU (208 mg, 0.547 mmol), NEt (123 μL, 0.882 mmol), and then (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (137 mg, 0.546 mmol) were added, and the reaction was stirred at 40° C. for 1 h. Workup and purification similar to that described for Example 42 was followed by further purification by preparative HPLC [Method 2: 20-100% MeCN in water (0.1% formic acid)]. Example 85: White solid (28 mg, 8%). LCMS (Method C) 506.4 [M+H]+ in 3.73 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.56 (d, J = 8.0 Hz, 1H), 9.43 (dd, J = 7.0, 1.7 Hz, 1H), 9.01 (dd, J = 4.3, 1.7 Hz, 1H), 7.96 (dd, J = 9.6, 7.5 Hz, 1H), 7.68-7.61 (m, 1H), 7.54-7.48 (m, 1H), 7.48-7.40 (m, 5H), 7.34-7.23 (m, 4H), 5.45 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H). Example 86: White solid (14 mg, 3%). LCMS (Method C) m / z 518.5 [M+H] in 3.96 min + . 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.50 (d, J = 8.0 Hz, 1H), 9.37 (dd, J = 7.0, 1.7 Hz, 1H), 8.95 (dd, J = 4.3, 1.7 Hz, 1H), 7.67-7.61 (m, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.53-7.48 (m, 1H), 7.48-7.41 (m, 4H), 7.37 (dd, J = 7.0, 4.3 Hz, 1H), 7.34-7.28 (m, 2H), 7.28-7.22 (m, 1H), 6.89 (d, J = 7.4 Hz, 1H), 5.41 (d, J = 7.9 Hz, 1H), 3.74 (s, 3H), 2.43 (s, 3H).

[0432] 87. N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide (Procedure F)

[0433] [ka]

[0434] A solution of Intermediate 45A (58 mg, 0.217 mmol) and LiOH·HO (91 mg, 2.174 mmol) in MeOH:THF:water (2:2:1; 5 mL) was heated to 50 °C for 2 h. The reaction mixture was cooled to rt, neutralized with 1 M aq. HCl to pH ≈ 7, and then concentrated under reduced pressure. The crude product was dissolved in DMF (1.5 mL), and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (55 mg, 0.217 mmol) and NEt (91 μL, 0.651 mmol) were added, followed by HATU (83 mg, 0.217 mmol). The reaction was stirred at rt for 18 h, quenched with water (10 mL), and the resulting precipitate was filtered and washed with water. The precipitate was dissolved in 10% MeOH / CH2Cl2, passed through a phase separation cartridge, concentrated under reduced pressure, and purified by column chromatography (0-10% MeOH in CH2Cl2) to give an off-white solid (30 mg, 29%). LCMS (Method D) m / z 473.4 [M+H] at 3.89 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.34 (d, J = 7.4 Hz, 1H), 8.86 (dd, J = 4.5, 1.6 Hz, 1H), 8.38 (dd, J = 9.2, 1.6 Hz, 1H), 8.01-7.95 (m, 2H), 7.68 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.57-7.39 (m, 9H), 7.36 (dd, J = 8.1, 1.4 Hz, 2H), 7.29 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 5.54 (d, J = 7.4 Hz, 1H).

[0435] The following compounds of the present invention were prepared by the amide coupling procedure F described for the compound of Example 87. The procedure was carried out using 5 eq. of NEt for Examples 95-105 and 10 eq. of NEt for Example 106. Example 107 was subjected to additional purification by reverse-phase column chromatography (5-60% MeCN in 10 mM (NH)CO aq. solution).

[0436] [Table 22-1]

[0437] [Table 22-2]

[0438] [Table 22-3]

[0439] [Table 22-4]

[0440] [Table 22-5]

[0441] [Table 22-6]

[0442] [Table 22-7]

[0443] [Table 22-8]

[0444] [Table 22-9]

[0445] 108. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(1-methylazetidin-3-yl)oximidazo[1,2-b]pyridazine-3-carboxamide

[0446] [ka]

[0447] HATU (61 mg, 0.161 mmol) was added to a solution of crude Intermediate 56A (55 mg, 0.161 mmol), (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (43 mg, 0.161 mmol), and NEt3 (112 μL, 0.803 mmol) in DMF (3 mL), and the reaction was stirred at rt overnight. Workup and purification similar to that described for Example 87 afforded an off-white solid (30 mg, 31%). LCMS (Method D) m / z 594.4 [M+H] at 3.85 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.89 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 9.7 Hz, 1H), 7.65-7.41 (m, 8H), 7.37-7.16 (m, 5H), 5.55 (d, J = 7.5 Hz, 1H), 5.51 (p, J = 5.4 Hz, 1H), 3.92 (t, J = 7.1 Hz, 1H), 3.85 (t, J = 7.2 Hz, 1H), 3.27-3.19 (m, 2H), 2.22 (s, 3H).

[0448] 109. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-(1-methylazetidin-3-yl)oxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide

[0449] [ka]

[0450] Prepared by a procedure similar to that described for the compound of Example 108. LCMS (Method D) m / z 576.4 [M+H] at 4.05 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.01 (d, J = 7.3 Hz, 1H), 8.29 (d, J = 9.7 Hz, 1H), 7.93-7.84 (m, 2H), 7.63 (ddd, J = 9.9, 8.2, 1.4 Hz, 1H), 7.60-7.52 (m, 3H), 7.51-7.44 (m, 2H), 7.43-7.31 (m, 4H), 7.22 (dd, J = 9.4, 7.8 Hz, 2H), 5.62 (d, J = 7.3 Hz, 1H), 5.45 (p, J = 5.4 Hz, 1H), 3.91 (t, J = 7.1 Hz, 1H), 3.85 (t, J = 7.4 Hz, 1H), 3.22 (d, J = 15.4 Hz, 2H), 2.23 (s, 3H).

[0451] 110. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(2-methoxyethoxy)imidazo[1,2-b]pyridazine-3-carboxamide

[0452] [ka]

[0453] Prepared by a procedure similar to that described for the compound in Example 108, using 10 eq. NEt3 at the amide coupling step and additional purification by reverse-phase column chromatography [10-60% MeCN in 10 mM (NH4)2CO3 aq. solution]. LCMS (Method D) m / z 582.6 [M+H] at 4.20 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.23 (d, J = 7.2 Hz, 1H), 8.31 (d, J = 9.7 Hz, 1H), 7.59 (t, J = 9.2 Hz, 1H), 7.56-7.41 (m, 7H), 7.33 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 9.8 Hz, 1H), 7.25 (td, J = 7.5, 1.1 Hz, 1H), 7.23-7.18 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 5.52 (d, J = 7.1 Hz, 1H), 4.84 (ddd, J = 12.0, 5.8, 3.1 Hz, 1H), 4.71 (ddd, J = 12.0, 5.4, 3.0 Hz, 1H), 3.78 (ddd, J = 7.1, 4.5, 3.1 Hz, 2H), 3.33 (s, 3H).

[0454] 111. 6-Methoxy-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide

[0455] [ka]

[0456] LiOH (1.5 M aq; 1.75 mL, 2.625 mmol) was added to a solution of Intermediate 45C (180 mg, 0.597 mmol) in MeOH:water (1:1; 4 mL) and heated to 100 °C for 1 h by MWI. The reaction was cooled to rt, acidified with 1 M aq. HCl (3 mL), and then concentrated under reduced pressure to give an off-white solid (161 mg), which was carried directly to the next reaction. A portion of the crude residue (80 mg, 0.297 mmol) was dissolved in DMF (1.8 mL), and HATU (113 mg, 0.298 mmol), NEt (124 μL, 0.891 mmol), and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (75 mg, 0.297 mmol) were added, and the reaction mixture was stirred at 40 °C overnight. Similar workup and purification as described for Example 42 gave a white solid (32 mg, 22%). LCMS (Method C) m / z 503.4 [M+H] at 4.32 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.36 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 9.7 Hz, 1H), 7.92-7.86 (m, 2H), 7.70-7.63 (m, 1H), 7.55-7.32 (m, 10H), 7.32-7.25 (m, 1H), 7.22 (d, J = 9.7 Hz, 1H), 5.51 (d, J = 7.1 Hz, 1H), 4.21 (s, 3H).

[0457] The following compounds of the present invention were prepared by a procedure similar to that described for the compound of Example 111, with additional purification by reverse-phase column chromatography (10-65% MeCN in water w / 0.1% formic acid) for Examples 113 and 114.

[0458] [Table 23-1]

[0459] [Table 23-2]

[0460] 115. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide

[0461] [ka]

[0462] A solution of Intermediate 45D (45 mg, 0.141 mmol) and LiOH·HO (59 mg, 1.41 mmol) in MeOH:THF:water (2:2:1; 5 mL) was heated at 50 °C for 18 h. The reaction was cooled to rt, acidified with 1 M aq. HCl to pH ≈ 4, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (1.5 mL), and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (40 mg, 0.141 mmol) and NEt (39 μL, 0.281 mmol) were added, followed by HATU (54 mg, 0.141 mmol). The reaction was stirred at rt for 3 h. Similar workup and purification as described for Example 42, followed by further purification by reverse-phase column chromatography [5-75% MeCN in 10 mM (NH)CO aq. solution] afforded an off-white solid (18 mg, 23%). LCMS (Method C) m / z 539.4 [M+H] at 4.13 min. + . 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.30 (d, J = 7.2 Hz, 1H), 8.31 (d, J = 9.7 Hz, 1H), 7.60 (t, 1H), 7.55-7.42 (m, 7H), 7.32 (td, J = 8.0, 4.9 Hz, 1H), 7.29-7.15 (m, 4H), 5.54 (d, J = 7.2 Hz, 1H), 4.24 (s, 3H).

[0463] 116. 6-Chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide

[0464] [ka]

[0465] A solution of Intermediate 45D (45 mg, 0.141 mmol) and LiOH HO (59 mg, 1.41 mmol) in THF:water (2:1; 3 mL) was heated to 50 °C for 3 h. The reaction mixture was cooled to rt, neutralized with 1 M aq. HCl to pH ≈ 7, and then concentrated under reduced pressure. The crude residue was dissolved in DMF (3 mL), and (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (38 mg, 0.141 mmol) and NEt (20 μL, 0.141 mmol) were added, followed by HATU (54 mg, 0.141 mmol), and the reaction was stirred at rt for 18 h. Similar workup and purification as described for Example 42, followed by purification by reverse-phase column chromatography [15-75% MeCN in 10 mM (NH)CO aq. solution] afforded an off-white solid (13 mg, 17%). LCMS (Method D) m / z 543.4 [M+H] at 4.18 min. + . 1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.92 (d, J = 7.4 Hz, 1H), 8.50 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.65-7.58 (m, 2H), 7.58-7.44 (m, 6H), 7.37-7.22 (m, 3H), 7.18 (d, J = 7.7 Hz, 1H), 5.54 (d, J = 7.3 Hz, 1H).

[0466] 117. 6-Chloro-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide

[0467] [ka]

[0468] A solution of Intermediate 46F (63 mg, 0.179 mmol) and 1.5 M aq. LiOH (0.359 mL, 0.538 mmol) in THF (3 mL) was stirred at rt overnight. The reaction mixture was acidified with 1 M aq. HCl to pH ≈ 4 and then concentrated under reduced pressure. The crude residue was dissolved in DMF (1.8 mL), (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (48 mg, 0.179 mmol) and NEt (75 μL, 0.538 mmol) were added, followed by HATU (68 mg, 0.179 mmol), and the reaction was stirred at rt for 30 min. Workup and purification similar to that described for Example 42 afforded a beige solid (50 mg, 48%). LCMS (Method C) m / z 554.4 [M+H] in 2.77 min + . 1H NMR (500 MHz, DMSO-d6) δ 11.04-11.00 (m, 1H), 10.18 (d, J = 7.2 Hz, 1H), 9.05-9.00 (m, 1H), 8.46 (d, J = 9.5 Hz, 1H), 8.26 (dd, J = 8.1, 2.3 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.66-7.60 (m, 1H), 7.59-7.53 (m, 3H), 7.48 (t, J = 7.4 Hz, 2H), 7.39-7.31 (m, 2H), 7.21 (d, J = 7.9 Hz, 1H), 5.61 (d, J = 7.2 Hz, 1H), 2.82 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

[0469] 118. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-(5-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide

[0470] [ka]

[0471] A solution of Intermediate 46C (130 mg, 0.308 mmol) and LiOH (74 mg, 3.083 mmol) in MeOH:THF:water (4:3:3; 10 mL) was heated at 50 °C for 1 h. The reaction was cooled to rt, acidified with 1 M aq. HCl to pH ≈ 4, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (6 mL), (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (83 mg, 0.308 mmol) and NEt (214 μL, 1.539 mmol) were added, followed by HATU (117 mg, 0.308 mmol), and the reaction was stirred at rt for 1 h. Workup and purification similar to that described for Example 87 afforded a yellow solid (40 mg, 24%). LCMS (Method C) m / z 536.4 [M+H] in 2.63 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.42 (d, J = 7.1 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 9.7 Hz, 1H), 8.05 (s, 1H), 7.61 (t, J = 9.3 Hz, 1H), 7.54-7.49 (m, 3H), 7.45 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 5.9 Hz, 1H), 7.26 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.60 (d, J = 6.9 Hz, 1H), 4.23 (s, 3H), 2.35 (s, 3H).

[0472] The following compounds of the invention were prepared by procedures analogous to those described for the compound of Example 118.

[0473] [Table 24]

[0474] 121. 2-(6-Ethylpyridin-3-yl)-6-methoxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide

[0475] [ka]

[0476] LiOH (1.5 M aq; 0.643 mL, 0.965 mmol) was added to a solution of Intermediate 46F (68 mg, 0.193 mmol) in THF:MeOH (1:1; 4 mL) and stirred at rt for 4 days. The reaction was then acidified with 1 M aq. HCl to pH ≈ 4 and concentrated under reduced pressure to give an off-white solid (123 mg), which was carried directly to the next reaction. A portion of the crude residue (58 mg, 0.193 mmol) was dissolved in DMF (1.5 mL), and NEt3 (81 μL, 0.579 mmol) and (3S)-3-amino-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (53 mg, 0.196 mmol) were added, followed by HATU (74 mg, 0.195 mmol), and the reaction mixture was stirred at rt for 1 h. The reaction was quenched with water (15 mL), and the resulting precipitate was filtered and washed with water (2 × 15 mL). The precipitate was dissolved in CHCl, concentrated under reduced pressure, and purified by column chromatography (0–5% MeOH in CHCl). Further purification by preparative HPLC Method 4 [20–100% MeCN in water (0.1% formic acid)] afforded a white solid (9.7 mg, 9%). LCMS (Method C) m / z 550.1 [M+H] at 1.02 min + . 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.42 (d, J = 7.0 Hz, 1H), 8.93-8.88 (m, 1H), 8.31 (d, J = 9.7 Hz, 1H), 8.14 (dd, J = 8.1, 2.3 Hz, 1H), 7.66-7.58 (m, 1H), 7.56-7.49 (m, 3H), 7.48-7.43 (m, 2H), 7.37-7.32 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 9.7 Hz, 1H), 7.22-7.17 (m, 1H), 5.60 (d, J = 7.1 Hz, 1H), 4.24 (s, 3H), 2.79 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

[0477] 122. 6-Ethoxy-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide

[0478] [ka]

[0479] A solution of Intermediate 46F (60 mg, 0.172 mmol) and 1.5 M aq. LiOH (0.572 mL, 0.858 mmol) in EtOH:THF (1:1; 4 mL) was heated at 50 °C for 1 h. The reaction was cooled to rt, acidified with 1 M aq. HCl to pH ≈ 4, and the solvent was removed under reduced pressure. The crude residue was dissolved in DMF (1.5 mL), (3S)-3-amino-9-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (46 mg, 0.172 mmol) and NEt (72 μL, 0.515 mmol) were added, followed by HATU (68 mg, 0.178 mmol), and the reaction was stirred at rt for 1.5 h. The reaction was diluted with EtOAc (50 mL), washed with brine (3 × 50 mL), dried (NaSO), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (0-3% MeOH in CHCl) and reverse-phase column chromatography [35-65% MeCN (0.1% formic acid) in water (0.1% formic acid)]. The resulting material was dissolved in CHCl / iPrOH (3:1; 25 mL), washed with sat. aq. NaHCO (2 × 20 mL), and dried (NaSO) to give a white solid (17 mg, 18%). LCMS (Method C) m / z 540.3 [M+H] at 3.63 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.30 (d, J = 7.2 Hz, 1H), 8.63-8.59 (m, 1H), 8.53-8.48 (m, 1H), 8.34 (d, J = 9.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.57-7.50 (m, 1H), 7.52-7.42 (m, 4H), 7.37-7.28 (m, 2H), 7.17 (d, J = 7.9 Hz, 1H), 5.54 (d, J = 7.1 Hz, 1H), 4.25 (s, 3H).

[0480] 123. 2-(6-Ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-6-( 2 H3) Methoxyimidazo[1,2-b]pyridazine-3-carboxamide

[0481] [ka]

[0482] Prepared by amide coupling procedure A described for the compound of Example 1. LCMS (Method C) m / z 553.4 [M+H] at 2.72 min + . 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.41 (d, J = 7.1 Hz, 1H), 8.92-8.87 (m, 1H), 8.30 (d, J = 9.7 Hz, 1H), 8.14 (dd, J = 8.1, 2.3 Hz, 1H), 7.65-7.57 (m, 1H), 7.55-7.48 (m, 3H), 7.47-7.42 (m, 2H), 7.36-7.31 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.59 (d, J = 7.1 Hz, 1H), 2.78 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

[0483] 124. 2-(6-[(3S * )-3-Methylmorpholin-4-yl]pyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0484] [ka]

[0485] Example 67 (40 mg) was purified by preparative chiral HPLC [70% MeCN in water (0.1% ammonia)] to afford the title compound as a single diastereomer of unknown absolute configuration, with arbitrarily defined stereocenters marked with an asterisk. Second eluting enantiomer. Yellow solid (12 mg, 30%). Analytical chiral HPLC: 8.99 min. LCMS (Method D) 573.4 [M+H] at 3.95 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.87 (d, J = 7.8 Hz, 1H), 9.38 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 8.9, 2.4 Hz, 1H), 7.70-7.63 (m, 1H), 7.56-7.41 (m, 5H), 7.39-7.32 (m, 3H), 7.32-7.25 (m, 1H), 6.80 (d, J = 9.0 Hz, 1H), 5.52 (d, J = 7.8 Hz, 1H), 4.42-4.36 (m, 1H), 3.98-3.91 (m, 2H), 3.73 (d, J = 11.3 Hz, 1H), 3.63 (dd, J = 11.3, 3.1 Hz, 1H), 3.48 (td, J= 11.3, 3.1 Hz, 1H), 3.15-3.05 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H).

[0486] 125. N-[(3S)-9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-{6-[(3S * )-3-Methylmorpholin-4-yl]pyridin-3-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0487] [ka]

[0488] Example 68 (40 mg) was purified by preparative chiral SFC [50% MeOH:MeCN (1:1) w / 0.1% ammonia] to afford the title compound as a single diastereomer of unknown absolute configuration, with an asterisk at the arbitrarily defined stereocenter. Second eluting enantiomer. Yellow solid (3.8 mg, 9%). Analytical SFC: 7.86 min. LCMS (Method D) m / z 591.5 [M+H] at 3.94 min. + . 1 H NMR (500 MHz, DMSO-d6) δ 9.88 (d, J = 7.8 Hz, 1H), 9.38 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 8.9, 2.3 Hz, 1H), 7.65-7.58 (m, 1H), 7.57-7.50 (m, 3H), 7.50-7.41 (m, 2H), 7.39-7.30 (m, 2H), 7.19 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 5.60 (d, J = 7.7 Hz, 1H), 4.42-4.36 (m, 1H), 3.98-3.92 (m, 2H), 3.76-3.70 (m, 1H), 3.67-3.60 (m, 1H), 3.52-3.43 (m, 1H), 3.15-3.05 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H).

[0489] Example 127: In vitro efficacy Compounds were subjected to the RSV plaque reduction assay according to the following protocol: Plaque EC 50 and cytotoxic CC 50 Values are the average of at least two experiments and numbers are rounded to whole units.

[0490] Plaque reduction assay. Hep-G2 cells (ECACC, 85011430) were passaged in flasks and seeded into 24-well plates in DMEM containing antibiotics and supplemented with 10% FBS. During inoculation and subsequent incubation, cells were cultured in DMEM containing 2% FBS. 100 plaque-forming units / well of RSV (RSV A2 ECACC, 0709161v) were mixed with eight serial dilutions of compound. 100 μL of the virus / compound mixture was then added to the confluent Hep-G2 cell monolayer. The cells and virus / compound mixture were incubated for 2 h at 37°C in a humidified 5% CO2 incubator before removal of the inoculum and addition of 1 mL of compound dilution overlay (DMEM containing 2% FBS and 0.8% CMC). The cells were incubated for 2 days at 37°C in a humidified 5% CO2 incubator.

[0491] Cells were washed with PBS for 3 minutes before adding 75 / 25% v / v EtOH / MeOH. The fixative was removed from the plates, and the plates were washed with PBS. A pre-titrated amount of primary antibody was added in 200 μL PBS / 2% milk powder, and the plates were incubated at 37°C for 90 minutes. The plates were washed three times with PBS / 0.05% Tween 20, and rabbit anti-goat horseradish peroxidase was added in 2000 μL PBS / 2% milk powder and incubated at 37°C for 1 hour. After three washing steps with PBS / 0.05% Tween 20, 200 μL of ready-to-use TrueBlue was added, and the plates were incubated at room temperature for 10–15 minutes and washed with water. After removing the water, the plates were air-dried in the dark.

[0492] Plates were scanned and analyzed using an Immunospot S6 macroanalyzer equipped with BioSpot analysis software to count immunostained plaques (virospots). Plaque counts were used to calculate % infection relative to the average plaque count in virus control wells for RSV. EC 50Values were calculated as the respective 50% signal reduction by interpolation of inhibition curves fitted to a 4-parameter nonlinear regression with variable slope in Dotmatics. 50 and cytotoxic CC 50 Values are the average of at least two experiments and numbers are rounded to the nearest whole unit.

[0493] [Table 25-1]

[0494] [Table 25-2]

[0495] [Table 25-3]

[0496] [Table 25-4]

[0497] Example 128: Thermodynamic Solubility Test compound (2.5 mg solid; n=1) was weighed into an amber glass vial, and buffer (0.5 mL) was added (typically phosphate-buffered saline pH 7.4). The solution was stirred overnight at ambient temperature using a vial roller system. The solution was then filtered (0.45 μm pore size; no presaturation). Duplicate aliquots (50 μL) of sample were taken from the filtrate and diluted with 1 volume of Milli-Q water and methanol (1:1 v / v) and analyzed by HPLC-UV. A standard was prepared in DMSO at 10 mg / mL (n=1), which was then diluted 10-fold in Milli-Q water and methanol (1:1 v / v) to obtain a 1 mg / mL solution. The concentration of the test compound in the filtrate was quantified relative to the concentration standard. Analysis was performed using a gradient HPLC-MS system.

[0498] [Table 26]

[0499] Example 129: In vitro pharmacokinetics The compounds were subjected to the following assays to investigate liver microsomal and hepatocyte stability.

[0500] Microsome incubation: experimental procedure Pooled liver microsomes were purchased from a reliable commercial supplier and stored at -80°C before use. Microsomes (final protein concentration 0.5 mg / mL), 0.1 M phosphate buffer pH 7.4, and test compounds (final substrate concentration 1 μM; final DMSO concentration 0.25%) were preincubated at 37°C before initiating the reaction by adding NADPH (final concentration 1 mM). The final incubation volume was 50 μL. Control incubations were included for each tested compound, in which 0.1 M phosphate buffer pH 7.4 was added instead of NADPH (minus NADPH). Two control compounds included each species. All incubations were performed singly for each test compound. Each compound was incubated for 0, 5, 15, 30, and 45 minutes. The control (minus NADPH) was incubated for only 45 minutes. Reactions were terminated at the appropriate time points by transferring the incubations to acetonitrile at a 1:3 ratio. The stopped plate was centrifuged at 3,000 rpm for 20 minutes at 4°C to precipitate the proteins. After protein precipitation, the sample supernatants were combined in cassettes of up to four compounds, an internal standard was added, and the samples were analyzed by LC-MS / MS. The slope of the line was determined from a plot of the ln peak area ratio (compound peak area / internal standard peak area) versus time. The half-life (t 1 / 2 ) and intrinsic clearance (CL int ) was calculated. Compounds with low clearance (>80% remaining at 45 min) under the assay conditions had a t 1 / 2 >140 minutes.

[0501] [Table 27-1]

[0502] [Table 27-2]

[0503] Hepatocyte incubation: experimental procedure Cryopreserved pooled hepatocytes were purchased from a reliable commercial supplier and stored in liquid nitrogen before use. Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES and test compounds (final substrate concentration 3 μM; final DMSO concentration 0.25%) were pre-incubated at 37°C, and cryopreserved hepatocytes (in Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES at a final cell density of 0.5 x 10 6 The reaction is initiated by the addition of 100 μL of viable cells / mL. The final incubation volume is 500 μL. Two control compounds were included for each species, along with the appropriate vehicle controls. The reaction is stopped by transferring 50 μL of the incubate to 100 μL of acetonitrile containing the internal standard at the appropriate time point. Samples were removed at six time points (0, 5, 15, 30, 45, and 60 min) over the course of a 60-min experiment. The stopped plate is centrifuged at 2500 rpm for 30 min at 4°C to precipitate proteins. After protein precipitation, sample supernatants were combined in cassettes of up to four compounds and analyzed using generic LC-MS / MS conditions. The slope of the line is determined from a plot of the ln peak area ratio (compound peak area / internal standard peak area) versus time. The half-life (t1 / 2) and intrinsic clearance (CL int ) was calculated. Compounds with low clearance (>80% remaining at 60 min) under the assay conditions had a t 1 / 2 >186 minutes.

[0504] [Table 28]

[0505] Example 130: In vivo pharmacokinetics The pharmacokinetics of the compound was studied in vivo in rats at doses of 1 mg / kg (IV) and 10 mg / kg (PO).

[0506] Pharmacokinetics in rats method Male Sprague Dawley (SD) rats surgically prepared with a jugular cannula were treated with experimental compounds intravenously (IV; n = 3; 1 mg / kg) or orally (PO; n = 3; 10 mg / kg). Compounds were formulated as a 40:60 dimethylacetamide:saline solution (IV administration) and a 10% DMSO, 20% cremaphor (70%) aqueous solution (PO administration). Animals were observed for any obvious clinical signs or symptoms. Serial blood samples were collected via the cannula at 0.02, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after IV compound administration and at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral compound administration. Plasma was prepared by centrifugation and immediately stored at -80°C. Samples were then thawed, prepared for analysis by protein precipitation with acetonitrile, and analyzed by tandem LCMS with electrospray ionization using a matrix-matched calibration curve. PK parameters were calculated from the resulting data.

[0507] [Table 29]

[0508] Canine Pharmacokinetics The pharmacokinetics of the compound was studied in vivo in dogs at doses of 0.5 mg / kg (IV) and 4 mg / kg (PO).

[0509] method Male beagle dogs were treated with experimental compounds intravenously (n = 2; 0.5 mg / kg) or orally (n = 2; 3 or 4 mg / kg). Compounds were formulated as a solution of 20% dimethylacetamide / 80% (2-hydroxypropyl)-β-cyclodextrin (20% w / v) (IV administration) or 10% dimethylacetamide / 90% (2-hydroxypropyl)-β-cyclodextrin (20% w / v) (PO administration). Animals were observed for any obvious clinical signs or symptoms. Serial blood samples were collected from the jugular vein at 0.03, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after IV compound administration and at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral compound administration. Plasma was prepared by centrifugation and immediately stored at -80°C. Samples were then thawed, prepared for analysis by protein precipitation with acetonitrile, and analyzed by tandem LCMS with electrospray ionization using a matrix-matched calibration curve. PK parameters were calculated from the resulting data.

[0510] [Table 30]

[0511] Example 131: Aqueous Formulation The compound of Example 1 is formulated as a solution in 30% w / v captisol (ie, sulfobutylether-β-cyclodextrin) at pH 4 according to the following procedure.

[0512] A 30% w / v captisol (i.e., sulfobutylether-β-cyclodextrin) carrier is prepared by weighing the required amount of captisol into a suitable container, adding approximately 80% of the final volume of water, and magnetically stirring until a solution is formed. The carrier is then made up to volume with water.

[0513] An aqueous solution of the compound of Example 1 is prepared by weighing 175 mg of the compound into a suitable container and adding approximately 80% of the required volume of carrier. The pH is adjusted to pH 2 using an aqueous solution of hydrochloric acid, and the resulting mixture is magnetically stirred until a solution is formed. The formulation is then made up to volume with carrier, and the pH is adjusted to pH 4 using an aqueous solution of sodium hydroxide.

[0514] Example 132: Tablet Composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention, are prepared as follows:

[0515] Composition for 10,000 tablets Compound of the present invention (250 g) Lactose (800 g) Cornstarch (415 g) Talc powder (30 g) Magnesium stearate (5 g)

[0516] The compound of the present invention, lactose, and half of the cornstarch are mixed. The mixture is then passed through a 0.5 mm mesh sieve. Cornstarch (10 g) is suspended in warm water (90 mL). The resulting paste is used to granulate the powder. The granules are dried and crushed into small fragments on a 1.4 mm mesh sieve. The remaining amount of starch, talc, and magnesium are added, carefully mixed, and processed into tablets.

[0517] Example 133: Injectable Formulation 200 mg of the compound of the present invention Hydrochloric acid solution 0.1M or Sufficient 0.1M sodium hydroxide solution for a pH of 4.0-7.0 Enough sterile water to make 10 mL

[0518] A compound of the invention is dissolved in a large amount of water (35°-40° C.) and the pH adjusted to between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as needed. The batch is then made up to volume with water and filtered through a sterile fine pore filter into a sterile 10 mL amber glass vial (Type 1) and sealed with a sterile closure and overseal.

[0519] Example 134: Intramuscular injection 200 mg of the compound of the present invention Benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for injection, sufficient for 3.00 ml

[0520] The compound of the present invention is dissolved in glycofurol. Benzyl alcohol is then added and dissolved, and water is added to make 3 mL. The mixture is then filtered through a sterile fine-pore filter and sealed in a sterile 3 mL glass vial (Type 1).

[0521] Example 135: Syrup Formulation 250 mg of the compound of the present invention Sorbitol solution 1.50 g 2.00 g glycerol Sodium benzoate 0.005 g Flavoring 0.0125 mL Enough purified water to make 5.00 mL

[0522] The compound of the present invention is dissolved in a mixture of glycerol and a large amount of purified water. An aqueous solution of sodium benzoate is then added to the solution, followed by a sorbitol solution, and finally, flavoring. The mixture is brought to volume with purified water and mixed thoroughly.

Claims

1. 2-[4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2,4-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2,5-difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2,5-difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-fluoro-5-methoxyphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-fluoro-3-methoxyphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-chlorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[4-(propan-2-ylamino)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(1-methyl-2,3-dihydroindol-6-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-fluoro-4-methoxyphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-fluoro-4-propan-2-yloxyphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-[2-fluoro-4-(methylamino)phenyl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide; 6-chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-methylimidazo[1,2-b]pyridazine-3-carboxamide; 6-chloro-2-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 2-(2-fluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-(furan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-(2-Fluoro-5-methylphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-5-methylphenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(5-chloropyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(5-chloropyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Cyclopropylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Cyclopropylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(5-Cyclopropylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-5-methylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,4-Difluorophenyl)-5-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-7-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-5-(morpholin-4-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,3-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,3-Difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2,6-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-4-pyrrolidin-1-ylphenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 6-Methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-[5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-[6-(cyclopropylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(2-Methoxyethyl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethoxypyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethyl-2-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-ethyl-2-methylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-propan-2-ylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(6-propan-2-ylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[4-methyl-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1-methylindazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(ethylamino)-2-fluoropyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(3-methylmorpholin-4-yl)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(3-methylmorpholin-4-yl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[2-Fluoro-6-(propan-2-ylamino)pyridin-3-yl]-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[2-fluoro-6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-morpholin-4-ylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-2-Oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[6-(propan-2-ylamino)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-[6-(2-hydroxy-2-methylpropyl)pyridin-3-yl]-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-fluoropyridin-2-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-morpholin-4-ylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-morpholin-4-yl-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-5-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Fluoro-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 2-(2-Methoxy-6-methylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(2,4-Difluorophenyl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methylimidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide 6-(Azetidin-1-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine-3 -Carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-pyridin-3-ylimidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-2-(2-methylpyridin-4-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 2-(3-Fluoropyridin-4-yl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3-fluoropyridin-4-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide 2-(5-Fluoropyridin-3-yl)-6-methyl-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(5-fluoropyridin-3-yl)-6-methylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(5-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 6-Methyl-2-(6-morpholin-4-ylpyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methyl-2-(6-morpholin-4-ylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 6-(Ethylamino)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(1-methylazetidin-3-yl)oximidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-(1-methylazetidin-3-yl)oxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-(2-methoxyethoxy)imidazo[1,2-b]pyridazine-3-carboxamide 6-Methoxy-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-2-Oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenyl-6-(trideuteriomethoxy)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-phenyl-6-(trideuteriomethoxy)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide 6-chloro-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(2-fluorophenyl)imidazo[1,2-b]pyridazine-3-carboxamide 6-chloro-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-(5-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3-fluoropyridin-4-yl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-6-methoxy-2-(6-methylpyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide 2-(6-Ethylpyridin-3-yl)-6-methoxy-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 6-Ethoxy-2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide 2-(6-ethylpyridin-3-yl)-N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-6-( 2 H 3 )Methoxyimidazo[1,2-b]pyridazine-3-carboxamide 2-(6-[(3S*)-3-Methylmorpholin-4-yl]pyridin-3-yl)-N-[(3S)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[(3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-{6-[(3S*)-3-methylmorpholin-4-yl]pyridin-3-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(3S)-9-Fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(1H-indazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide or a pharmaceutically acceptable salt thereof.

2. 2-(2-Fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof.

3. 10. A pharmaceutical composition comprising a compound as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

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