Pyrazolo derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors for use as antiviral agents

Abstract

The present invention relates to hDHODH inhibitors, particularly 2-hydroxypyrazolo[1,5-a]pyridine derivatives, for use as antiviral agents. The hDHODH inhibitors for use according to the present invention are effective as inhibitors of the replication of a broad spectrum of both DNA and RNA viruses, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), influenza A virus, influenza B virus, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome-associated coronavirus (MERS-CoV).

Description

[Technical Field]

[0001] Field of Invention This invention relates to a human dihydroorotate dehydrogenase (hDHODH) inhibitor for use as an antiviral agent. The hDHODH inhibitor for use according to this invention is effective as an antiviral agent by triggering host cell pyrimidine depletion due to inhibition of hDHODH. The hDHODH inhibitor for use according to this invention is effective, in particular, against a broad spectrum of both RNA viruses and DNA viruses, including SARS-CoV-2, as well as other important human viral pathogens. [Background technology]

[0002] Background of the Invention While the long-term social and economic impacts of the COVID-19 pandemic are unpredictable, the strategic decisions made now and in the coming months will be among the most important of generations to come. Strategic actions recommended after numerous emerging and re-emerging RNA virus outbreaks, such as investment in broad-spectrum antivirals (BSAAs), to better prepare for other viral disease outbreaks remain insufficient, and this has led to the current crisis scenario. Among BSAAs, which can adapt rapidly from pandemic events to others, host-targeted antivirals (HTAs) work by interfering with the cellular biochemical pathways normally used by various viruses for replication, thereby overcoming viral specificity and potential viral mutagenesis.

[0003] Human dihydroorotic acid dehydrogenase (hDHODH, EC 1.3.99.11), located in the inner mitochondrial membrane, is a flavin-dependent enzyme involved in denovopyrimidine biosynthesis. It catalyzes the rate-limiting step in denovopyrimidine biosynthesis, converting dihydroorotic acid (DHO) to orotic acid (ORO). hDHODH has already been validated as a therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Furthermore, hDHODH has also been shown to be a target for triple-negative breast cancer. 1 PTEN-mutated tumors 2 KRAS-driven tumors 3 Acute myeloid leukemia (AML) and viral infections 4 It has also recently been identified as a relevant target in the treatment of AML. The link to AML opens the door to a completely new perspective on the treatment of this disease and in the field of hDHODH. Perhaps all of these diverse malignancies converge on similar pathways of metabolic reprogramming that drive their dependence on pyrimidine synthesis and sensitivity to DHODH inhibition.

[0004] The present inventors have recently found that the efficacy of the enzyme hDHODH, in particular, has been significantly increased (hDHODH, C 50 Compound 1 (1.2 nM) and compound 1 (reference) which has excellent drug-like properties. 6 A novel class of hDHODH inhibitors, including compound 4 (in this context). 5 This was confirmed and characterized. [Overview of the project]

[0005] Summary of the Invention Unexpectedly, the inventors have now discovered that Compound 1 and its derivatives exemplified by the following formulas (I)-(V) are also potent and broad-spectrum antiviral agents, including against SARS-CoV-2. The studies conducted by the inventors have devoted time to investigating the use of Compound 1 and its derivatives as broad-spectrum antiviral agents (BSAAs), and to refining the structure-activity relationship (SAR) of this class of hDHODH inhibitors. As exemplified in detail below, the tested hDHODH inhibitors for use according to the present invention advantageously showed high activity in vitro. In particular, Compound 1 can block virus replication at a concentration logarithmically one order of magnitude lower than that obtained by brequinar, so Compound 1 is superior to brequinar in terms of antiviral efficacy and safety profile. EC 50 74 nM and a surprisingly potent SI (>7900, CC 50 >500 μM) in its ability to inhibit SARS-CoV-2 replication, Compound 1 has one of the most potent and safe in vitro profiles obtained to date against SARS-CoV-2 replication in E6 cells. Compound 1 was also investigated as a BSAA against other viruses and showed similar efficacy.

[0006] To open the way for future preclinical and clinical applications, the inventors have also conducted several studies on the pK, oral and intravenous half-lives, in vivo toxicity and metabolism of the compounds for use according to the present invention, and their in vitro activity against several selected pathogenic viruses. Those tests are exemplified below. These compounds were tested against the following viruses: herpes simplex virus types 1 and 2, influenza virus, and several pathogenic viruses related to the respiratory tract such as respiratory syncytial virus (RSV), which is one of the main causes of hospitalization and death in infants, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the same family as the causative viruses of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

Mode for Carrying Out the Invention

[0007] Detailed description of the invention The present invention relates to a class of hDHODH inhibitors, which are 2-hydroxypyrazolo[1,5-a]pyridines based on uncommon carboxyl group bioequations, for use as antiviral agents, i.e., inhibitors of viral replication.

[0008] 2-Hydroxypyrazolo[1,5-a]pyridine is a system that has not been extensively explored in the literature. This description reports on its scaffold-hopping use as a bioequivalent of a carboxyl functional group (often present in DHODH inhibitor structures) in the preparation of two series of derivatives. In the first series, in addition to examining the moiety itself (compounds 2-5, Figure 1A), the inventors also investigated the effect of introducing chloro and methyl groups into the pyridine ring to improve its lipophilic interaction with the hDHODH subsite 4 (compounds 2, 3, and 4, Figure 1), or the effect of replacing the pyridine moiety with a tetrahydrolyzed pyridine (piperidine) moiety, as in compound 5. The second ring of the biphenyl scaffold was also studied by inserting either a polar moiety (compounds 6, 8, 9, 14) or a lipophilic moiety (compounds 7, 10-13, 15-17).

[0009] In the second series (compounds 18, 23, 24, 26-37, Figures 2A and 2B), the inventors replaced biphenyl substituents with more flexible diphenyl ethers to improve their pharmacokinetic properties and provide a wider range of drug-like compounds. The theoretical design, synthesis, SAR, biological assays, physicochemical characteristics, and preliminary ADME profiles of these compounds are presented and discussed below.

[0010] Accordingly, a first aspect of the present invention is a 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based hDHODH inhibitor of formula (I), (II), (III), (IV), or (V) as illustrated below, for use in inhibiting viral replication or as an antiviral agent. [ka]

[0011] In equations (I) through (V) above: R1, R2, R4, and R5 are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group, a cycloalkyloxy group, an alkylthio group, a haloalkyl group, a haloalkyloxy group, a nitro group, a cyano group, and an alkylamino group; R3 is selected from optionally substituted phenyl groups, heteroaryl groups, pyridinyl groups, piperidinyl groups, phenoxy groups, pyridinoxy groups, piperidinyloxy groups, phenylthio groups, azinyl groups, phenylsulfonyl groups, phenylsulfinyl groups, phenylsulfonylamino groups, alkyl groups, alkyloxy groups, alkylthio groups, haloalkyl groups, and haloalkyloxy groups; R7, R8, and R9 are independently selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, a haloalkyl group, a thioalkyl group, an aminoalkyl group, an alkyl group, and a hydroxyalkyl group; R6 is selected from alkyloxy groups, halogen atoms, acyloxy groups, monophosphate groups, hydroxyl groups, thiol groups, amino groups, or salts thereof; X, Y, and Z are independently selected from carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms, wherein one of X, Y, or Z is nitrogen, oxygen, or sulfur, and the remaining two are carbon atoms; In formula (I), T is a carbon atom or a heteroatom-like nitrogen atom, provided that when T is a nitrogen atom, R in formula (I) 5 It does not exist; In formula (IV), M is selected from sp2 carbon atoms, sp3 nitrogen atoms, sp2 nitrogen atoms, carbonyl groups, and sulfonyl groups; In formula (IV), Q is selected from sp2 carbon atoms, carbonyl groups, thiocarbonyl groups, sulfonyl groups, polyhalogenated C2-alkyl chains, carbonylamino groups, aminocarbonyl groups, sp2 nitrogen atoms, and sp3 nitrogen atoms; However, if M is an sp2 carbon atom, then Q is an sp2 carbon atom; if M is an sp3 nitrogen atom, then Q is a carbonyl group, a thiocarbonyl group, a sulfonyl group, a polyhalogenated C2-alkyl chain, a carbonylamino group, or an aminocarbonyl group; if M is an sp2 nitrogen atom, then Q is an sp2 nitrogen atom; if M is a carbonyl group or a sulfonyl group, then Q is an sp3 nitrogen atom; In formula (V), Het is selected from azoles such as imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, and tetrazole.

[0012] In a preferred embodiment, at least one of R1, R2, R4, and R5 is or contains a halogen atom. A preferred halogen atom is a fluorine atom (F). In a particularly preferred embodiment, all of R1, R2, R4, and R5 are fluorine (F).

[0013] The preferred alkyls in the definitions of R1, R2, R4, and R5 are C1-C6 alkyls, and more preferably C1-C4 alkyls. The alkyls are either linear or branched.

[0014] The particularly preferred meanings of R1, R2, R4 and / or R5 are H (hydrogen), F (fluorine), Cl (chlorine), -CH3, -CH(CH3)2, -O-CH(CH3)2, -O-cyclobutyl, -O-CH(CH3)(CH2CH3), -O-CH(CH2CH3)2, and -O-CH(CH3)(CH2CH2CH3).

[0015] In the definition of R3, preferred alkyls are C1-C12 alkyls. The alkyls are either linear or branched.

[0016] The particularly preferred meaning of R3 is an optionally substituted radical of phenyl, phenoxy, thiophenol, morpholine, thiophene, pyridine, and indole. Preferred substituents are, for example, halogen atoms (e.g., F or Cl), alkyl or alkoxy groups (methyl, methoxy, ethylethoxy, propyl, propoxy, etc.); haloalkyl or haloalkoxy groups (trifluoroalkyl, trifluoroalkoxy, difluoroalkyl, difluoroalkoxy, fluoroalkyl, fluoroalkoxy, etc., where alkyl is preferably methyl, ethyl, propyl, or butyl); -OH; oxyketones and oxyalcohols (oxypropanone, oxypropanol, etc.).

[0017] The preferred alkyl in the definitions of R7, R8, and R9 is a C1-C6 alkyl, and more preferably a C1-C4 alkyl. The alkyl is either linear or branched.

[0018] In the definition of R6, if R6 is an OH group or a monophosphate, the preferred salt is Na + , K + Ca or Cs 2+ It is salt.

[0019] In all of the embodiments described above, the preferred C1-C4 alkyl groups for R7 and R8 are methyl groups, while X, Y, and Z are all sp2 carbon atoms.

[0020] The following equation (Ia) illustrates a preferred embodiment of equation (I), where X=Y=Z is sp 2 It is a carbon atom, and R9 is a proton: [ka]

[0021] Preferred compounds that fall within the range of formulas (I) and (Ia) are compounds 1-4, 6-18, 23-24, 26-37, and 40-43, as illustrated in Figures 1 and 2.

[0022] The following equation (IIa) illustrates a preferred embodiment of equation (II), where X=Y=Z is sp 3 It is a carbon atom, and R9 is a proton: [ka]

[0023] Preferred compounds that fit into formulas (I) to (V) are compounds 1 to 43, illustrated in Figures 1A, 1B, and 2A, 2B, and 2C.

[0024] Particularly preferred inhibitors for use according to the present invention are compounds 1 and 17, which have the structural formulas shown below: [ka]

[0025] Particularly preferred compounds 1 (also known as "MEDS433") and 17 exhibit Brekinal-like hDHODH efficacy levels in vitro and demonstrate superior antiviral efficacy and selectivity for blocking viral replication at concentrations that are an order of magnitude lower logarithmically than those achieved in experiments with Brekinal.

[0026] A second aspect of the present invention is an antiviral pharmaceutical composition comprising a 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based hDHODH inhibitor of formulas (I) to (V) as defined above as an antiviral agent, and a pharmaceutically acceptable carrier, excipient and / or diluent.

[0027] A third aspect of the present invention is a 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based hDHODH inhibitor of the previously defined general formulas (I) to (V) for use in the therapeutic treatment of viral infections in subjects, wherein the virus is preferably pathogenic.

[0028] In all of the aforementioned aspects of the present invention, the virus is a DNA virus or an RNA virus. Preferably, the virus is selected from the group consisting of the Herpesviridae, Orthomyxoviridae, Paramyxoviridae, and Coronaviridae families. More preferably, the virus is selected from the group consisting of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), influenza A virus, influenza B virus, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome-associated coronavirus (MERS-CoV).

[0029] The following experimental section is provided solely for illustrative purposes and is not intended to limit the scope of the invention as defined by the attached claims. [Brief explanation of the drawing]

[0030] In the experimental section, the following diagrams are to be referenced: [Figure 1A] Figures 1A, 1B and 2A, 2B, 2C show the structures of compounds 1-43, which are preferred compounds for use in accordance with the present invention. [Figure 1B] Figures 1A, 1B and 2A, 2B, 2C show the structures of compounds 1-43, which are preferred compounds for use in accordance with the present invention. [Figure 2A] Figures 1A, 1B and 2A, 2B, 2C show the structures of compounds 1-43, which are preferred compounds for use in accordance with the present invention. [Figure 2B] Figures 1A, 1B and 2A, 2B, 2C show the structures of compounds 1-43, which are preferred compounds for use in accordance with the present invention. [Figure 2C] Figures 1A, 1B and 2A, 2B, 2C show the structures of compounds 1-43, which are preferred compounds for use in accordance with the present invention. [Figure 3]Figure 3 includes two schematic diagrams showing that the antiviral activity of compound 1 against RSV is rescued by uridine and orotic acid. [Figure 4] Figure 4 is a graph showing that compound 1 inhibits SARS-CoV-2 replication in VeroE6 cells.

[0031] Experiment Part Synthesis scheme: [ka] Scheme 1. Synthetic methods for the synthesis of compounds 1, 5, and 10-13: i) Oxalyl chloride, anhydrous DMF, anhydrous THF; ii) AlMe3, anhydrous toluene, reflux; iii) H2, Pd / C, 37% w / w HCl, ethanol; iv) H2, Pd / C, anhydrous THF, 40 bar, 65°C, SynthWAVE.

[0032] [ka] Scheme 2. Synthetic methods for the synthesis of compounds 6-9 and 14-17: i) Cs2CO3, 4-MeOBnBr, anhydrous DMF; ii) 5M NaOH, ethanol, 75°C; iii) nitrogen atmosphere, oxalyl chloride, anhydrous DMF, anhydrous THF; iv) AlMe3, anhydrous toluene, reflux; v) a) Pd(Ph3)4, K2CO3, dioxane / water (9:1v / v), 1h, rt, b) corresponding boronic acid, reflux; vi) nitrogen atmosphere, morpholine, Cs2CO3, Pd(OAc)2, BINAP, anhydrous toluene, sealed tube, 110°C; vii) thioanisole, trifluoroacetic acid, 70°C.

[0033] [ka] Scheme 3. Synthesis method for compound 4: i) Cs2CO3, tert-butoxycarbonyl anhydride, anhydrous THF, reflux; ii) a) nitrogen atmosphere, lithium hexamethyldisilazide (LiHMDS, 1.0M, anhydrous THF), -78℃, 1h; b) nitrogen atmosphere, hexachloroethane, rt; iii) trifluoroacetic acid, anhydrous dichloromethane, rt; iv) benzyl bromide, Cs2CO3, anhydrous DMF, rt; v) 6M NaOH, anhydrous ethanol, 75℃; vi) nitrogen atmosphere, oxalyl chloride, anhydrous DMF, anhydrous THF; vii) AlMe3, anhydrous toluene, reflux; viiii) thioanisole, trifluoroacetic acid, 70℃.

[0034] [ka] Scheme 4. Synthetic methods for the synthesis of compounds 19-24, 28-30 and 37: i) oxalyl chloride, anhydrous DMF, anhydrous THF, nitrogen atmosphere; ii) anhydrous toluene, anhydrous pyridine; iii) H2, Pd / C, anhydrous THF.

[0035] [ka] Scheme 5. Synthetic methods for the synthesis of compounds 26, 31-36: i) Oxalyl chloride, anhydrous DMF, anhydrous THF, nitrogen atmosphere; ii) anhydrous toluene, anhydrous pyridine; iii) thioanisole, trifluoroacetic acid, 70°C.

[0036] [ka] Scheme 6. Synthesis method for compounds 25 and 38: i) NaNO2, HNO3, water, 0°C; ii) aqueous solution at pH 10, 0°C.

[0037] [ka] Scheme 7. Synthetic method for the synthesis of compound 39: i) CH3I, Cs2CO3, anhydrous DMF, rt; ii) hydrazine monohydrate, EtOH, 80°C; iii) 4-bromo-2,3,5,6-tetrafluorobenzoic acid, POCl3, 50°C; iv) Pd(PPh3)4, K2CO3, phenylboronic acid, dioxane:H2O 9 / 1v / v, 90°C; v) BBr31M, anhydrous DCM, 0°C.

[0038] [ka] Scheme 8. Synthetic method for the synthesis of compound 40: i) Oxalyl chloride, anhydrous DMF, anhydrous THF, rt; ii) 4-bromo-2,3,5,6-tetrafluoroaniline, lithium bis(trimethylsilyl)amide (LiHMDS), 1M in THF, 70℃; iii) 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), anhydrous DMF, chloroacetone, rt; iv) diethylaminosulfur trifluoride (trifluoride) (DAST), DCM, rt; v) K2CO3, PdCl2 (dppf), bis(pinacorato)diborone, dioxane, 100℃; vi) K2CO3, Pd(PPh3)4, dioxane / water (9:1v / v), 90℃; vii) TFA, thioanisole, rt;

[0039] [ka] Scheme 9. Synthesis methods for compounds 41 and 43: i) K2CO3, PdCl2(dppf), bis(pinacolato)diborone, dioxane, 100°C; ii) K2CO3, Pd(PPh3)4, dioxane / water (9:1v / v), 90°C; iii) TFA, thioanisole, rt; iv) NaBH4, anhydrous EtOH, rt;

[0040] [ka] Scheme 10. Synthetic method for the synthesis of compound 42: i) Diisopropyl azodicarboxylate (DIAD), PPh3, 1,3-propanediol, anhydrous THF, rt; ii) NaH, di-tert-butyl dicarbonate, anhydrous THF, rt; iii) K2CO3, PdCl2 (dppf), bis(pinacolato)diborone, dioxane, 100℃; iv) K2CO3, Pd(PPh3)4, dioxane / water (9:1v / v), 90℃; iii) TFA, thioanisole, rt.

[0041] Results and Discussion Chemistry: Synthesis of Compounds 2-43 For the synthesis of compounds 5 and 10-13, a previously studied chemical strategy was used for lead compound 1 (see Scheme 1). This scheme starts from the protected 2-hydroxypyrazolo[1,5-a]pyridine building block 45, the latter of which was obtained by step 44 in two steps. 6 From 45, the corresponding acilclorides were obtained and used directly without further purification. Because the reactivity with these acilclorides was poor, each aniline (46-50) was converted to the more reactive dimethylamidoaluminum, and these latters were reacted with the acilclorides to obtain the desired amides 51-55 in a yield range of 31-40%. Note how the benzyl protecting group is transposed from the extra-ring oxygen to the intra-ring N1 nitrogen in the pyrazolo[1,5-a]pyridine system during this coupling step. 6 The removal of the benzyloxy moiety of 51 was always affected by the presence of a side reaction leading to a trace amount of reduced 5. In this case, by applying stronger catalytic hydrogenation conditions (40 bar) and using a SynthWAVE apparatus, 5 was obtained in 44% yield. Conversely, to avoid such side reactions, compounds 52-55 were converted to the desired target compounds 10-13 by applying catalytic hydrogenation at atmospheric pressure in the presence of 37% w / w HCl.

[0042] For the synthesis of compounds 6-9 and 14-17, the inventors designed a convergent synthetic approach (Scheme 2) involving the Suzuki coupling of compound 58 as a general intermediate. In this case as well, the scheme began with 2-hydroxypyrazolo[1,5-a]pyridine 44, which was protected with 4-methoxybenzyl bromide, yielding positional isomers 56a and 56b in 61% and 27% ratios, respectively (see SI for spectroscopic characterization of the two positional isomers). The 4-methoxybenzyl protecting group can be readily removed under acidic conditions and is applicable to molecules containing sulfur atoms and pyridine rings, both of which are known to be detrimental to metal catalysts during co-hydrogenation. Ester 56a was then hydrolyzed under basic conditions to obtain the corresponding acid 57 (quantitative yield), which was subsequently used to prepare general intermediate 58. Starting with acid 57, the corresponding asyl chloride was obtained by treatment with oxalyl chloride, which was used without further purification in the reaction of 2,3,5,6-tetrafluoro-4-bromoaniline with dimethylamidoaluminum to provide the desired amide 58 in 55% yield. In this case as well, transposition of the benzyl protecting group from the extracyclic oxygen to the intracyclic N1 nitrogen of the pyrazolo[1,5-a]pyridine was observed. Compound 58 was used as a commune building block for the desired compounds 59, 60-66. First, Buchwald-Hartwig coupling with morpholine was performed. 7 By applying the conditions, compound 59 was obtained (yield 59%), and then 60-66 were obtained by the Suzuki reaction involving the corresponding boronic acid (yield range: 70-94%). Compounds 59 and 66 were then converted to the desired targets 6-9 and 14-17 by treatment with trifluoroacetic acid (TFA) in the presence of thioanisole as a scavenger.

[0043] A specialized synthetic scheme was applied to the synthesis of compound 4 (Scheme 3). In this case, the hydroxyl group of 44 was O-protected with a Boc group to provide 67. Lithium hexamethyldisilazide was used for 67, and the pyrazolo[1,5-a]pyridine moiety was selectively deprotonated at position 7; followed by Cl +The lithium salt of compound 67 was quenched using hexachloroethane, which was used as a source of the electrophile, and compound 68 was provided in good yield. 8 To move along this reaction scheme and prepare for the subsequent coupling step, the Boc group was ideally replaced with a benzyl group. The Boc group was quantitatively removed under mild acidic conditions (TFA) to obtain hydroxyazole 69, which was reacted with benzyl bromide to yield compound 70 (90% for both steps). It is noteworthy that in this case, due to the presence of chlorine at position 7, only trace amounts of the intraring N1 isomer were obtained. Next, ester 70 was hydrolyzed under basic conditions to obtain the corresponding acid 71 (quantitative yield), which was used as dimethylamidoaluminum to prepare amide 72 using the previously described conditions involved in the activation of 2,3,5,6-tetrafluoro-4-phenylaniline, yielding the desired amide 72 in 38% yield. Compound 72 was then converted to the desired target 4 by treatment with TFA in the presence of thioanisole as a scavenger.

[0044] The synthetic strategies used to produce 2-aryloxypyrazolo[1,5-a]pyridine building blocks 45 and 57, which are useful for the synthesis of target compounds 19-24, 26 and 28-37, are described in our prior publications. 6This was achieved using the procedures and conditions detailed in (Scheme 4). Starting with acid 45, compounds 73-82 were prepared by a known procedure (see Scheme 4), and the corresponding acilclorides were obtained by treatment with oxalyl chloride, which were dried and used directly without further purification. In contrast to our earlier studies focused on hDHODH, this acilcloride could react directly with the previously synthesized corresponding aniline (83-92). The desired amides 73-82 were obtained in a yield range of 50-92%. Proceeding further, compounds 73-82 were converted to the desired target compounds 19-24, 28-30, and 37 by applying catalytic hydrogenation at atmospheric pressure. Starting with acid 57, compounds 93-99 were prepared (see Scheme 5), and the corresponding acilclorides were obtained by treatment with oxalyl chloride, which were dried and used directly without further purification. This acyl chloride could react directly with the previously synthesized corresponding aniline (100-106). The desired amides 93-99 were obtained in a yield range of 61-94%. Proceeding further, compounds 93-99 were converted to the desired targets 26, 31-36 by treatment with trifluoroacetic acid (TFA) in the presence of thioanisole as a scavenger. In contrast to the strategy applied in Scheme 1, a 4-methoxybenzyl protecting group was used because it can be easily removed under acidic conditions and is applicable to molecules containing sulfur atoms and pyridine rings, both of which have been found to be detrimental to the metal catalyst during hydrogenation in the final step.

[0045] The synthetic strategy used to produce compounds 25 and 38 was achieved by diazotization of 2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-amine and commercially available 4-phenoxyaniline using sodium nitrite and nitric acid, and coupling with 108 under basic conditions (Scheme 6). Compound 108 can be assimilated to phenol, and the carbon atom with the highest electron density is usually the preferred coupling position for the diazonium salt. Due to the direct influence of the hydroxyl group in the pyrazolo[1,5-a]pyridine-2-ol system, the coupling occurs at position 3.

[0046] The synthetic strategy (Scheme 7) used to produce compound 39 began with 2-hydroxypyrazolo[1,5-a]pyridine 44, which was protected with methyl iodide to yield positional isomers 110a and 110b in proportions of 77% and 13%, respectively. This methyl protecting group can be readily removed under acidic conditions. Positional isomer 110a could be reacted with hydrazine monohydrate to yield compound 111. These reactions proceeded through cyclocondensation of 111 with 4-bromo-2,3,5,6-tetrafluorobenzoic acid to obtain compound 112. This latter was functionalized by the Suzuki reaction to obtain compound 113. Proceeding further, compound 113 was converted to the desired target 39 by treatment with BBr3.

[0047] For the synthesis of compounds 40-43, the inventors designed a convergent synthetic approach involving a Suzuki coupling of compound 114 as a general intermediate. In this case as well, the scheme began with compound 57, which was then used to prepare the general intermediate 114. Starting with acid 57, the corresponding acyl chloride was obtained by treatment with oxalyl chloride, which was used without further purification in the reaction with the lithium salt of 2,3,5,6-tetrafluoro-4-bromoaniline to give the desired amide 114 in 80% yield. In this case, the transposition of the benzyl protecting group from the extracyclic oxygen to the intracyclic N1 nitrogen did not result in the presence of pyrazolo[1,5-a]pyridine compounds, and the yield was increased. Compound 57 was used as a commune building block for the synthesis of the desired compounds 119, 121, and 125 by a Suzuki reaction involving the corresponding boronic acid pinacol ester (see schemes 8, 9, and 10 for this synthesis). Next, compounds 119, 121, and 125 were converted to the desired targets 40-42 by treatment with trifluoroacetic acid (TFA) in the presence of thioanisole as a scavenger. Finally, compound 43 was obtained from compound 41 by ketone reduction using NaBH4.

[0048] hDHODH inhibitory activity and SAR. The inventors used three clinical trial candidates (brequinar, BAY-2402234, and ASLAN003) and 1 as a comparative example to evaluate the recombinant hDHODH inhibitory activity of compound 4-43. BAY-2402234 was purchased from a commercial supplier, while brequinar was synthesized according to known procedures. To complete this scenario and prepare for the following cell-based study considerations, LogD 7.4 , solubility in PBS, and protein binding were also measured for each compound.

[0049] SAR analysis of the pyridine ring (A ring) of the 2-hydroxypyrazolo[1,5-a]pyridine scaffold.

Chemical formula

[0050] Table 1: Enzyme inhibitory activities of compounds 2-17, brequinar, BAY-2402234, ASLAN003 and 1 as a comparative example, and relative LogD 7.4 , solubility and protein binding. The effects of these compounds are represented as IC 50 values. Limit of detection (LOD): value 6 μM. The note "nd" indicates that the compound was not tested in that particular assay.

Table 1

[0051] SAR analysis of the D-ring of the biphenyl-based scaffold: Phenyl replacement / modification. Moving on to the D-ring, the inventors first assigned the first four compounds (6-9) to the study of their possible isosteric replacements (Table 1). Incorporation of the morpholine substituent (6, IC 50 = 90.9 nM) was poorly tolerated as a phenyl ring and resulted in a decrease in potency of approximately 50-fold compared to 1. Introduction of a heteroatom that may interact with the lipophilic subpocket composed of Pro69 and Leu68 is repulsive as a decrease in potency is also observed for the pyridine derivative 9 (Figure 1A). However, 6 is the most soluble in this series and shows almost twice the solubility of brequinar. Replacement of the D-ring with the classical bioisostere thiophene (7, IC 50 = 1.35 nM) retained the inhibition profile. The optimal logD 7.4 range for optimal drug absorption is considered to be in the range of 1-3 via the phenomenon of passive permeability or diffusion. 13 . For hDHODH inhibitors, the literature points out an optimal logD 7.4 value that is excellent for the adsorption issue with a decrease of 2.50.11 Regarding activity, substitution of the phenyl position at 1 with classical equivalent nitrogen, such as at 8 and 9, resulted in a loss of activity (IC). Meta substitution is more tolerant. 50 (=6.23nM and 150nM). To better understand this result, 9 is the case where -CF3 is still present at the meta position, but nitrogen has been ideally removed 13 (IC 50 It should be compared with (6.34 nM). These two pyridine analogs 8 and 9 showed better solubility than 1, 4 times and 1.5 times, respectively. Some significant improvement in protein binding was observed.

[0052] Next, the inventors investigated suitable positions on the D ring for substitution in compound 10-17. The bonding modes of 1 and its derivatives involve positioning the D ring adjacent to the entrance of the ubiquinone bond pocket, with the meta position exposed in the vacant region of the bond site on the boundary between the pocket and the vacuum. The inventors investigated the effect of lipophilic substitutions such as F and CF3 at the para (10, 12) and meta (11, 13) positions of the D ring using 10-13. These results were analyzed (Table 1), and each IC was determined. 50 =2.03nM and IC 50 How does the meta replacement of 11 and 13, which is 6.34nM, affect IC? 50 =17.7nM and IC 50It can be acknowledged that it was better accepted than para-isomers 10 and 12, which have a mM of 71.8 nM. Since fluorine is a biological equivalent substitution of a classical proton, it is not surprising that the activity of 11 is in the same range as 1; however, this cannot be said for 13, where a small lipophilic group such as -CF3 was well accepted. This substitution validated the presumed bonding mode of 13, where trifluoromethyl was placed in the vacant region of the binding site. These modifications resulted in a more lipophilic compound, as expected, but unfortunately this property was associated with insolubility, and these values ​​were well below the reference limit of 6 μM. Focusing on meta-positional substitutions, the inventors have found that 1 is equivalent to 1 itself in terms of efficacy, but is characterized by better solubility (approximately 5 times greater) because the oxygen atom can form hydrogen bonds with water, and is equivalent to that of Brekinal itself (logD). 7.4 Compound 14 (IC) has 50 A value of 2.78 nM was obtained. By ideally modifying 14, the inventors introduced substitutions to the phenolic oxygen, producing 15-17 (Table 1) and 40-43 (Table 2). This modification yields an IC value equivalent to 1. 50 This generates a re-estimated bonding mode and provides LogD for each compound. 7.4 This was related to the increase in LogD. The most interesting compounds are 17, 40-43, which are characterized by the introduction of a propoxy group. These are the most interesting compounds in the series described herein, as they are equivalent to Lead 1 in terms of efficacy, although compound 17 has similar solubility but a higher LogD. 7.4 This indicates (exceeding 2.5 times the threshold).

[0053] SAR analysis of biphenyl-based scaffolds. While their potent inhibition of hDHODH was evaluated in vitro, the solubility profile of compound 1 differed significantly from that of Brekinal, and the presence of tetrafluorobiphenyl substituents was detrimental to its solubility. With the goal of obtaining alternative scaffolds that are expected to provide comparable hDHODH inhibition to compound 1, a novel series of inhibitors was developed, starting from the lead structure of compound 18. 6 As a result, 18 analogues lacking the biphenyl scaffold (compounds 19-24, 26-37) were designed to explore novel possibilities (Figures 2A and 2B). This idea was inspired by the literature of Das et al. 14 The study obtained from the research described how the “Breknal-like” activity was reproduced by analogs containing substituted diaryl ethers. The rationale behind the design of target 26 arose from the concept of equivalents. Compound 18 showed good interaction within the enzyme binding pocket, so the overall structure of this molecule was maintained, but a more polar compound was realized. This led to the decision to develop a pyridine ring with an oxygen bridge between the C and D rings, which is changed to a sulfur bridge, a target in which the D ring is replaced by a more polar equivalent: Target 27-35 represent compounds proposed after SAR testing of compound 18 in an attempt to increase their binding affinity. The presence of additional ether substituents allows exploration of still largely unexplored regions in its binding site. Research into the possibility of additional hydrophobic interactions with several lipophilic amino acid residues in subsite 1 contributed to the development of differently substituted diaryl ethers that allow these compounds to acquire efficacy and selectivity for hDHODH. Table 2 shows the results of SAR tests in which modification 18 was instructed to be different from 1, regarding the presence of an aryloxy moiety that was asked to interact with hDHODH subsite 1.

[0054] Substitution of the phenoxyphenyl moiety with azo-modified partial indole-5-yl, N-phenylindole-5-yl, N1-phenylbenzominidazole-5-yl, or N1-phenylbenzotriazolyl (compounds 19-22, respectively), as well as substitution of one of the two phenyl groups with a pyridine ring (compounds 23, 24, 26), is detrimental to its activity. Removal of the ortho-positional methyl from the amide functional group (compound 27) reduces its activity by a factor of ten, while removal of the meta-positional methyl (compound 28) is detrimental, highlighting the importance of small substituents at the meta position. Indeed, substitution of a meta-positional methyl substituent with a larger chain such as isopropyl (compound 30) halves its activity. Moving to the ortho position, large substituents such as isopropyl (compound 29) increase its activity, while substitution with various alkyloxy moieties (compounds 31-35) neutralizes its activity. Similarly, in the phenoxyphenyl flame, the para-position trifluoromethyl substituent (compound 37) reduces its activity.

[0055] SAR analysis of “MQ” and “Het” linkers. Substitution of amide functional groups with diazo functional groups in IC of derivatives 25 and 38. 50 As shown, its activity is maintained only in the presence of tetrafluorobiphenyl substituents, indicating that the biological equivalence properties between the amide linker and the diazo linker exist only in compound 25. On the other hand, derivative 39 has a very low IC compared to compound 1. 50 As shown, substitution of the amide functional group with the 1,3,5-oxadiazole moiety is not beneficial to its activity.

[0056] Table 2: Enzyme inhibitory activity of compounds 18-43 and relative LogD 7.4 and solubility. The action of the compound is IC 50 It is expressed as a value. Limit of Detection (LOD): 6 μM. [Table 2]

[0057] Physicochemical properties Determining the major physicochemical properties governing the ADME profile involves determining the lipophilicity (logD) of all compounds at physiological pH. 7.4 This was carried out by measuring the solubility of the substance.

[0058] Thermodynamic solubility was determined using the equilibrium shake flask thermodynamic solubility method in phosphate-buffered saline (PBS, pH=7.4), which was selected for its ability to simulate plasma pH and osmotic molar concentration.

[0059] Lipophilicity. The shaking flask method was selected to determine logD7.4. In addition, lipophilicity was estimated in silico, and clogP was calculated for each compound using Bio-Loom software for Windows® version 1.5.

[0060] In summarizing these results, we observed an optimization in solubility for compound 6 (438 μM), resulting from the loss of a second aromatic ring and the insertion of a morpholine ring. This substitution provided two significant polar contributions to the molecule: amine and ether. Compounds 8 and 14 also represent efforts to increase solubility, with the introduction of a pyridine ring and a phenol ring in place of the C ring. These compounds can move from 12 μM of analog compound 1 to 47 μM and 55 μM, respectively. Target 17, with its propoxy chain, has almost the same low solubility as compound 1 (12.9 μM), and therefore does not show an effective improvement in this sense.

[0061] In general, it can be said that all measured solubility is far from Brekinal's solubility, and this low solubility has a reasonable interpretation as the complete deprotonation (pKa ~ 5-6) of the hydroxyl moiety of most compounds at pH = 7.4, and it is assumed that reinforced intramolecular hydrogen bonds occur between the amide hydrogen and the deprotonated hydroxyl group, resulting in the formation of a stable six-term ring. [Chem.]

[0062] In this way, the amide hydrogen is available for hydrogen-bonding (HBD) to water molecules and thus does not contribute to solubility. This hypothesis is confirmed by the crystallographic pose of the molecule in the enzyme, where intramolecular HB is emphasized.

[0063] All compounds have an optimal logD value and a good lipophilic-hydrophilic balance with respect to favorable pharmacokinetic behavior: the difference observed between clogP and measured logD 7.4 is consistent with the high ionization of these compounds at physiological pH.

[0064] The goal regarding lipophilicity is a value between 1 and 3, which is the optimal value for absorption by passive diffusion permeability after oral dosing. Compounds 6, 8, and 14, characterized by a morpholine ring, a pyridine ring, and a phenol ring, have very low lipophilicity and, instead, high solubility: as a result, these molecules will probably not be able to cross the membrane. Compound 17 shows a propoxy substituent that contributes to its ability to easily cross the phospholipid bilayer. Even if this target seems to be in a good position to reach the enzyme target, it is very insoluble and thus difficult to use in in vitro tests. A good compromise seems to be compound 26, where the presence of pyridine allows for better solubility and, at the same time, the thioether allows for a good lipophilic-hydrophilic balance.

[0065] Antiviral profile of the selected compounds Compound 1 as a novel, potent BSAA candidate. To study the feasibility of targeting hDHODH activity for the development of a pan-coronavirus HTA, thirteen newly designed hDHODH inhibitors (Table 3) were selected for their antiviral activity against prototype human β-CoV, hCoV-OC43, using FFRAs in which the test compounds were present pre-infection, during infection, and post-infection (complete-treatment). As shown in Table 3, when tested at 0.1 μM, six hDHODH inhibitors (1, 9, 15, 16, 17, 40) were able to reduce hCoV-OC43 replication by more than 50%. Notably, compound 1, MEDS433, was the most effective of the hDHODH inhibitors tested, because it completely inactivated hCoV-OC43 replication. Therefore, compound 1 was selected for further study. Having such an interesting preclinical hDHODH inhibitor under consideration, the inventors assayed compound 1 for its antiviral activity against a large panel of human viruses.

[0066] Table 3. Percentage reduction in hCoV-OC43 replication in the presence of 0.1 μM of inhibitor. HCT8 cells were pre-treated and treated with either a vehicle (DMSO) or 0.1 μM of different hDHODH inhibitors at the time of infection with hCoV-OC43 (100 PFU / well) and throughout the experiment. Viral foci were immunostained at 72 hpi, and the average number of foci in the treated cultures was compared to that of DMSO-treated and hCoV-OC43-infected control HCT8 cell monolayers. [Table 3]

[0067] Herpes simplex virus. The incidence and severity of HSV infections have been increasing over the past decade due to the growing number of immunocompromised individuals, and genital herpes infections have become one of the most prevalent sexually transmitted infections (STIs) worldwide. The lack of an effective preventive vaccine makes the management of HSV infections, particularly genital herpes, a high priority. These facts highlight the need for the development of novel anti-HSV agents, possibly with a different mechanism of action than those of approved nucleoside analogs (acyclovir, famciclovir, valacyclovir), whose long-term use could lead to treatment failure due to the development of antiviral-resistant bacteria. To this end, we tested 1 against HSV-1 and HSV-2 compared to Brequinal. As shown in Table 4, 1 potently inhibited the replication of HSV-1 and HSV-2 (PRA, Vero cells), respectively, and EC 50 The concentrations were 0.110 μM and 0.170 μM. Notably, the anti-HSV activity of 1 was approximately an order of magnitude greater and more potent than that of Brechnal, and even lower than that of the reference drug ACV (0.180 μM). Further preliminary findings indicate that the anti-HSV activity of 1 is associated with the inhibition of viral DNA synthesis and late protein expression, while very early proteins are not significantly reduced. Therefore, it is suggested that 1 targets the HSV replication cycle phase prior to viral DNA replication, which is consistent with its ability to inhibit hDHODH activity and thus cause pyrimidine loss.

[0068] Table 4: Activity of compounds 1 and 17 against the replication of different viruses compared to EIDD-1931, a drug released by prequinal, remdesivir, and the prodrug mornupyravir. [Table 4]

[0069] Respiratory viruses: Respiratory viral infections (RVIs) are a global health concern in terms of morbidity and mortality. Among them, influenza virus, respiratory syncytial virus, and coronavirus are the most common viruses that cause lower respiratory tract infections.

[0070] Influenza viruses. Influenza viruses A and B are major human pathogens that cause widespread outbreaks, seasonal epidemics, and pandemics. Seasonal vaccines represent the most effective measure to prevent and control influenza infections. Treatment of influenza infections can also benefit from two classes of approved DAA drugs, such as matrix protein inhibitors and neuraminidase inhibitors. However, their use is severely limited by the selection of resistant strains. Therefore, the development of alternative anti-influenza compounds that are effective against antigenically different viruses and characterized by novel mechanisms of action is an urgent priority. Accordingly, 1 was tested against a reference strain of influenza A virus (A / Puerto Rico / 8 / 34), and it showed potent inhibitory activity (EC). 50 0.120 μM, PRA, MDCK cells, Table 4). Again, 1 is 6 times lower EC than Blechnal. 50 It worked better with the value.

[0071] Respiratory syncytial virus. Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infections in infants and young children, leading to severe bronchiolitis and pneumonia. However, a vaccine is not yet available, and antiviral treatment is limited to palivizumab for prophylactic treatment and ribavirin, a nucleoside purine analog that suffers from significant drawbacks. Therefore, there is an urgent medical need to develop a novel compound that can block RSV replication. Considering this, the inventors tested compound 1 against RSV and found that it exhibits very potent antiviral activity (EC2). 50 0.008 μM) (Table 3) is effective SI (>10,000, CC) 50 In relation to 84 μM, it was measured in HEp-2 cells, as well as in Brechnal's cells (EC2).50 It showed a slightly superior profile to 0.015 μM. Furthermore, to verify whether the observed inhibition of RSV replication by 1 resulted from a block in pyrimidine biosynthesis, an antiviral assay using uridine-supplemented culture medium was repeated. Since uridine can be converted to UMP via the salvage pathway (Figure 3), cells can bypass the need for de novo pyrimidine biosynthesis. As shown in Figure 3, uridine supplementation inactivates anti-RSV of 1, thus confirming that this pyrimidine pathway is affected by 1 in RSV-infected cells. However, UMP, from which all other pyrimidines are induced, can be produced by both the salvage pathway and de novo biosynthesis. To distinguish these two pathways, we tested the effect of adding substrates (dihydroorotic acid, DHO) or products (orotic acid, ORO) of hDHODH on their ability to restore RSV replication. Consistent with the central role of hDHODH inhibition in the anti-RSV activity of 1, the addition of ORO instead of DHO reversed the inhibitory effect of 1 (Figure 3). In summary, these preliminary findings suggest that the mechanism of antiviral activity against RSV involves the specific targeting of hDHODH activity by 1.

[0072] Alpha- and beta-coronaviruses. Effective pan-CoV antiviral agents can be of great value in filling the gap in controlling the emergence of CoV diseases as they rapidly move from one pandemic event to another. Significant concentration-dependent inhibition of hCoV-OC43 replication was then confirmed in HCT-8 cells treated with compound 1 (Table 4). Measured EC 50 The concentration was 0.0124 ± 0.0034 μM. Compound 1 is also highly effective against another hCoV, prototype β-hCoV-229E, and its replication in MRC5 fibroblasts is EC 50 The value was significantly impaired, at 0.022 ± 0.003 μM (Table 4). Comparison with the reference drug RDV, used as a positive control for anti-hCoV antiviral activity, was found to be less effective than that of RDV (EC). 50While emphasizing the anti-hCoV-229E efficacy of compound 1 (equivalent to 0.0348±0.005μM), this hDHODH inhibitor also has an effect against hCoV-OC43, specifically RDV (EC 50 It was far more effective than (0.147 ± 0.034 μM). In contrast, compound 1 was more effective against hCOV-229E than Brekinal, and the latter was more effective against EC 50 While the EC of Brekinal against hCoV-OC43 is 0.0427±0.003 μM, 50 (0.022±0.003μM) was equivalent to that of compound 1. Finally, the anti-hCoV activity of compound 1 was not due to the cytotoxicity of the target cells themselves, but rather because of the cytotoxic concentration (CC) determined in uninfected cells. 50 The concentration was 78.48 ± 4.6 μM for HCT8 cells and 104.80 ± 19.75 μM for MRC5 fibroblasts, and the Selective Index (SI) was greater than 6,329 and 4,763 for hCoV-OC43 and hCoV-299E, respectively.

[0073] SARS-CoV-2. The emergence of COVID-19 as a global public health emergency over the past few months prompted the inventors to immediately investigate the susceptibility of SARS-CoV-2 to 1. As shown in Table 4 and Figure 4, the inventors found a very safe profile (SI>7900, CC). 50 The action of potent antiviral agents against the COVID-19 virus (EC) related to >500μM 50 (0.063 μM) (PRA, Vero E6 cells) was examined. Just before assigning these values, the anti-SARS-CoV-2 activity of 1 was the best available treatment remdesivir (EC) 50 It is an order of magnitude more potent than that of the 0.77 μM formulation, and five times more potent than EIDD-1931, a drug released by the prodrug mornupyravir.

[0074] Overall, these preliminary results strongly support a robust theory regarding the development of hDHODH inhibitors as BSAAs and strongly advocate for the further development of 1 as an effective anti-SARS-CoV-2 agent and a potent and safe BSAA, which would be extremely valuable in future pandemic scenarios.

[0075] conclusion The inventors have identified a novel class of inhibitors based on hydroxyl-pyrazolo[1,5-a]pyridine, an uncommon bioequation of the carboxylic acid functional group. Compounds 1 and 17, the most potent hDHODH inhibitors discovered to date, exhibit Blechnal-like hDHODH efficacy levels in vitro and demonstrate superior antiviral efficacy and selective blocking of viral replication at concentrations an order of magnitude lower logarithmically than those achieved in experiments with Blechnal.

[0076] Compounds 1 and 17 target the cellular gene product (DHODH), and since viruses likely cannot overcome the need for pyrimidine nucleotides, their therapeutic effects are unlikely to be impaired by the development of viral resistance. This can be particularly important for RNA viruses, whose high mutation rates often facilitate the evasion of direct-acting antiviral agents.

[0077] The key to successful COVID-19 treatment lies not only in having an effective molecule, but also in having a dosage that can be safely delivered and maintains exposure in the blood to inhibit viral replication or infection.

[0078] Therefore, it is clear that compound 1 exhibits an optimal toxicity profile and high selectivity for target activity, making it an ideal candidate for further in vivo testing in a SARS-CoV-2 model. For other viruses as well, compound 1 exhibits its EC (Environmental Control) 50 It was found that it is always effective at 170 nM or less. [Examples]

[0079] Materials and methods chemistry General Methods. All chemical reagents were obtained from commercial suppliers (Sigma Aldrich, Alfa Aesar, FluoroChem) and used without further purification. Thin-layer chromatography (TLC) was performed to monitor the progress of the reactions. Analytical-grade solvents (acetonitrile, diisopropyl ether, diethyl ether, dichloromethane [DCM], dimethylformamide [DMF], ethanol 99.8% v / v, ethyl acetate [siRNA], hexane, methanol [MeOH], petroleum ether bp 40-60°C [petroleum ether], toluene) were used without further purification. Where necessary, solvents were dried on a 4 Å molecular sieve. Tetrahydrofuran (THF) was distilled from Na and benzophenone under N2 immediately before use. Thin-layer chromatography (TLC) on silica gel was performed on 5 × 20 cm plates with a layer thickness of 0.25 mm. Anhydrous Na₂SO₄ was used as a drying agent for the organic phase. The purification of the compounds was achieved by flash column chromatography on silica gel (Merck Kieselgel 60, 230-400 mesh ASTM) using the eluent specified in the procedure for each compound, or by using the eluent specified in the procedure for each compound, with a CombiFlash® Rf 200 (Teledyne Isco (with automatic injection valve)) at 5-200 mL / min, 200 psi, and a RediSep Rf silica column (Teledyne Isco). Compounds synthesized in the inventors' laboratory generally varied in purity between 90% and 99%. Biological experiments were performed with compounds that had a purity of at least 95%. Purity was checked using two UHPLC analytical methods. HPLC analysis was performed on a UHPLC chromatography system (Perkin Elmer, Flexar). The analytical columns used were UHPLC Acquity CSH fluorophenyl (2.1 × 100 mm, particle size 1.7 μm, Waters) and reversed-phase (RP) C18 Phenomenex column (2.1 × 100 mm, particle size 1.7 μm). The compounds were dissolved in acetonitrile and injected through a 20 μl loop.The mobile phase consisted of acetonitrile / 0.1% trifluoroacetic acid-containing water (ratio 60 / 40 to 40 / 60, depending on the retention factor of the compound). UHPLC retention times were obtained at a flow rate of 0.5 mL / min, and the column effluent was monitored at 254 nm and 262 nm, with reference to 360 nm wavelength. The melting point (mp) was measured on a capillary apparatus (Buchi 540). The final mp was determined by placing the sample at a temperature 10°C lower than its mp and applying a heating rate of 1°C per minute. All compounds were... 1 H- and 13 Routine checks were performed using 1C-NMR and mass spectrometry. IR spectra of solid compounds were recorded on FT-IR (PerkinElmer SPECTRUM BXII, KBr dispersion) using a diffuse reflector DRIFT ACCY. MS spectra were performed on a Waters Micromass ZQ equipped with an ESCi source for electrospray ionization mass spectrometry. 1 H- and 13 ¹¹C-NMR spectra were performed on a JEOL ECZR600. The following abbreviations were used for the coupling pattern: br=broad line, s=single line, d=double line, dd=double double line, t=triple line, q=quadruline, m=multiline. Chemical shifts (δ) were indicated in parts per million (ppm). In this work, protons and carbons were labeled according to the diagram in the supporting information (a, b, c, d, e, f, g, h, l, m, n, o, p, q, r, and s). Asterisk ( * , ** and *** Values ​​marked with ) are interchangeable. Detailed information on tetrafluorobiphenyl compounds (final compounds 4-17 and protected final compounds) 13 The 1C spectra have not been fully reported due to their particularly complex patterns (resulting from multiple couplings between fluorine and carbon atoms). Regarding these spectra, heterocyclic substructures and non-aromatic carbons are involved. 13Only the C signal is assigned. For the final compound 4-17, the HRMS spectrum was recorded on an LTQ-Orbitrap XL Plus (Thermo Scientific, Bremen, Germany) mass spectrometer equipped with an atmospheric pressure interface and an ESI ion source. Compounds 44 and 45 were described previously. 6,18 It is prepared as described.

[0080] Ethyl 2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate (56a) and ethyl N-(4-methoxybenzyl)-2-oxo-pyrazolo[1,5-a]pyridine-3-carboxylate (56b). 4-methoxybenzyl bromide (645 mg, 3.20 mmol, 1.10 eq) was added dropwise to a mixture of 44 (600 mg, 2.91 mmol) and Cs2CO3 (2.295 g, 7.04 mmol, 2.4 eq) in anhydrous DMF (15 mL). The reaction mixture was stirred overnight at room temperature, and then water (100 mL) was added. The mixture was extracted with ELISA (4 × 70 mL), and the combined organic layers were dried under Na2SO4 and evaporated under reduced pressure to provide a yellow oily substance. The latter showed two spots on TLC (eluent: petroleum ether / siRNA at 60 / 40 v / v), which were considered to be two pyrazolo[1,5-a]-pyridine positional isomers. This mixture was separated using flash chromatography (eluent: petroleum ether / siRNA at 2 / 1 v / v, followed by dichloromethane / MeOH at 95 / 5 v / v).

[0081] 56a) Elutenated primary isomer. White solid (111.3-112.5°C) after grinding with hexane and then water. Yield 61%. 1H NMR (600 MHz, クロロホルム-d) δ 1.40 (t, J=7.1 Hz, 3H, -OCH2CH3); 3.81 (s, 3H, -OCH3), 4.36 (q, J=7.1 Hz, 2H, -OCH2CH3), 5.43 (s, 2H, -OCH2Ar), 6.83 (t, 1H, J=6.7 Hz, Hb), 6.91 (d, 2H, J=8.6 Hz, Hn), 7.35 (t, 1H, J=7.7 Hz, Hc), 7.48 (d, 2H, J=8.5 Hz, Hm), 8.00 (d, 1H, J=8.8 Hz, Hd), 8.29 (d, 1H, J=6.8 Hz, Ha); 13 C NMR (151 MHz, クロロホルム-d) δ 14.7 (-OCH2CH3), 55.4 (-OCH3), 59.7 (-OCH2CH3), 70.7 (-OCH2Ar), 88.5 (Cf), 112.6 (Cb), 113.9 (Cn), 118.3 (Cd), 127.8 (Cc) * , 128.9 (Ca) * , 129.0 (Cl) * , 129.3(Cm), 142.9 (Ce), 159.5 (Co), 163.4 (Cg) * , 165.2 (Ch) * MS (ES+): 327 (M+1).

[0082] 56b) Dissolve the second body of the opposite sex. White solid substance (ジイソプロピルエーテルから158.3-159.2℃). The yield is 27%. 1H NMR (600 MHz, DMSO-d6) δ 1.28 (t, 3H, J=7.1 Hz, -OCH2CH3); 3.69 (s, 3H, -OCH3), 4.21 (q, 2H, J=7.1 Hz, -OCH2CH3), 5.35 (s, 2H, -NCH2Ar), 6.88 (d, 2H, J=8.5 Hz, Hn), 6.96 (t, 1H, J=6.8 Hz, Hb), 7.19 (d, 2H, J=8.4 Hz, Hm), 7.58 (t, 1H, J=8.0 Hz, Hc), 7.91 (d, 1H, J=8.8 Hz, Hd), 8.45 (d, 1H, J=6.8 Hz, Ha); 13 C NMR (151 MHz, DMSO-d6) δ 14.6 (-OCH2CH3), 43.2 (-NCH2Ar), 55.1 (-OCH3), 58.5 (-OCH2CH3), 83.5 (Cf), 112.4 (Cb), 114.3 (Cn), 116.3 (Cd), 125.3 (Ca), 125.7 (Cl), 128.8 (Cm), 132.4 (Cc), 142.8 (Ce), 159.0 (Co), 160.0 (Ch) * , 163.2 (Cg) * MS (ES+): 327 (M+1).

[0083] 2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid (57). 6M NaOH (5.0 eq) was added to a solution of compound 56a (785 mg, 2.40 mmol) in EtOH (20 mL). The mixture was stirred at 75°C for 4 hours, then neutralized with 6M HCl and concentrated under reduced pressure. The mixture was cooled to 0°C and then acidified with 2M HCl to pH 2 to obtain a suspension. This was filtered to obtain 57 as a white solid (162.8–163.9°C, from water). Yield 90%. 1H NMR (600 MHz, DMSO-d6) δ 3.76 (s, 3H, -OCH3), 5.34 (s, 2H, -OCH2Ar), 6.96 (d, 2H, J=8.4 Hz, H-n), 7.02 (t, 1H, J=6.7 Hz, H-b), 7.45 (d, 2H, J=8.3 Hz, H-m), 7.51 (t, 1H, J=7.9 Hz, H-c), 7.92 (d, 1H, J=8.8 Hz, H-d), 8.66 (d, 1H, J=6.7 Hz, H-a), 12.07 (s, 1H, -COOH); 13 C NMR (151 MHz, DMSO-d6) δ 55.1 (-OCH3), 70.1 (-OCH2Ar), 87.6 (C-f), 113.1 (C-b), 113.8 (C-n), 117.3 (C-d), 128.4 (C-a) * , 128.5 (C-l) * , 129.5 (C-c) * , 129.9 (C-m), 142.3 (C-e), 159.2 (C-o), 163.5 (C-h) * , 164.4 (C-g) * ;MS (ES+): 299 (M+1)。

[0084] N-(4-bromo-2,3,5,6-tetrafluorophenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (58). Oxalyl chloride (0.54 mL, 6.30 mmol, 3.0 eq) and anhydrous DMF (1 drop) were added to a cooled (0°C) solution of 57 (630 mg, 2.10 mmol) in anhydrous THF (15 mL) maintained under nitrogen atmosphere; the resulting mixture was stirred at room temperature for 2 hours. In parallel, a 2 M solution of AlMe3 in toluene (1.8 mL, 3.57 mmol, 1.7 eq) was added to a solution of 4-bromo-2,3,5,6-tetrafluoroaniline (769 mg, 3.15 mmol, 1.5 eq) in anhydrous toluene (10 mL) under nitrogen atmosphere. The resulting suspension was stirred at room temperature for 3 hours. Next, the acilcloride solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL; this step was repeated three times). The acilcloride was dissolved in anhydrous toluene (15 mL), and this solution was added to the suspension described above. The reaction mixture was stirred overnight at 85°C, then cooled to room temperature, quenched with methanol, and then evaporated. The residue was dissolved in HCl (80 mL), then 0.5 M HCl (50 mL) was added, and the layers were separated. The combined organic layers were washed with brine, dried, and evaporated under reduced pressure. The crude material was purified by flash chromatography (eluent: petroleum ether / siRNA / DCM 2 / 1 / 1 v / v / v), and the title compound was provided as a white solid (177.4–178.0°C, ground with diisopropyl ether). Yield 55%. 1 H NMR (600 MHz, chloroform-d) δ 3.79 (s, 3H, -OCH3), 5.41 (s, 2H, -NCH2Ar), 6.77 (t, 1H, J=6.9 Hz, Hb), 6.90 (d, 2H, J=8.5 Hz, Hn), 7.21 (d, 2H, J=8.5 Hz, Hm), 7.46 (t, 1H, J=7.9, Hz, Hc), 7.75 (d, 1H, J=6.9 Hz, Ha), 8.27 (t, 1H, J=8.8 Hz, Hd), 9.98 (s, 1H, -NH); 13C NMR (151 MHz, クロロホルム-d) δ 45.2 (-NCH2Ar), 55.5 (-OCH3), 87.1 (C-f), 96.4 (t, J=22.6 Hz, C-s) * , 112.9 (C-b), 115.0 (C-n), 117.0 (t, J=14.8 Hz, C-p) * , 118.3 (C-d), 123.1 (C-a), 124.2 (C-l), 128.6 (C-m), 131.8 (C-c), 142.5 (C-e), 142.8 (dd, J=251.6, 14.9 Hz, (C-r) ** , 145.2 (dd, J=246.4, 14.2 Hz, (C-q) ** , 160.0 (C-o) *** , 161.4 (C-h) *** , 162.2 (C-g) *** ;MS (ES+): 524 / 526 (M+1)。

[0085] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-4-morpholinophenyl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (59). To a solution of 58 (420 mg, 0.80 mmol, 1.00 eq) and morpholine (209 mg, 2.40 mmol, 3.00 eq) in toluene (30 mL), Cs2CO3 (782 mg, 2.4 mmol, 3.00 eq) was added. After degassing with nitrogen for 10 minutes, Pd(OAc)2 (18 mg, 0.08 mmol, 0.10 eq) and BINAP (100 mg, 0.16 mmol, 0.20 eq) were added, and the mixture was degassed again for 5 minutes. The resulting suspension was heated at 110°C in a sealed flask under a nitrogen atmosphere. After 3.5 hours, heating was stopped, the mixture was concentrated under reduced pressure, and then water was added. The resulting suspension was extracted with toluene (3 × 50 mL), the combined organic fraction was collected, dried, and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / toluene / DCM 1 / 1 / 1 v / v / v), and the crude solid was provided. This was ground with diisopropyl ether to obtain the title compound as a white solid (237.2–237.5°C). Yield: 59%. 1 H NMR (600 MHz, chloroform-d) δ 3.24 - 3.28 (m, 4H, -NCH2CH2O-), 3.79 (s, 3H, -OCH3), 3.81 - 3.85 (m, 4H, -NCH2CH2O-), 5.40 (s, 2H, -NCH2Ar), 6.74 (t, 1H, J=6.9 Hz, Hb), 6.90 (d, 2H, J=8.5 Hz, Hn), 7.21 (d, 2H, J=8.5 Hz, Hm), 7.44 (t, 1H, J=7.9 Hz, Hc), 7.73 (d, 1H, J=6.9, Hz, Ha), 8.28 (d, 1H, J=8.9Hz, Hd), 9.75 (s, 1H, -NH); 13C NMR (151 MHz, chloroform-d) δ 45.1 (-NCH2Ar), 51.5 (-NCH2CH2O-), 55.5 (-OCH3) , 67.5 (-NCH2CH2O-), 87.2 (Cf), 111.3 (t, J=15.5 Hz, Cp) * , 112.6 (Cb), 114.9 (Cn), 118.3 (Cd), 123.1 (Ca), 124.3 (Cl), 127.8 (t, J=11.0 Hz, Cs), 128.6 (Cm), 131.6 (Cc), 142.5 (Ce), 143.2 (d, J=248.2 Hz, Cq) ** , 143.5 (d, J=247.9, Hz, Cr) ** , 160.0 (Co) *** , 162.0 (Ch) *** , 162.1 (Cg) *** MS (ES+): 553 (M+Na).

[0086] General procedure: The Suzuki reaction used for the purification of compounds 60-66. Pd(PPh3)4 (90 mg, 0.08 mmol, 0.20 eq) was added to a solution of 58 (200 mg, 0.38 mmol, 1.00 eq) and K2CO3 (158 mg, 1.14 mmol, 3.00 eq) in a dioxane / water mixture (9:1 v / v). The resulting mixture was stirred under nitrogen atmosphere at rt for 1 hour, and then the corresponding boronic acid (0.760 mmol, 2.0 eq) was added; the reaction mixture was then refluxed under nitrogen atmosphere. After 2 hours, an additional amount of boronic acid (0.38 mmol, 1.0 eq) was added, and the reaction mixture was refluxed for a further 2 hours, then cooled to room temperature and concentrated under reduced pressure. This crude substance was dissolved in water (100 mL), and this mixture was extracted with toluene (3 × 60 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. This biomass was purified by flash chromatography (see conditions below).

[0087] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-4-(thiophen-2-yl)phenyl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (60). This biosubstance was purified by flash chromatography (eluent: petroleum ether / ethyl acetate 1 / 1 v / v) to obtain a crude solid, which was recrystallized from acetonitrile (8 mL) to obtain the title compound as a white solid (197.4-198.1°C, from acetonitrile). Yield: 72%. 1 H NMR (600 MHz, chloroform-d) δ 3.79 (s, 3H, -OCH3), 5.41 (s, 2H, -NCH2Ar), 6.76 (t, 1H, J=6.6 Hz, Hb), 6.90 (d, 2H, J=8.5 Hz, Hn), 7.16 - 7.20 (m, 1H, aromatic proton), 7.21 (d, 2H, J=8.5 Hz, Hm), 7.45 (t, 1H, J=7.7 Hz, Hc), 7.54 (d, 1H, J=5.0 Hz, aromatic proton), 7.59 (d, 1H, J=3.2 Hz, aromatic proton), 7.75 (d, 1H, J=6.9 Hz, Ha), 8.28 (d, 1H, J=8.8 Hz, Hd), 10.00 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d) δ 45.2 (-NCH2Ar), 55.5 (-OCH3), 87.2 (Cf), 112.3 (Cb), 115.0 (Cn), 115.7 (t, J=16.2 Hz, Cp) * , 118.4 (Cd), 123.1 (Ca), 124.3 (Cl), 127.3 (thiophene carbon), 127.9 (thiophene carbon), 128.1 (t, J=3.3 Hz, Cs) * , 128.6 (Cm), 128.5 (thiophene carbon), 130.0 (t, J=5.3 Hz, thiophene carbon), 131.7 (Cc), 142.6 (Ce), 142.9 (dd, J=248.0, 15.8 Hz, Cq) **, 144.0 (d, J=247.0, Hz, Cr) ** , 160.0 (Co) *** , 161.6 (Ch) *** , 162.2 (Cg) *** MS (ES+): 528.2 (M+1).

[0088] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-4-(pyridine-3-yl)phenyl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (61). This biosubstance was purified by flash chromatography (eluent: petroleum ether / siRNA 6 / 4v / v to 3 / 7v / v) to obtain a crude solid. This was then ground with diisopropyl ether to obtain the title compound as a white solid (from grinding with diisopropyl ether at mp202.6-203.8°C). Yield: 90%. 1 H NMR (600 MHz, chloroform-d) δ 3.78 (s, 3H, -OCH3), 5.41 (s, 2H, -NCH2Ar), 6.77 (t, 1H, J=6.7 Hz, Hb), 6.89 (d, 2H, J=8.5 Hz, Hn), 7.21 (d, 2H, J=8.5 Hz, Hm), 7.43 - 7.49 (m, 2H, aromatic proton and Hc), 7.77 (d, 1H, J=6.9 Hz, Ha), 7.84 (d, 1H, J=7.8 Hz, aromatic proton), 8.27 (d, 1H, J=8.8 Hz, Hd), 8.69 (d, 1H, J=2.9 Hz, aromatic proton), 8.76 (s, 1H, aromatic proton), 10.06 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d) δ 45.2 (-NCH2Ar), 55.5 (-OCH3), 87.1 (Cf), 112.9 (Cb), 114.0 (t, J=16.9 Hz, Cp) * , 115.0 (Cn), 117.4 (t, J=15.8 Hz, Cs) *, 118.3 (Cd), 123.1 (Ca), 123.7 (pyridine carbon), 124.2 (Cl), 124.3 (pyridine carbon), 128.6 (Cm), 131.8 (Cc), 137.9 (pyridine carbon), 142.6 (Ce), 142.9 (d, J=252.7 Hz, Cq) ** , 144.2 (d, J=249.7 Hz, Cr) ** , 149.9 (pyridine carbon), 150.5 (pyridine carbon), 160.0 (Co) *** , 161.6 (Ch) *** , 162.2 (Cg) *** MS (ES+): 523 (M+1).

[0089] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-4-(2-(trifluoromethyl)pyridine-4-yl)phenyl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (62). This biosubstance was purified by flash chromatography (eluent: petroleum ether / siRNA 6 / 4v / v to 3 / 7v / v) to obtain a crude solid. This was ground with diisopropyl ether to obtain the title compound as a pale yellow solid (m.p 192.7-193.9°C, from grinding with diisopropyl ether). Yield: 70%. 1¹H NMR (600 MHz, chloroform-d) δ 3.79 (s, 3H, -OCH3), 5.42 (s, 2H, -NCH2Ar), 6.79 (t, 1H, J=6.7 Hz, Hb), 6.90 (d, 2H, J=8.5 Hz, Hn), 7.22 (d, 2H, J=8.5 Hz, Hm), 7.48 (t, 1H, J=7.9 Hz, Hc), 7.64 (d, 1H, J=4.9 Hz, pyridine proton), 7.78 (d, 1H, J=6.9 Hz, Ha), 7.84 (s, 1H, pyridine proton), 8.29 (d, 1H, J=8.8 Hz, Hd), 8.88 (d, 1H, J=4.9 Hz, pyridine proton), 10.15 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d) δ 45.3 (-NCH2Ar), 55.5 (-OCH3), 87.1 (Cf), 113.0 (Cb), 113.2 (t, J=15.6 Hz, Cp) * , 115.0 (Cn), 118.4 (Cd), 118.9 (t, J=14.7 Hz, Cs) * , 121.5 (q, J=274.5 Hz, -CF3), 121.7 (q, J=2.1 Hz, pyridine carbon), 123.1 (Ca), 124.2 (Cl), 127.6 (pyridine carbon), 128.6 (Cm), 131.9 (Cc), 137.9 (pyridine carbon), 142.6 (Ce), 142.8 (d, J=247.0 Hz, Cq) ** , 144.2 (d, J=245.4 Hz, Cr) ** , 149.0 (q, J=34.9 Hz, pyridine carbon), 150.6 (pyridine carbon), 160.1 (Co) *** , 161.4 (Ch) *** , 162.3 (Cg) *** MS (ES+): 591.

[0090] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (63). This biosubstance was purified by flash chromatography (eluent: petroleum ether / 1 / 2 v / v ELISA) to obtain a crude solid. This was then ground with diisopropyl ether to remove O=PPh3O, and the title compound was obtained as a white solid (236.9-237.4°C, from diisopropyl ether). Yield: 79%. 1 H NMR (600 MHz, DMSO-d6) δ 3.71 (s, 3H, -OCH3), 5.49 (s, 2H, -NCH2Ar), 6.88 - 6.97 (m, 5H, aromatic protons and Hn), 7.07 (t, 1H, J=7.1Hz, Hb), 7.28 (d, 2H, J=8.3 Hz, Hm), 7.35 (t, 1H, J=8.1 Hz, aromatic proton), 7.67 (t, 1H, J=7.9 Hz, Hc), 8.03 (d, 1H, J=8.8 Hz, Hd), 8.57 (d, 1H, J=6.9 Hz, Ha), 9.78 (br s, 1H, -OH), 10.07 (s, 1H, -NH); 13 C NMR (151 MHz, DMSO-d6) δ 43.8 (-NCH2Ar), 55.1 (-OCH3), 85.5 (Cf), 113.2 (Cb), 114.4 (Cn), 116.2 (Cd), 116.3 (aromatic carbon), 116.6 (t, J=14.6 Hz, Cp) * , 116.9 (2 carbon atoms, partially overlapping aromatic carbon atoms and Cs) * , 120.7 (aromatic carbon), 125.3 (Ca), 125.4 (Cl), 127.7 (aromatic carbon), 128.8 (Cm), 129.9 (aromatic carbon), 132.9 (Cc), 141.4 (Ce), 142.3 (d, J=248.9 Hz, Cq) ** , 143.3 (d, J=251.3 Hz, Cr)** , 157.5 (aromatic carbon), 159.1 (Co) *** , 160.7 (Ch) *** , 161.7 (Cg) *** MS (ES+): 538 (M+1).

[0091] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (64). This biosubstance was purified by flash chromatography (eluent: petroleum ether / DCM 2 / 1v / v) to obtain a crude solid. This was then ground with diisopropyl ether to obtain the title compound as a white solid (162.7-163.0°C, from diisopropyl ether). Yield: 82%. 1 H NMR (600 MHz, chloroform-d) δ 3.80 (s, 3H, -OCH3), 5.42 (s, 2H, -NCH2Ar), 6.77 (t, 1H, J=6.9 Hz, Hb), 6.91 (d, 2H, J=8.5 Hz, Hn), 7.22 (d, 2H, J=8.5 Hz, Hm), 7.32 (d, 1H, J=8.1 Hz, aromatic proton), 7.37 (s, 1H, aromatic proton), 7.43 (d, 1H, J=7.7 Hz, aromatic proton), 7.47 (t, 1H, J=7.9 Hz, Hc), 7.53 (t, 1H, J=8.0 Hz, aromatic proton), 7.76 (d, 1H, J=6.9 Hz, Ha), 8.31 (d, 1H, J=8.8 Hz, Hd), 10.03 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d) δ 45.2 (-NCH2Ar), 55.4 (-OCH3), 87.1 (Cf), 112.8 (Cb), 115.0 (Cn), 115.9 (t, J=16.1 Hz, Cp) * , 117.0 (t, J=15.6 Hz, Cs) *, 118.3 (Cd), 120.6 (q, J=257.6 Hz, -OCF3), 121.5 (aromatic carbon), 123.0 (aromatic carbon), 123.1 (Ca), 124.2 (Cl), 128.5 (Cm), 128.8 (aromatic carbon), 129.4 (aromatic carbon), 130.1 (aromatic carbon), 131.7 (Cc),, 142.5 (Ce), 142.8 (d, J=247.5 Hz, Cq) ** , 144.0 (d, J=249.5 Hz, Cr) ** , 149.3 (aromatic carbon), 160.0 (Co) *** , 161.6 (Ch) *** , 162.2 (Cg) *** MS (ES+): 606.6, 628.6.

[0092] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxami(65). This biosubstance was purified by flash chromatography (eluent: petroleum ether / siRNA / dichloromethane 1.5 / 1 / 2v / v / v) to obtain the title compound as a beige solid (172.9-173.8°C, from diisopropyl ether). Yield: 94%. 1H-NMR (600 MHz, Chroloholm-d): δ 3.79 (s, 3H, -OCH3), 3.85 (s, 3H, -OCH3), 5.42 (s, 2H, -NCH2Ar), 6.76 (t, 1H, J=6.9 Hz, Hb), 6.90 (d, 2H, J=8.5 Hz, Hn), 6.97 - 7.03 (m, 2H, aromatic protons), 7.06 (d, 1H, J=7.5 Hz, aromatic protons), 7.22 (d, 2H, J=8.5 Hz, Hm), 7.41 (t, 1H, J=7.9 Hz, aromatic protons), 7.45 (t, 1H, J=7.9 Hz, Hc), 7.75 (d, 1H, J=6.9 Hz, Ha), 8.29 (d, 1H, J=8.8 Hz, Hd), 9.99 (s, 1H, -NH); 13 C-NMR (150 MHz, Chroloholm-d): δ 45.2 (-NCH2Ar), 55.5 (2 x -OCH3), 87.2 (Cf), 112.3 (Cb), 114.9 (aromatic carbon), 115.0 (Cn), 115.8 (aromatic carbon), 116.3 (t, J=15.0 Hz, Cp) * , 117.6 (t, J=19.6 Hz, Cs) * , 118.4 (Cd), 122.7 (aromatic carbon), 123.1 (Ca), 124.3 (Cl), 128.6 (Cm), 128.8 (aromatic carbon), 129.7 (aromatic carbon), 131.7 (Cc), 142.6 (Ce), 142.9 (d, J=248.6 Hz, Cq) ** ,, 144.2 (d, J=244.2, Hz, Cr) ** , 159.7 (aromatic carbon) *** , 160.0 (Co) *** 161.7 (Ch) **** , 162.2 (Cg) **** MS (ES+): 552.5 (M+1).

[0093] 1-(4-methoxybenzyl)-2-oxo-N-(2,3,5,6-tetrafluoro-3'-propoxy-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (66). This biosubstance was purified by flash chromatography (eluent: petroleum ether / ethyl acetate 2 / 3 v / v) to obtain the title compound as a beige solid (168.8-169.9°C, from diisopropyl ether). Yield: 86%. 1 H NMR (600 MHz, chloroform-d) δ 1.06 (t, 3H, J=7.4 Hz, -OCH2CH2CH3), 1.84 (h, 2H, J=7.3 Hz, -OCH2CH2CH3), 3.80 (s, 3H, -OCH3), 3.96 (t, 2H, J=6.6 Hz, -OCH2CH2CH3), 5.42 (s, 2H, -NCH2Ar), 6.76 (t, 1H, J=7.0 Hz, Hb), 6.91 (d, 2H, J=8.6 Hz, Hn), 6.99 (dd, 1H, J=8.4, 2.2 Hz, aromatic proton), 7.00 (s, 1H, aromatic proton), 7.04 (d, 1H, J=7.6 Hz, aromatic proton), 7.22 (d, 2H, J=8.6 Hz, Hm), 7.39 (t, 1H, J=7.9 Hz, aromatic proton), 7.46 (t, 1H, J=7.9 Hz, Hc), 7.75 (d, 1H, J=7.0 Hz, Ha), 8.31 (d, 1H, J=8.8 Hz, Hd), 9.98(s, 1H, -NH); 13 C NMR (151 MHz, Chloroform-d) δ 10.6 (-OCH2CH2CH3), 22.7 (-OCH2CH2CH3), 45.2 (-NCH2Ar), 55.5 (-OCH3), 69.8 (-OCH2CH2CH3), 87.2 (Cf), 112.8 (Cb), 115.0 (Cn), 115.5 (aromatic carbon), 116.2 (t, J=15.6 Hz, Cp) * , 116.4 (aromatic carbon), 117.7 (t, J=16.8 Hz, Cs)* , 118.3 (Cd), 122.5 (aromatic carbon), 123.1 (Ca), 124.3 (Cl), 128.6 (Cm), 128.7 (aromatic carbon), 129.7 (aromatic carbon), 131.7 (Cc), 142.5 (Ce), 142.8 (dd, J=248.5, 15.3 Hz, Cq) ** , 144.2 (d, J=248.5 Hz, Cr) ** , 159.2 (aromatic carbon) *** , 160.0 (Co) *** 161.7 (Ch) **** , 162.2 (Cg) **** MS (ES+): 580 (M+1).

[0094] General procedure for the synthesis of aniline 47-50 Pd(PPh3)4 (90 mg, 0.08 mmol, 0.20 eq) was added to a solution of 4-bromo-2,3,5,6-tetrafluoroaniline (200 mg, 0.38 mmol, 1.00 eq) and K2CO3 (158 mg, 1.14 mmol, 3.00 eq) in 1,2-dimethoxyethane (35 mL). The resulting mixture was stirred under nitrogen atmosphere at rt for 1 hour, and then the corresponding boronic acid (0.760 mmol, 2.0 eq) was added; the reaction mixture was then refluxed under nitrogen atmosphere. After 2 hours, an additional amount of boronic acid (0.38 mmol, 1.0 eq) was added, and the reaction mixture was refluxed for a further 2 hours, then cooled to room temperature and concentrated under reduced pressure. This crude substance was dissolved in water (100 mL), and this mixture was extracted with toluene (3 × 60 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. This biomass was purified by flash chromatography (see conditions below).

[0095] 2,3,4',5,6-Pentafluoro-[1,1'-biphenyl]-4-aniline (47). Flash chromatography (eluent: petroleum ether / SiO4 from 95:5v / v). White solid (from grinding with diisopropyl ether at mp134.1-134.7°C). Yield 74%. 1 ¹H NMR (600 MHz, chloroform-d): δ 4.05 (s, 2H, -NH2), 7.11 - 7.17 (m, 2H, aromatic proton), 7.37 - 7.42 (m, 2H, aromatic proton); 13 C NMR (151 MHz, CDCl3): δ 107.3 (t, J=16.8 Hz), 115.7 (d, J=21.7 Hz), 124.0 (d, J=1.7 Hz), 125.6 (t, J=14.1 Hz), 132.2 (d, J=7.7 Hz), 136.9 (d, J=238.0 Hz), 144.1 (d, J=243.5 Hz), 162.7 (d, J=248.3 Hz). MS (ES-) 258 (M-1).

[0096] 2,3,3',5,6-Pentafluoro-[1,1'-biphenyl]-4-aniline (48). Flash chromatography (eluent: petroleum ether / SiO4 from 95:5v / v). White solid (mp108.8-109.7°C, from grinding with diisopropyl ether). Yield 90%. 1 ¹H NMR (600 MHz, chloroform-d): δ 4.08 (s, 2H, -NH2), 7.10 (t, 1H, J=8.4 Hz aromatic proton), 7.15 (d, 1H, J=9.7 Hz, aromatic proton), 7.21 (d, 1H, J=7.5 Hz, aromatic proton), 7.38 - 7.44 (m, 1H, aromatic proton); 13C NMR (151 MHz, CDCl3): δ 107.0 (t, J=17.6 Hz), 115.3 (d, J=20.8 Hz), 117.5 (d, J=22.3 Hz), 125.9 (t, J=14.2 Hz), 126.2, 130.0 (d, J=8.3 Hz), 130.1, 136.8 (dd, J=238.4, 16.2 Hz), 144.1 (d, J=243.9 Hz), 162.7 (d, J=245.9 Hz). MS (ES-) 258 (M-1).

[0097] 2,3,5,6-Tetrafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-aniline (49). Flash chromatography (eluent: petroleum ether / ethylacetate from 95:5v / v). White solid (from grinding with diisopropyl ether at mp163.9-164.8°C). Yield 60%. 1 ¹H NMR (600 MHz, chloroform-d): δ 4.12 (s, 2H, -NH2), 7.56 (d, 2H, J=8.0 Hz, aromatic proton), 7.71 (d, 2H, J=8.2 Hz, aromatic proton); 13 C NMR (151 MHz, CDCl3): δ 106.8 (t, J=15.1 Hz), 124.1 (q, J=271.7 Hz, -CF3), 125.5 (q, J=6.7 Hz), 126.4 (t, J=3.8 Hz), 130.4 (q, J=32.7 Hz), 130.8, 132.0, 136.9 (d, J=238.7 Hz), 144.2 (d, J=244.2 Hz). MS (ES-) 308 (M-1).

[0098] 2,3,5,6-Tetrafluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-aniline (50). Flash chromatography (eluent: petroleum ether / ethylacetate from 95:5v / v). Pale yellow solid (mp 46.6-47.0°C, from grinding with diisopropyl ether). Yield 92%. 1¹H NMR (600 MHz, chloroform-d): δ 4.11 (s, 2H, -NH2), 7.55 -7.60 (m, 1H, aromatic proton), 7.61 (d, 1H, J=7.2 Hz, aromatic proton), 7.65 (d, 1H, J=7.4 Hz, aromatic proton), 7.70 (s, 1H, aromatic proton); 13 C NMR (151 MHz, CDCl3): δ 106.7 (t, J=16.6 Hz), 124.1 (q, J=272.7 Hz, -CF3), 125.2 (q, J=3.8 Hz), 126.3 (t, J=14.3 Hz), 127.3, 129.0, 129.1, 131.5 (q, J=32.7 Hz), 133.8, 136.9 (dd, J=239.4, 16.5 Hz), 144.2 (d, J=244.2 Hz). MS (ES-) 308 (M-1).

[0099] General procedure for the synthesis of amides 52-55 related to pyrazolo[1,5-a]pyridine. Oxalyl chloride (3.0 mmol) and anhydrous DMF (1 drop) were added under nitrogen atmosphere to a cooled (0°C) solution of O-protected pyrazolo[1,5-a]pyridic acid (1.0 mmol) in anhydrous THF (20 mL). The resulting solution was stirred at room temperature for 2 hours. This solution was then concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL; this step was repeated three times). The resulting asyl chloride was used immediately without further purification, dissolved in 10 mL of anhydrous toluene, and transferred to the solution described later. Trimethylaluminum (2.0 M in hexane, 1.5 mmol) was added under nitrogen atmosphere to a solution (15 mL) of suitable aniline (see supporting information for synthesis, 1.5 mmol) in anhydrous toluene. The resulting mixture was stirred at room temperature for 2 hours to produce a brown suspension, and then the solution of asyl chloride in anhydrous toluene described earlier (30 mL) was quantitatively added. The mixture was heated overnight at 90°C and then cooled to rt. This reaction was quenched with 1 M HCl. The layers were separated, and the aqueous phase was thoroughly extracted with RINKAN. The combined organic layers were washed with 1 M NaOH and brine, dried, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography.

[0100] 1-Benzyl-2-oxo-N-(2,3,4',5,6-pentafluoro-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (52). 2,3,4',5,6-pentafluoro-[1,1'-biphenyl]-4-aniline was used. Flash chromatography (eluent: petroleum ether / ELISA from 80:20 v / v to 50:50 v / v). Gray solids (from grinding with diisopropyl ether at mp2 34.2-235.4°C). Yield 31%. 1H NMR (600 MHz, Chromo-d): δ 5.48 (s, 2H, -NCH2Ph), 6.77 (t, 1H, J=6.9 Hz, Hb), 7.19 (t, 2H, J=8.6 Hz, aromatic protons), 7.28 (d, 2H, J=7.4 Hz, aromatic protons), 7.32 -750 (m, 6H, aromatic protons), 7.73 (d, 1H, J=6.9, Ha), 8.30 (d, 1H, J=8.8, Hd), 9.98 (s, 1H, -NH); 13 C NMR (151 MHz, Chroroholm-d): δ 45.7 (-NCH2Ph), 87.2 (Cf), 112.9 (Cb), 115.9 (d, J=21.9 Hz, Aromatic Carbon), 116.4 (t, J=17.1 Hz, Cp) * , 116.7 (d, J=16.7 Hz, Cs) * , 118.4 (Cd), 123.0 (Ca), 123.5 (aromatic carbon), 127.1 (aromatic carbon), 129.0 (aromatic carbon), 129.7 (aromatic carbon), 131.8 (Cc), 132.8 (d, J=8.4 Hz, aromatic carbon), 132.5 (aromatic carbon), 142.6 (Ce), 142.8 (d, J=244.1 Hz, Cq) ** , 144.2 (d, J=250.7 Hz, Cr) ** , 161.7 (Cg) *** , 162.2 (Ch) *** , 163.1 (d, J=249.5 Hz, -CF); MS (ESI) 510 (M+1).

[0101] 1-Benzyl-2-oxo-N-(2,3,3',5,6-pentafluoro-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (53). 2,3,3',5,6-pentafluoro-[1,1'-biphenyl]-4-aniline was used. Flash chromatography (eluent: petroleum ether / ELISA from 80:20 v / v to 50:50 v / v). Pale yellow solid (from grinding with diisopropyl ether at mp195.4-196.3°C). Yield 40%. 1 H NMR (600 MHz, DMSO-d6): δ 5.57 (s, 2H, -NCH2Ph), 7.07 (t, 1H, J=6.9 Hz, Hb), 7.29 - 7.45 (m, 7H, aromatic proton), 7.50 (d, 1H, J=9.5 Hz, aromatic proton), 7.62 (dd, 1H, J=14.3, 7.7 Hz, aromatic proton), 7.68 (t, 1H, J=7.9 Hz, Hc), 8.05 (d, 1H, J=8.7 Hz, Hd), 8.53 (d, 1H, J=7.0 Hz, Ha), 10.12 (s, 1H, -NH); 13 C NMR (151 MHz, DMSO-d6): δ 44.2 (-NCH2Ph), 85.4 (Cf), 113.3 (Cb), 115.4 (t, J=17.3 Hz, Cp) * , 116.2 (Cd), 116.4 (d, J=20.8 Hz, aromatic carbon), 117.0 (Cs) * , 117.2 (d, J=23.1 Hz, aromatic carbon), 125.2 (Ca), 126.5 (Cl), 127.2 (aromatic carbon), 128.2 (Cc), 128.8 (d, J=9.8 Hz, aromatic carbon), 129.1 (aromatic carbon), 130.9 (d, J=8.4 Hz, aromatic carbon), 132.9 (aromatic carbon), 133.7 (aromatic carbon), 141.4 (Ce), 142.2 (d, J=242.5 Hz, Cq) ** , 143.3 (d, J=245.8 Hz, Cr)** , 144.1, 160.6 (Cg) *** , 161.2 (Ch) *** , 162.0 (d, J=244.3 Hz, aromatic carbon); MS (ESI) 508 (M-1).

[0102] 1-Benzyl-2-oxo-N-(2,3,5,6-tetrafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (54). Using 2,3,5,6-tetrafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-aniline; flash chromatography eluent: petroleum ether / siRNA from 80:20 v / v to 50:50 v / v. Pale yellow solid (from grinding with diisopropyl ether at mp2 62.2-263.5°C). Yield 41%. 1 H NMR (600 MHz, chloroform-d): δ 5.49 (s, 2H, -NCH2Ph), 6.78 (t, 1H, J=6.8 Hz, Hb), 7.29 (d, 2H, J=7.4 Hz, aromatic proton), 7.33 - 7.43 (m, 3H, aromatic proton), 7.48 (t, 1H, J=7.9 Hz, Hc), 7.62 (d, 2H, J=7.9 Hz, aromatic proton), 7.73 (d, 1H, J=6.9 Hz, Ha), 7.76 (d, 2H, J=8.1 Hz, aromatic proton), 8.31 (d, 1H, J=8.8 Hz, Hd), 10.04 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d): δ 45.7 (-NCH2Ph), 87.2 (Cf), 112.9 (Cb), 116.1 (t, J=16.5 Hz, Cp) * , 117.2 (t, J=15.6 Hz, Cs) *, 118.4 (Cd), 123.0 (Ca), 124.0 (q, J=272.5 Hz, -CF3), 125.7 (q, J=3.8 Hz, aromatic carbon), 127.1 (aromatic carbon), 129.0 (Cc), 129.7 (aromatic carbon), 130.8 (aromatic carbon), 131.1 (q, J=32.8 Hz, aromatic carbon), 131.4 (aromatic carbon), 131.9 (aromatic carbon), 132.5 (aromatic carbon), 142.6 (Ce), 142.8 (dd, J=251.8, 17.4 Hz, Cq) ** , 144.1 (dd, J=244.7, 15.4 Hz, Cr) ** , 161.6 (Cg) *** , 162.2 (Ch) *** MS (ESI) 560 (M+1).

[0103] 1-Benzyl-2-oxo-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (55). Using 2,3,5,6-tetrafluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-aniline; flash chromatography eluent: petroleum ether / siRNA from 80:20 v / v to 50:50 v / v. White solid (from grinding with diisopropyl ether at mp190.9-191.8°C). Yield 40%. 1H NMR (600 MHz, Chromo-d): δ 5.49 (s, 2H, -NCH2Ph), 6.78 (t, 1H, J=6.8 Hz, Hb), 7.29 (d, 2H, J=7.3 Hz, aromatic protons), 7.33 - 7.42 (m, 3H, aromatic protons), 7.48 (t, 1H, J=7.9 Hz, Hc), 7.64 (t, 1H, J=7.7 Hz, aromatic protons), 7.68 (d, 1H, J=7.5 Hz, aromatic protons), 7.72 (t, 2H, J=7.6 Hz, aromatic protons), 7.76 (s, 1H, aromatic プロトン), 8.31 (d, 1H, J=8.8, Hd), 10.04 (s, 1H, -NH); 13 C NMR (151 MHz, クロロホルム-d): δ 45.7 (-NCH2Ph), 87.2 (Cf), 112.9 (Cb), 116.4 (t, J=16.2 Hz, Cp) * , 117.2 (t, J=15.2 Hz, Cs) * , 118.5 (Cd), 123.0 (Ca), 124.0 (q, J=272.1 Hz, -CF3), 125.9 (q, J=3.9 Hz, Aromatic Carbon), 127.1 (Aromatic Carbon), 127.2 (Aromatic Carbon), 128.5 (Aromatic Carbon), 129.0 (Aromatic Carbon), 129.3 (Aromatic Carbon), 129.7 (Aromatic Carbon), 131.3 (q, J=32.4 Hz), 131.8 (Cc), 132.5 (Aromatic Carbon), 133.7 (Aromatic Carbon), 142.7 (Ce), 142.8 (d, J=252.0 Hz, Cq) ** , 144.2 (d, J=248.2 Hz, Cr) ** , 161.6 (Cg) *** , 162.2 (Ch) *** MS (ESI) 560 (M+1).

[0104] General procedure: Removal of the 4-MeO benzyloxy moiety for the formation of compounds 7-9 and 15-17. Thianisole (220 μL, 1.87 mmol, 5.0 eq to 10 eq) was added to a solution of the corresponding starting material (200 mg, 0.37 mmol, 1.0 eq) in TFA (3 mL). This mixture was heated at 70°C for 2 hours and then cooled to rt. The mixture was concentrated to some extent, and this biomass was dissolved in water to obtain a suspension, which was filtered, and the solid was washed with an additional amount of cold water. The obtained solid was ground with diisopropyl ether to provide the title compound, sometimes directly in its pure form (see details above).

[0105] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-4-morpholinophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (6). Compound 59 (200 mg, 0.38 mmol, 1.0 eq) was dissolved in a solution of thioanisole (250 μL, 2.26 mmol, 6.0 eq) in TFA (2 mL). The residue was ground with hexane and diisopropyl ether, and then purified by flash chromatography (eluent: petroleum ether / DCM / MeOH 5 / 4 / 0.4 v / v / v). The resulting crude solid was ground with diisopropyl ether, and the title compound was provided as a white solid (276.5–277.2 °C, from diisopropyl ether). Yield: 42%. 1 H NMR (600 MHz, DMSO-d6) δ 3.18 - 3.25 (m, 4H, -NCH2CH2O-), 3.68 - 3.75 (m, 4H, -NCH2CH2O-), 7.0 (t, 1H, J=6.8 Hz, Hb), 7.48 (t, 1H, J=7.8 Hz, Hc), 7.94 (d, 1H, J=8.7 Hz, Hd), 8.58 (d, 1H, J=6.7 Hz, Ha), 8.76 (s, 1H, -NH), 12.83 (v br s, 1H, -OH); 13C NMR (151 MHz, DMSO-d6) δ 51.0 (-NCH2CH2O-), 66.7 (-NCH2CH2O-), 88.2 (Cf), 111.5 (t, J=15.1 Hz, Cp) * , 113.1 (Cb), 116.8 (Cd), 127.5 (t, J=11.2 Hz, Cs) * , 128.2 (Ca), 129.1 (Cc), 141.7 (Ce), 142.2 (dd, J=243.5, 6.2 Hz, Cq) ** , 143.4 (dd, J=244.6, 14.4 Hz, Cr) ** , 160.8 (Ch) *** , 162.7 (Cg) *** . MS (ES-): 409 (M-1). ESI-HRMS (m / z): [MH] - C 18 H 13 The calculated value for F4N4O3 is 409.0929; the measured value is 409.0925.

[0106] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-4-(thiophen-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (7). This solid was recrystallized three times from acetonitrile (20 mL) to obtain the title compound as a gray solid (278.4–279.9°C, from acetonitrile). Yield: 23%. 1 H NMR (600 MHz, DMSO-d6) δ 7.03 (t, 1H, J=6.6 Hz, Hb), 7.31 (t, 1H, J=4.3 Hz, aromatic proton), 7.51 (t, 1H, J=7.8 Hz, Hc), 7.64 (d, 1H, J=2.8 Hz, aromatic proton), 7.92 (d, 1H, J=5.0 Hz, aromatic proton), 7.97 (d, 1H, J=8.8 Hz, Hd), 8.61 (d, 1H, J=6.7 Hz, Ha), 8.95 (s, 1H, -NH), 12.90 (br s, 1H, -OH); 13C NMR (151 MHz, DMSO-d6) δ 88.2 (Cf), 110.9 (t, J=15.6 Hz, Cp) * , 113.8 (Cb), 17.03 (t, J=16.5 Hz, Cs) * , 116.8 (Cd), 126.2 (thiophene carbon), 127.8 (thiophene carbon), 128.4 (Ca), 129.2 (thiophene carbon), 129.5 (Cc), 130.7 (t, J=4.0 Hz, thiophene carbon), 141.8 (Ce), 143.0 (dd, J=246.5, 14.3 Hz, Cq and Cr), 160.4 (Ch) ** , 162.7(Cg) ** . MS (ES-): 406 (M-1). ESI-HRMS (m / z): [MH] - C 18 The calculated value for H8F4N3O2S was 406.0279; the measured value was 406.0275.

[0107] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-4-(pyridine-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (8). Pale yellow solid (from grinding with diisopropyl ether at mp283.4-286.7°C). Yield: 76%. 1 H NMR (600 MHz, DMSO-d6) δ 6.98 (t, 1H, J=6.7 Hz, Hb), 7.47 (t, 1H, J=7.9 Hz, Hc), 7.61 (dd, 1H, J=7.7, 5.0 Hz, aromatic proton), 7.95 (d, 1H, J=8.6 Hz, Hd), 8.05 (d, 1H, J=7.4 Hz, aromatic proton), 8.57 (d, 1H, J=6.5 Hz, Ha), 8.71 (d, 1H, J=4.1 Hz, aromatic proton), 8.78 (s, 1H, aromatic proton), 9.30 (br s, 1H, -NH); 13C NMR (151 MHz, DMSO-d6) δ 88.3 (Cf), 112.9 (Cb), 113.8 (t, J=17.4 Hz, Cp) * , 116.6 (Cd), 117.9 (t, J=14.7 Hz, Cs) * , 123.3 (pyridine carbon), 124.0 (pyridine carbon), 128.0 (Ca), 128.9 (Cc), 137.9 (pyridine carbon), 141.7 (Ce), 142.6 (dd, J=245.2, 15.1 Hz, Cq) ** , 143.4 (dd, J=245.7, 17.2 Hz, Cq) ** , 150.2 (pyridine carbon), 150.3 (pyridine carbon), 160.6 (Ch) *** , 163.9 (Cg) *** . MS (ES+): 403 (M+H). ESI-HRMS (m / z): [M+H] + C 19 H 11 The calculated value for F4N4O2 is 403.0813; the measured value is 403.0810.

[0108] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-4-(2-(trifluoromethyl)pyridine-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (9). Pale yellow solid (from grinding with diisopropyl ether at mp258.4-259.2℃). Yield: 55%. 1 H NMR (600 MHz, DMSO-d6) δ 7.01 (t, 1H, J=6.6 Hz, Hb), 7.49 (t, 1H, J=7.7 Hz, Hc), 7.96 (d, 1H, J=8.6 Hz, Hd), 8.00 (d, 1H, J=3.5 Hz, aromatic proton), 8.22 (s, 1H, aromatic proton), 8.59 (d, 1H, J=6.6 Hz, Ha), 8.99 (d, J=4.6 Hz, 1H, aromatic proton), 9.22 (br s, 1H, -NH); 13¹³C NMR (151 MHz, DMSO-d6) δ 88.2 (Cf), 113.1 (Cp overlapping with Cb) * ), 116.7 (Cd), 118.9 (t, J=13.5 Hz, Cs) * , 121.5 (q, J=274.6 Hz, -CF3), 121.8 (pyridine carbon), 128.2 (Ca), 128.5 (Cc), 129.1 (q, J=12.5 Hz, pyridine carbon), 137.3 (pyridine carbon), 141.7 (Ce), 142.6 (d, J=246.8 Hz, Cq) ** , 143.3 (d, J=247.0 Hz, Cr) ** , 147.1 (q, J=34.1 Hz, pyridine carbon), 151.0 (pyridine carbon), 160.3 (Ch) *** , 163.4 (Cg) *** . MS (ES+): 470 (M+H). ESI-HRMS (m / z): [M+H] + C 20 H 10 The calculated value for F7N4O2 is 471.0686; the measured value is 471.0684.

[0109] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (14). White solid (from diisopropyl ether at 275.9–276.4°C). Yield: 58%. 1 H NMR (600 MHz, DMSO-d6) δ 6.84 - 6.99 (m, 3H, aromatic proton), 7.03 (t, 1H, J=6.8 Hz, Hb), 7.35 (t, 1H, J=8.2 Hz, aromatic proton), 7.51 (t, 1H, J=7.8 Hz, Hc), 7.98 (d, 1H, J=7.4 Hz, Hd), 8.61 (d, 1H, J=4.5 Hz, Ha), 8.90 (s, 1H, -Ar-OH), 9.78 (s, 1H, -NH), 12.86 (s, 1H, -OH);13 C NMR (151 MHz, DMSO-d6) δ 88.2 (Cf), 113.3 (Cb), 114.7 (t, J=13.5 Hz, Cp) * , 116.3 (Cd), 116.8 (aromatic carbon), 117.4 (t, J=16.3 Hz, Cs) * , 120.7 (aromatic carbon), 127.6 (aromatic carbon), 128.4 (Ca), 128.3 (aromatic carbon), 129.1 (Cc), 129.9 (aromatic carbon), 141.7 (Ce), 142.7 (d, J=248.4 Hz, Cq) ** , 143.2 (d, J=244.8 Hz, Cr) ** , 157.5 (aromatic carbon), 160.4 (Ch) *** , 162.6 (Cg) *** ; MS (ES-): 416 (M-1). ESI-HRMS (m / z): [M+H] + C 20 H 12 The calculated value for F4N3O3 is 418.0809; the measured value is 418.0807.

[0110] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (15). This biosubstance was dissolved in methanol, the insoluble solid was filtered, partially evaporated, and precipitated by the addition of diisopropyl ether. Beige solid (228.1-229.5°C, from diisopropyl ether). Yield: 26%. 1¹H NMR (600 MHz, DMSO-d⁶) δ 7.03 (t, ¹H, J=6.7 Hz, Hb), 7.51 (t, ¹H, J=7.8 Hz, Hc), 7.55 (d, ¹H, J=8.0 Hz, aromatic protons), 7.60 - 7.67 (m, 2H, aromatic protons), 7.71 (t, ¹H, J=7.9 Hz, aromatic protons), 7.98 (d, ¹H, J=8.7 Hz, Hd), 8.61 (d, 1H, J=6.7 Hz, Ha), 8.97 (s, ¹H, -NH), 12.94 (br s, ¹H, -OH); 13 C NMR (151 MHz, DMSO-d6) δ 88.2 (Cf), 113.2 (Cb), 115.5 (t, J=17.2 Hz, Cp) * , 116.8 (Cd), 117.6 (t, J=15.1 Hz, Cs) * , 120.1 (q, J=257.0 Hz, -OCF3), 122.1 (aromatic carbon), 123.0 (aromatic carbon), 128.4 (Ca), 128.8 (aromatic carbon), 129.2 (Cc), 129.5 (aromatic carbon), 130.9 (aromatic carbon), 141.7 (Ce), 142.7 (dd, J=246.2, 13.6 Hz, Cq) ** , 143.3 (d, J=245.6 Hz, Cr) ** , 148.4 (aromatic carbon), 160.3 (Ch) *** , 162.7 (Cg) *** ;MS (ES-): 484 (M-1). ESI-HRMS (m / z): [M+H] + C 21 H 11 The calculated value of F7N3O3 is 486.0683; the measured value is 486.0681.

[0111] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (16). The residue was treated with diethyl ether and purified by flash chromatography (eluent: DCM / MeOH 97 / 3v / v, then petroleum ether / dichloromethane / methanol 5 / 4 / 0.6v / v / v) to obtain the title compound as a white solid (223.6-224.1°C, from diisopropyl ether). Yield: 47%. 1 H NMR (600 MHz, DMSO-d6) δ 3.81 (s, 3H, -OCH3), 7.02 (t, 1H, J=6.6 Hz, Hb), 7.08 - 7.16 (m, 3H, aromatic protons), 7.45 - 7.54 (m, 2H, Hc and aromatic protons), 7.98 (d, 1H, J=8.6 Hz, Hd), 8.61 (d, 1H, J=6.6 Hz, Ha), 8.99 (br s, 1H, -NH); 13 C-NMR (150 MHz, DMSO-d6): δ 55.4 (-OCH3), 88.2 (Cf), 113.2 (Cb), 115.0 (Cd), 115.8 (aromatic carbon), 116.8 (aromatic carbon), 117.0 (t, J=16.1 Hz, Cs and Cp) * , 122.3 (aromatic carbon), 127.8 (Ca), 128.3 (aromatic carbon), 129.1 (Cc), 130.0 (aromatic carbon), 141.8 (Ce), 142.9 (d, J=246.3 Hz, Cq) ** , 143.4 (d, J=252.5 Hz, Cr) ** , 159.4 (aromatic carbon), 160.5 (Ch) **** , 163.0 162.2 (Cg) **** ;MS (ES-): 430 (M-1), MS (ES+) 432 (M+1). ESI-HRMS (m / z): [M+H] + C 21 H 14The calculated value for F4N3O3 is 432.0966; the measured value is 432.0969.

[0112] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-propoxy-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (17). Beige solid (from diisopropyl ether at 209.4-210.0°C). Yield: 69%. 1 H NMR (600 MHz, DMSO-d6) δ 0.98 (t, 3H, J=7.2 Hz, -OCH2CH2CH3), 1.68 - 1.81 (m, 2H, -OCH2CH2CH3), 3.98 (t, 2H, J=6.1 Hz, -OCH2CH2CH3), 7.02 (t, 1H, J=6.5 Hz, Hb), 7.05 - 7.14 (m, 3H, aromatic proton), 7.46 (t, 1H, J=7.8 Hz, aromatic proton or Hc), 7.51 (t, 1H, J=7.6 Hz, aromatic proton or Hc), 7.99 (d, 1H, J=8.7 Hz, Hd), 8.61 (d, 1H, J=6.5 Hz, Ha), 8.91 (s, 1H, -NH), 12.86 (s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6) δ 10.4 (-OCH2CH2CH3), 22.0 (-OCH2CH2CH3), 69.2 (-OCH2CH2CH3), 88.2 (Cf), 113.3 (Cb), 115.5 (Cd), 116.2 (aromatic carbon), 116.8 (aromatic carbon), 116.9 - 117. 7 (m, Cs and Cp), 122.2 (aromatic carbon), 127.8 (aromatic carbon), 128.4 (Ca), 129.2 (Cc), 129.9 (aromatic carbon), 141.7 (Ce), 142.8 (dd, J=245.5, 21.8 Hz, Cq) ** , 143.3 (d, J=245.6 Hz, Cr) ** , 158.8 (aromatic carbon) *** , 160.4 (Ch)**** , 162.6 (Cg) **** ;MS (ES-): 458 (M-1). MS (ES+): 460 (M+1). ESI-HRMS (m / z): [M+H] + C 23 H 18 The calculated value for F4N3O3 is 460.1279; the measured value is 460.1280.

[0113] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide (5). Palladium supported on carbon (Pd / C, 20% w / w) was added to a solution of compound 51 (1.0 mmol) in anhydrous THF (10 mL). The resulting mixture was stirred for 3 hours at 65°C under a 40 bar hydrogen atmosphere using a microwave SynthWAVE. This suspension was filtered through Celite, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure. The resulting solid was further purified by flash chromatography (eluent: dichloromethane / siRNA / HCOOH, 80:20:1 v / v / v). White solid (mp2 70.9–272.9°C, from diisopropyl ether). Yield: 40%. 1 ¹H NMR (600 MHz, DMSO-d6): δ 1.70–1.80 (m, 2H, Hb), 1.89–1.98 (m, 2H, Hc), 2.92 (t, 2H, J=6.1 Hz, Hd), 3.86 (t, 2H, J=5.8 Hz, Ha), 7.49–7.55 (m, 5H, aromatic proton), 9.11 (s, 1H, -NH), 11.94 (v br s, 1H, -OH). Interchangeable proton signals overlapping with the water signal; 13 C NMR (151 MHz, DMSO-d6): δ 18.5 (Cb), 22.1 (Cd), 22.9 (Cc), 46.5 (Ca), 95.5 (Cf), 116.8 (t, J=14.3 Hz, Cs) * , 117.0 (t, J=17.4 Hz, Cp)* , 126.7 (aromatic carbon), 128.9 (aromatic carbon), 129.4 (aromatic carbon), 130.1 (aromatic carbon), 141.8 (Ce) 143.2 (d, J=248.4, 21.8 Hz, Cq) ** , 144.3 (d, J=244.0 Hz, Cr) ** , 159.7 (Cg) *** , 160.7 (Ch) *** ;MS (ES-) 404 (M-1). IR (KBr) v (cm -1 ): 3338, 2924, 2519, 1685, 1577, 1522, 1437, 1374, 1316, 1283, 1241, 1144, 992. ESI-HRMS (m / z): [M+H] + C 20 H 16 The calculated value for F4N3O2 is 406.1173; the measured value is 406.1170.

[0114] General hydrogenation procedure for obtaining target compound 10-13. Palladium supported on carbon (Pd / C, 6% w / w) was added to a solution of a suitable amide (compound 52-55, 1.0 mmol) and HCl (1.0 mmol) in anhydrous THF (15 mL). The resulting mixture was vigorously stirred under a hydrogen atmosphere for 6 hours. This suspension was filtered through Celite, and the cake was then washed with methanol. The filtrate was concentrated under reduced pressure. If necessary, the resulting solid was further purified by flash chromatography (see details below).

[0115] 2-Hydroxy-N-(2,3,4',5,6-pentafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (10). Obtained from 52. Flash chromatography (eluent: dichloromethane / siRNA / HCOOH 80:20:1v / v / v). White solid (from grinding with diisopropyl ether at mp2 93.4-294.5°C). Yield 75%. 1¹H NMR (600 MHz, DMSO-d⁶): δ 7.03 (t, ¹H, J=6.7 Hz, Hb), 7.42 (t, 2H, J=8.7 Hz, aromatic protons), 7.51 (t, 1H, J=7.8 Hz, Hc), 7.57 - 7.71 (m, 2H, aromatic protons), 7.98 (d, 1H, J=8.7, Hd), 8.62 (d, 1H, J=6.7, Ha), 8.93 (s, 1H, -NH), 12.88 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 88.2 (Cf), 113.3 (Cb), 116.0 (d, J=22.0 Hz, aromatic carbon), 116.3 (t, J=17.4 Hz, Cp) * , 116.8 (Cd), 117.1 (t, J=14.1 Hz, Cs) * , 123.0 (aromatic carbon), 128.4 (Ca), 129.2 (Cc), 132.5 (d, J=8.4 Hz, aromatic carbon), 141.7 (Ce), 142.8 (d, J=246.4 Hz, Cq) ** , 143.3 (d, J=248.6 Hz, Cr) ** 160.4 (Cg) *** , 162.6 (d, J=247.1 Hz, -CF), 162.7 (Ch) *** ;MS (ESI) 420 (M+1). ESI-HRMS (m / z): [M+H] + C 20 H 11 The calculated value of F5N3O2 is 420.0766; the measured value is 420.0766.

[0116] 2-Hydroxy-N-(2,3,3',5,6-pentafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (11). Obtained from 53. Flash chromatography eluent: dichloromethane / siRNA / HCOOH in a ratio of 80:20:1 v / v / v. White solid (from grinding with diisopropyl ether at mp2 55.4-256.2°C). Yield 75%. 1 H NMR (600 MHz, DMSO-d6): δ 7.03 (t, 1H, J=6.8 Hz, Hb), 7.33 - 7.56 (m, 4H, aromatic proton), 7.62 (dd, 1H, J=14.3, 7.7 Hz, aromatic proton), 7.99 (d, 1H, J=8.7, Hd), 8.62 (d, 1H, J=6.8, Ha), 8.94 (s, 1H, -NH), 12.83 (br s, 1H, -OH); 13 C NMR (151 MHz, CDCl3): δ88.2 (Cf), 113.3 (Cb), 115.9 (t, J=17.4 Hz, Cp) * , 116.4 (d, J=20.9 Hz, aromatic carbon), 116.9 (Cd), 117.2 (d, J=23.0 Hz, aromatic carbon), 117.4 (t, J=14.8 Hz, Cs) * , 126.5 (aromatic carbon), 128.4 (Ca), 128.7 (d, J=9.6 Hz, aromatic carbon), 129.2 (Cc), 130.9 (d, J=8.3 Hz, aromatic carbon), 141.7 (Ce), 142.8 (d, J=243.6 Hz, Cq) ** , 143.2 (d, J=244.6 Hz, Cr) ** , 160.4 (Cg) *** , 162.0 (d, J=244.4 Hz, -CF), 162.7 (Ch) *** ;MS (ESI) 418 (M-1). ESI-HRMS (m / z): [M+H] + C 20 H 11The calculated value for F5N3O2 is 420.0766; the measured value is 420.0763.

[0117] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (12). Obtained from 54. Flash chromatography eluent: dichloromethane / siRNA / HCOOH in a ratio of 80:20:1 v / v / v. White solid (from grinding with diisopropyl ether at mp286.1-286.8°C). Yield 95%. 1 H NMR (600 MHz, DMSO-d6): δ 7.03 (t, 1H, J=6.7 Hz, Hb), 7.51 (t, 1H, J=7.8 Hz, Hc), 7.83 (d, 2H, J=7.8 Hz, aromatic proton), 7.94 (d, 2H, J=8.0 Hz, aromatic proton), 7.98 (d, 1H, J=8.7 Hz, Hd), 8.61 (d, 1H, J=6.7 Hz, Ha), 9.00 (s, 1H, -NH), 12.92 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 88.2 (Cf), 113.3 (Cb), 115.7 (t, J=16.9 Hz, Cp) * , 116.8 (Cd), 117.8 (t, J=13.1 Hz, Cs) * , 124.0 (q, J=272.4 Hz, -CF3), 125.8 (q, J=3.3 Hz, aromatic carbon), 128.4 (Ca), 129.2 (Cc), 129.7 (q, J=32.3 Hz, aromatic carbon), 131.0 (aromatic carbon), 131.2 (aromatic carbon), 141.7 (Ce), 142.7 (dd, J=246.0, 14.9 Hz, Cq) ** , 143.2 (dd, J=244.9, 19.5 Hz, Cr) ** , 160.3 (Cg) *** , 162.7 (Ch) ***;MS (ESI) 468 (M-1). ESI-HRMS (m / z): [M+H] + C 21 H 11 The calculated value for F7N3O2 is 470.0734; the measured value is 470.0731.

[0118] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (13). Obtained from 55. Flash chromatography eluent: dichloromethane / siRNA / HCOOH in a ratio of 80:20:1 v / v / v. Pale pink solid (from grinding with diisopropyl ether at mp2 20.3-220.7°C). Yield 98%. 1 H NMR (600 MHz, DMSO-d6): δ 7.03 (t, 1H, J=6.7 Hz, Hb), 7.51 (t, 1H, J=7.8 Hz, Hc), 7.82 (t, 1H, J=7.7 Hz, aromatic proton), 7.91 (d, 2H, J=7.6 Hz, aromatic protons), 7.95 -8.02 (m, 2H, aromatic protons and Hd), 8.62 (d, 1H, J=6.7, Ha), 8.98 (s, 1H, -NH), 12.87 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 88.2 (Cf), 113.3 (Cb), 115.6 (t, J=17.0 Hz, Cp) * , 116.8 (Cd), 117.6 (t, J=15.6 Hz, Cs) * , 123.9 (q, J=271.9 Hz, -CF3), 126.2 (aromatic carbon), 126.9 (aromatic carbon), 127.9 (aromatic carbon), 128.4 (Ca), 129.2 (Cc), 129.7 (q, J=32.4 Hz, aromatic carbon), 130.1 (aromatic carbon), 134.4 (aromatic carbon), 141.7 (Ce), 143.8 (d, J=246.0 Hz, Cq) **, 143.9 (d, J=246.9 Hz, Cr) ** , 160.3 (Cg) *** , 162.7 (Ch) *** ;MS (ESI) 468 (M-1). ESI-HRMS (m / z): [M+H] + C 21 H 11 The calculated value for F7N3O2 is 470.0734; the measured value is 470.0735.

[0119] Ethyl 2-((tert-butoxycarbonyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate (67). Cs2CO3 (2.86 g, 8.74 mmol) and tert-butoxycarbonyl anhydride (0.699 g, 3.2 mmol) were added to a solution of 44 (0.600 g, 2.91 mmol) in anhydrous THF (25 mL). The reaction mixture was stirred overnight under reflux and allowed to reach room temperature. The solvent was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) and extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether / ethyl acetate, 80:20 v / v), and the title compound was provided as a white solid (from grinding with diisopropyl ether at 95.4–96.4°C). Yield 93%. 1 H NMR (600 MHz, chloroform-d3): δ 1.39 (t, 3H, J=7.1 Hz, -OCH2CH3), 1.58 (s, 9H, -OC(CH3)3), 4.36 (q, 2H, J=7.0 Hz, -OCH2CH3), 6.96 (t, 1H, J=6.8 Hz, Hb), 7.42 (t, 1H, J=7.9 Hz, Hc), 8.08 (d, 1H, J=8.8 Hz, Hd), 8.38 (d, 1H, J=6.6 Hz, Ha). 13C NMR (151 MHz, Chloroform-d3): δ 14.6 (-OCH2CH3), 27.8 (-C(CH3)3), 60.2 (-OCH2CH3), 84.8 (Cf), 93.4(-C(CH3)3), 114.1 (Cb), 119.2 (Cd), 128.0 (Ca), 129.3 (Cc), 142.3 (Ce), 150.2 (Ch), 158.2 (Cg) * , 162.1 (Ci) * MS (ESI) 307 (M+1).

[0120] Ethyl 2-((tert-butoxycarbonyl)oxy)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate (68). LiHMDS (1.0 M THF solution: 0.980 mL, 0.98 mmol, 1.5 eq) was added dropwise to a solution of 67 (0.400 g, 0.654 mmol) in anhydrous THF (10 mL) cooled to -78°C. This mixture was stirred at -78°C for 1 hour, and then a solution of hexachloroethane (0.170 g, 0.72 mmol, 1.1 eq) in anhydrous THF was added at -78°C. The reaction mixture was stirred at room temperature for 15 minutes. Subsequently, the reaction was quenched with saturated NH4Cl aqueous solution (100 mL). This aqueous phase was extracted with dichloromethane (4 × 100 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness under vacuum. The crude product was purified by flash chromatography (eluent: petroleum ether / ethyl acetate, 80:20 v / v), and the title compound was provided as a white solid (mp104.6-106.0°C, by grinding with diisopropyl ether). Yield 81%. 1¹H NMR (600 MHz, chloroform-d3): δ 1.40 (t, 3H, J=7.1 Hz, -OCH2CH3), 1.58 (s, 9H, -OC(CH3)3), 4.37 (q, 2H, J=7.2 Hz, -OCH2CH3), 7.11 (dd, 1H, J=7.5, 1.1 Hz, Hb), 7.39 (dd, 1H, J=8.9, 7.5 Hz, Hc), 8.09 (dd, 1H, J=8.9, 1.2 Hz, Hd). 13 C NMR (151 MHz, Chloroform-d3): δ 14.6 (-OCH2CH3), 27.8 (-C(CH3)3), 60.5 (-OCH2CH3), 85.0 (Cf)3, 95.2(-C(CH3)3), 114.4 (Cb), 117.5 (Cd), 128.2 (Cc), 131.0 (Ca), 143.9 (Ce), 150.0 (Ch), 158.0 (Cg) * , 161.8 (Ci) * . MS (ESI) 241 (M+1, -Boc).

[0121] Ethyl 7-chloro-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (69). Trifluoroacetic acid (10 mL) was added to a solution of 68 in anhydrous dichloromethane (25 mL), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with water, and the layers were separated. This aqueous solution was further extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over Na₂SO₄, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (eluent: dichloromethane / methanol 98:2v / v), and the title compound was provided as a white solid (mp1 34.0–135.8°C, by grinding with diisopropyl ether). Yield 94%. 1¹H NMR (600 MHz, chloroform-d3): δ 1.44 (t, 3H, J=7.2 Hz, -OCH2CH3), 4.44 (q, 2H, J=7.2 Hz, -OCH2CH3), 7.02 (dd, 1H, J=7.5, 1.2 Hz, Hb), 7.35 (dd, 1H, J=8.7, 7.5 Hz, Hc), 7.72 (dd, 1H, J=8.7, 1.2 Hz, Hd), 9.09 (s, 1H, -OH). 13 ¹³C NMR (151 MHz, chloroform-d3): δ 14.6 (-OCH2CH3), 60.9 (-OCH2CH3), 87.9 (Cf), 113.6 (Cb), 115.5 (Cd), 128.4 (Cc), 131.3 (Ca), 142.0 (Ce), 166.0 (Ch) * , 166.9 (Cg) * MS (ESI) 241 (M+1).

[0122] Ethyl 2-(benzyloxy)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate (70). Benzyl bromide (645 mg, 3.20 mmol, 1.10 eq) was added dropwise to a mixture of 69 (600 mg, 2.91 mmol) and Cs2CO3 (2.295 g, 7.04 mmol, 2.4 eq) in anhydrous DMF (15 mL). The reaction mixture was stirred overnight at room temperature, and then water (100 mL) was added. The mixture was extracted with siRNA (4 × 70 mL), and the combined organic layers were dried under Na2SO4 and evaporated under reduced pressure to obtain a yellow oily substance. This mixture was separated by flash chromatography (eluent: petroleum ether / siRNA 6 / 4 v / v), and the title compound was provided as a pale yellow solid (mp 98.2–99.3°C, by grinding with diisopropyl ether). Yield 85%. 1H NMR (600 MHz, chloroform-d3): δ 1.41 (t, 3H, J=7.1 Hz, -OCH2CH3), 4.38 (q, 2H, J=7.1 Hz, -OCH2CH3), 5.58 (s, 2H, -OCH2Ph), 6.96 (dd, 1H, J=7.4, 1.2 Hz, Hb), 7.27 - 7.34 (m, 2H, Hc and aromatic protons), 7.39 (t, 2H, J=7.5 Hz, aromatic protons), 7.59 (d, 2H, J=7.4 Hz, aromatic protons), 7.99 (dd, 1H, J=8.8, 1.2 Hz, HD). 13 ¹³C NMR (151 MHz, chloroform-d3): δ 14.6 (-OCH2CH3), 60.0 (-OCH2CH3), 71.1 (-OCH2Ph), 90.1 (Cf), 112.8 (Cb), 116.5 (Cd), 127.8 (aromatic carbon), 127.9 (aromatic carbon), 128.0 (Cc), 128.5 (aromatic carbon), 130.6 (Ca), 136.7 (aromatic carbon), 144.6 (Ce), 163.1 (Ch) * , 164.8 (Cg) * MS (ESI) 331 (M+1).

[0123] 2-(benzyloxy)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid (71). 6M NaOH (5.0 eq) was added to a solution of compound 70 (785 mg, 2.40 mmol) in anhydrous EtOH (20 mL). The mixture was stirred at 75°C for 4 hours, then neutralized with 6M HCl and concentrated under reduced pressure. The mixture was cooled to 0°C and then acidified with 2M HCl to pH 2 to obtain a suspension. This was filtered to obtain the title compound as a white solid (from grinding with diisopropyl ether at mp178.4–179.8°C, accompanied by gas generation). Yield 84%. 1¹H NMR (600 MHz, DMSO-d⁶): δ 5.48 (s, 2H, -OCH₂Ph), 7.31 (dd, 1H, J=7.5, 1.1 Hz, Hb), 7.35 (t, 1H, J=7.4 Hz, aromatic proton), 7.41 (t, 2H, J=7.4 Hz, aromatic proton), 7.52 (dd, 1H, J=8.7, 7.6 Hz, Hc), 7.55 (d, 2H, J=7.5 Hz, aromatic proton), 7.95 (dd, 1H, J=8.9, 1.1 Hz, Hd), 12.34 (br s, 1H, -COOH). 13 C NMR (151 MHz, DMSO-d6): δ 70.5 (-OCH2Ph), 89.4 (Cf), 113.3 (Cb), 116.1 (Cd), 127.9 (Ca), 128.1 (aromatic carbon), 128.4 (aromatic carbon), 128.9 (aromatic carbon), 129.4 (Cc), 136.4 (aromatic carbon), 144.1 (Ce), 163.3 (Ch) * , 164.0 (Cg) * MS (ESI) 301 (M-1).

[0124] 1-Benzyl-7-chloro-2-oxo-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxamide (72). Oxalyl chloride (3.0 mmol) and anhydrous DMF (1 drop) were added to a cooled (0°C) solution of 71 (1.0 mmol)1-3 in anhydrous THF (20 mL) under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. Next, this solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL; this step was repeated 3 times). The resulting acylchloride was used immediately without further purification, dissolved in 10 mL of anhydrous toluene, and transferred to the solution described later. Trimethylaluminum (2.0 M, 1.5 mmol in hexane) was added to a solution of 4-phenyl-2,3,5,6-tetrafluoroaniline (1.5 mmol) in anhydrous toluene (15 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours to produce a brown suspension, and then the previously described solution of acylchloride in anhydrous toluene (30 mL) was quantitatively added. This mixture was heated overnight at 90°C and then cooled to rt. The reaction was quenched with 1 M HCl, and these layers were separated. The aqueous phase was thoroughly extracted with RINKAN. The combined organic layers were washed with 1 M NaOH and brine, dried, and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA from 8:2 v / v to 4:6 v / v), and the title compound was provided as a white solid (mp201.1-202.4°C, by grinding with diisopropyl ether). Yield 38%. 1H NMR (600 MHz, Chromo-d3): δ 5.74 (s, 2H, -NCH2Ph), 6.73 (dd, 1H, J=7.5, 1.2 Hz, Hb), 7.06 (dd, 2H, J=7.4, 1.7 Hz, aromatic protons), 7.22–7.30 (m, 3H, aromatic protons), 7.35 (dd, 1H, J=8.8, 7.6 Hz, Hc), 7.42–7.53 (m, 5H, aromatic protons), 8.28 (dd, 1H, J=8.8, 1.2 Hz, Hd), 10.01 (s, 1H, -NH); 13 C NMR (151 MHz, クロロホルム-d3): δ 52.6 (-NCH2Ph), 89.2 (Cf), 114.6 (Cb), 115.9 (t, J=16.3 Hz, Cp) * , 116.7 (Cd), 118.0 (t, J=17.2 Hz, Cs) * , 127.2 (aromatic carbon), 127.6 (Ca), 128.6 (aromatic carbon), 128.7 (aromatic carbon), 129.1 (aromatic carbon), 129.2 (aromatic carbon), 130.4 (Cc), 130.6 (aromatic carbon), 133.7 (aromatic carbon), 133.8 (aromatic carbon), 142.8 (dd, J=248.8, 15.1 Hz, Cq) ** , 144.2 (d, J=248.3 Hz, Cr) ** , 150.3 (Ce), 161.2 (Cg) *** , 167.5 (Ch) *** MS (ESI) 526 (M-1).

[0125] 7-Chloro-2-hydroxy-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (4). Thianisole (240 μL, 1.90 mmol, 10.0 eq) was added to a solution of 72 (100 mg, 0.19 mmol, 1.0 eq) in TFA (2 mL). This mixture was heated at 70°C for 3 hours and then cooled to rt. This mixture was concentrated to some extent, and the biosubstance was dissolved in water to obtain a suspension, which was filtered, and the solid was washed with an additional amount of water. The obtained solid was ground with diisopropyl ether, and the title compound was provided in the form of a pure white solid (from grinding with diisopropyl ether at mp259.3-260.4°C). Yield 64%. 1 H NMR (600 MHz, DMSO-d6): δ 7.32 (dd, 1H, J=7.5, 1.1 Hz, Hb), 7.53 (dd, 1H, J=8.7, 7.5 Hz, Hc), 7.53 - 7.60 (m, 5H, aromatic proton), 8.02 (dd, 1H, J=8.8, 1.1 Hz, Hd), 8.99 (s, 1H, -NH), 13.33 (br s, 1H, -OH). 13 C NMR (151 MHz, DMSO-d6): δ 89.9 (Cf), 113.5 (Cb), 115.6 (Cd), 116.7 (t, J=17.8 Hz, Cp) * , 117.4 (t, J=17.7 Hz, Cs) * , 126.6 (Ca), 128.8 (aromatic carbon), 128.9 (aromatic carbon), 128.9 (Cc), 129.4 (aromatic carbon), 130.1 (aromatic carbon), 142.9 (d, J=246.6 Hz, Cq) ** , 143.2 (d, J=241.3 Hz, Cr) ** , 143.5 (Ce), 160.2 (Cg) *** , 162.6 (Ch) *** . MS (ESI) 436 (M+1). ESI-HRMS (m / z): [M+H]+ C 20H 11 The calculated value for ClF4N3O2 is 436.0470; the measured value is 436.0472.

[0126] General procedure for the synthesis of pyrazolo[1,5-a]pyridine-related amides (73-82). Oxalyl chloride (1.75 mL, 3.5 mmol) and anhydrous DMF (7 μL) were added under nitrogen atmosphere to a cooled (0°C) solution of 45 (1.0 mmol) in anhydrous THF (15 mL). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in anhydrous THF (10 mL), and this solution was concentrated again. This process was repeated three times. A suitable solution of aniline (83-92, 1.00 mmol) and anhydrous pyridine (3.0 mmol) in anhydrous toluene (5 mL) was added dropwise to the previously prepared solution of acyl chloride in anhydrous toluene (15 mL) while maintaining a nitrogen atmosphere. The resulting mixture was stirred under reflux overnight, cooled to room temperature, and only compounds 75-78 were quenched with 0.5 M HCl (25 mL). These layers were separated, the aqueous phase was further extracted with HCl (3 × 50 mL), and the combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure. This crude material was purified by flash chromatography (details are provided in the specific preparation methods for each).

[0127] 2-Benzyloxy-N-(5-phenoxypyridine-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (73). Obtained from 45 using aniline 83. Flash chromatography eluent: petroleum ether / siRNA 80 / 20 v / v. White solid (from grinding with diisopropyl ether at mp1 20.6-120.7°C). Yield 87%. 1H NMR (600 MHz, クロロホルム-d): δ 5.55 (s, 2H, -OCH2Ph), 6.86 - 6.92 (m, 2H, aromatic プロトン and びHb), 7.10 (d, 2H, J=7.9 Hz, Aromatic プロトン), 7.17 (t, 1H, J=7.4 Hz, Hc), 7.34 - 7.42 (m, 4H, aromatic プロトン), 7.45 (t, 2H, J=7.3 Hz, aromatic プロトン), 7.53 (d, 2H, J=7.2 Hz, aromatic プロトン), 8.01 (d, 1H, J=2.6 Hz, Aromatic Hd), 8.25 - 8.30 (m, 2H, Aromatic Hd), 8.32 (d, 1H, J=6.8 Hz, Ha), 8.64 (s, 1H, -NH). 13 C NMR (151 MHz, クロロホルム-d): δ 72.4 (-OCH2Ph), 90.5 (Cf), 111.8, 113.1 (Cb), 118.8 (Cd), 120.7, 124.4, 127.9 (Cc), 128.3, 128.8 (Ca), 129.1, 129.2, 129.8, 131.4, 131.9, 135.6, 138.6, 143.0 (Ce), 155.0 (Cs) * , 159.6 (Cv) * , 161.4 (Cg) * , 162.3 (Ch) * IR (KBr) v (cm -1 ): 3373, 3100, 3044, 2925, 1947, 1663, 1636, 1534, 1473, 1365, 1296, 1249, 1207, 1120, 1005. MS (ESI) 435 (M-1).

[0128] 2-Benzyloxy-N-5-[3-(trifluoromethyl)phenoxy]pyridine-2-ylpyrazolo[1,5-a]pyridine-3-carboxamide (74). Obtained from 45 using aniline 84. Flash chromatography eluent: petroleum ether / siRNA (70 / 30 v / v). White solid (ground with diisopropyl ether at mp1 33.6-135.9°C). Yield 50%. 1 ¹H NMR (600 MHz, chloroform-d): δ 5.65 (s, 2H, -OCH2Ph), 6.89 (t, 1H, J=6.7 Hz, Hb), 7.14 (dd, 1H, J=8.2, 1.9 Hz, aromatic proton), 7.23 (s, 1H, aromatic proton), 7.33 - 7.46 (m, 7H, aromatic proton), 7.60 (d, 2H, J=7.3 Hz, aromatic proton), 8.12 (d, 1H, J=2.8 Hz, aromatic proton), 8.29 (d, 1H, J=8.9 Hz, Hd), 8.31 (d, 1H, J=6.9 Hz, Ha), 8.42 (d, 1H, J=9.0 Hz, Aromatic proton), 9.40 (s, 1H, -NH). 13 C-NMR (151 MHz, Chloroform-d): δ 72.0 (-OCH2Ph), 90.7 (Cf), 113.1 (Cb), 114.6 (q, J=3.8 Hz), 114.9, 118.8 (Cd), 119.8 (q, J=3.8 Hz), 120.8, 123.8 (q, J=272.0 Hz, -CF3), 127.9, 128.0, 128.6, 128.8, 128.9, 129.7, 130.6, 132.5 (q, J=32.8 Hz), 135.9, 140.3, 143.2 (Ce), 148.3, 148.9 (Cs) * , 158.2 (Cv) * , 161.2 (Cg) * , 162.4 (Ch) * IR (KBr) v (cm -1): 3373, 3069, 2924, 2853, 1666, 1634, 1538, 1449, 1328, 1287, 1163, 1130, 1012. MS (ESI) 505 (M+1).

[0129] 2-(benzyloxy)-N-(2-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (75). Obtained from 45 using aniline 85. Flash chromatography (eluent: petroleum ether / siRNA 85 / 15v / v). Bright yellow solid (mp1 86.1-190.9℃, from diisopropyl ether). Yield 87%. 1 H NMR (600 MHz, chloroform-d): δ 1.83 (s, 3H, Ar-CH3), 5.54 (s, 2H, -OCH2Ph), 6.76 (d, J=2.2 Hz, 1H, Ht), 6.85 - 6.91 (m, 2H, aromatic proton), 6.96 (d, 2H, J=8.1, aromatic protons), 7.05 (t, 1H, J=7.3 Hz, Hb), 7.30 (t, 2H, J =7.8 Hz, aromatic protons), 7.34 - 7.45 (m, 4H, aromatic protons and Hc), 7.53 (d, 2H, J=6.3 Hz, aromatic proton), 8.20 (d, 1H, J=8.8 Hz, Hd), 8.29 - 8.37 (m, 2H, aromatic proton), 8.44 (s, 1H, -NH). 13 ¹³C NMR (151 MHz, chloroform-d): δ 17.6 (Ar-CH3), 72.6 (-OCH2Ph), 91.1 (Cf), 112.9 (Cb), 117.5 (Cd), 118.3, 119.0, 121.1, 122.8, 123.0, 127.6, 128.6, 129.0, 129.2, 129.4, 129.5, 129.7, 132.7, 135.4, 143.1 (Ce), 152.6 (Cg) * , 158.1 (Cs) * , 161.2 (Cv) *, 162.3 (Ch) * ;IR (KBr) ν (cm -1 ): 3391, 3308, 3040, 2922, 2737, 1963, 1882, 1660, 1590, 1588, 1362, 1334, 1219, 1151, 1130, 1101; MS (ESI) 450 (M+1).

[0130] 2-(benzyloxy)-N-(2-isopropyl-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (76). Obtained from 45 using aniline 86. Flash chromatography eluent: petroleum ether / siRNA (70 / 30 v / v). White solid (from grinding with diisopropyl ether at mp166.2-167.7°C). Yield 54%. 1 H NMR (600 MHz, chloroform-d): δ 0.90 (d, 6H, J=6.8 Hz, CH(CH3)2), 2.16 (s, 3H, Ar-CH3), 2.72 (hept, 1H, J=6.7 Hz, -CH(CH3)2), 5.55 (s, 2H, -OCH2Ph), 6.81 (s, 1H, Ht), 6.84 (d, 2H, J=8.1 Hz, aromatic proton), 6.87 (t, 1H, J=6.9 Hz, Hb), 6.98 (t, 1H, J=7.3 Hz, aromatic proton), 7.22 - 7.28 (m, 2H, aromatic proton), 7.34 - 7.45 (m, 4H, aromatic proton), 7.52 (d, 2H, J=6.9 Hz, aromatic proton), 8.02 (s, 1H, Hq), 8.31 (d, 1H, J=6.8 Hz, Ha), 8.35 (d, 1H, J=8.8 Hz, Hd), 8.48 (s, 1H, - NH). 13C NMR (151 MHz, Chloroform-d): δ 16.1 (Ar-CH3), 22.7 CH(CH3)2), 27.8 (-CH(CH3)2), 72.5 (-OCH2Ph), 91.1 (Cf), 112.9 (Cb), 116.3, 117.9, 119.1 (Cd), 121.8, 126.4, 127.6 (Cc), 128.3, 128.6, 129.0 (Ca), 129.1, 129.2, 129.7, 131.5, 135.5, 138.4, 143.2 (Ce), 150.4 (Cs) * , 158.7 (Cv) * , 161.5 (Ch) ** , 162.4 (Cg) ** ; IR (KBr) v (cm -1 ): 3398, 3040, 2963, 1652, 1636, 1528, 1490, 1445, 1402, 1368, 1289, 1220, 1181, 1147, 1127, 1044, 993; MS (ESI) 492 (M+1).

[0131] 2-(benzyloxy)-N-(5-isopropyl-2-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (77). Obtained from 45 using aniline 87. Flash chromatography (eluent: petroleum ether / siRNA 60 / 40 v / v). White solid (from grinding with diisopropyl ether at mp157.5-158.9°C). Yield 92%. 1H NMR (600 MHz, Chroloholm-d): δ 1.24 (d, 6H, J=6.8 Hz, -CH(CH3)2), 1.77 (s, 3H, Ar-CH3), 3.20 (hept, 1H, J=6.8 Hz, -CH(CH3)2), 5.54 (s, 2H, -OCH2Ph), 6.64 (s, 1H, Ht), 6.85 - 6.91 (m, 3H, aromatic protons and Hb), 7.01 (t, 1H, J=7.3 Hz, Hc), 7.20 - 7.45 (m, 6H, aromatic protons), 7.52 (d, 2H, J=6.4 Hz, Aromatic methane), 8.29 (s, 1H, Hq), 8.32 (d, 1H, J=6.8 Hz, Ha), 8.37 (d, 1H, J= 8.8 Hz, Hd), 8.47 (s, 1H, -NH). 13 C NMR (151 MHz クロロホルム-d): δ 17.1 (-CH(CH3)2), 23.2 (-CH(CH3)2), 27.4 (Ar-CH3), 72.6 (-OCH2Ph), 91.2 (Cf), 112.8 (Cb), 117.0, 119.1 (Cd), 120.2, 122.0, 122.1, 126.4, 127.5, 128.6, 128.9, 129.2, 129.4, 129.6, 133.6, 135.4, 138.8, 143.0 (Ce), 148.8 (Cs) * , 159.0 (Cv) * , 161.2 (Cg) ** , 162.3 (Ch) ** ;IR (KBr) ν (cm -1 ): 3392, 3045, 2970, 1652, 1636, 1597, 1533, 1486, 1456, 1407, 1360, 1290, 1223, 1146, 1129, 1007, 911; MS (ESI) 492 (M+1).

[0132] 2-(benzyloxy)-N-(2-isopropyl-5-methyl-4-(4-(trifluoromethyl)phenoxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (78). Obtained from 45 using aniline 88. White solid obtained by flash chromatography (eluent: petroleum ether / ethyl ethyl 85 / 15v / v) (186.2-187.3°C, from diisopropyl ether). Yield 95%. 1 ¹H NMR (600 MHz chloroform-d): δ 0.91 (d, 6H, J=6.8 Hz, -CH(CH3)2), 2.14 (s, 3H, Ar-CH3), 2.73 (hept, 1H, J=6.8 Hz, -CH(CH3)2), 5.56 (s, 2H, -OCH2Ph), 6.82 (s, 1H, Ht), 6.87 - 6.91 (m, 3H, aromatic proton and Hb), 7.36 - 7.46 (m, 4H, aromatic proton), 7.49 - 7.56 (m, 4H, aromatic proton), 8.10 (s, 1H, Hq), 8.33 (d, 1H, J=6.9 Hz, Ha), 8.35 (d, 1H, J=8.8 Hz, Hd), 8.53 (s, 1H, -NH). 13 C NMR (151 MHz, Chloroform-d): δ 16.0 (Ar-CH3), 22.7 (-CH(CH3)2), 27.8 (-CH(CH3)2), 72.6 (-OCH2Ph), 91.0 (Cf), 112.9 (Cb), 115.9, 118.2 (Cd), 119.0, 123.8 (q, J=33.2 Hz), 124.5 (q, J=270.9, -CF3), 126.4, 127.2 (q, J=3.7 Hz), 127.7, 128.4, 128.7, 129.0, 129.2, 129.3, 132.3, 135.5, 138.5, 143.2 (Ce), 149.2 (Cs), 161.4 (Cv) * , 161.5 (Cg) * , 162.4 (Ch) * ;IR (KBr) ν (cm -1): 3403, 3084, 3043, 2976, 2891, 1655, 1638, 1613, 1578, 1543, 1511, 1501, 1477, 1446, 1401, 1360, 1330, 12090, 1240, 1215, 1148, 1120, 1064, 1042, 994; MS (ESI) 560 (M+1).

[0133] 2-(benzyloxy)-N-(1H-indole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (79). Obtained from 45 using aniline 89. Flash chromatography (eluent: petroleum ether / siRNA 60 / 40 v / v). White solid (from grinding with diisopropyl ether at mp1 33.6-135.9°C). Yield 74%. 1 H NMR (600 MHz, DMSO-d6): δ 5.60 (s, 2H, -OCH2Ph), 6.38 (s, 1H, aromatic proton), 7.03 (t, 1H, J=6.9 Hz, Hb), 7.11 (dd, 1H, J=8.6, 1.6 Hz, aromatic proton), 7.30 - 7.34 (m, 2H, aromatic proton), 7.41 (t, 1H, J=7.4 Hz, Hc), 7.47 (t, 2H, J=7.5 Hz, aromatic proton), 7.50 - 7.54 (m, 2H, aromatic proton), 7.65 (d, 2H, J=7.4 Hz, aromatic proton), 7.88 (s, 1H, aromatic proton), 8.13 (d, 1H, J=8.8 Hz, Hd), 8.69 (d, 1H, J=6.8 Hz, Ha), 8.82 (s, 1H, -NH), 11.03 (s, 1H, -NH indole). 13C-NMR (151 MHz, DMSO-d6): δ 71.5 (-OCH2Ph), 90.4 (Cf), 101.1, 110.6, 111.4, 113.1 (Cb), 114.8, 117.5 (Cd), 126.1, 127.6, 128.1, 128.2, 128.5, 128.7, 129.4, 130.6, 132.8, 136.3, 141.9 (Ce), 160.0 (Cg) * , 161.6 (Ch) * MS (ESI) 505 (M+1).

[0134] 2-(benzyloxy)-N-(1-phenyl-1H-indole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (80). Obtained from 45 using aniline 90. Flash chromatography (eluent: petroleum ether / siRNA 60 / 40 v / v). White solid (from grinding with diisopropyl ether at mp1 33.6-135.9°C). Yield 74%. 1 H NMR (600 MHz, DMSO-d6): δ 5.60 (s, 2H, -OCH2Ph), 6.38 (s, 1H, aromatic proton), 7.03 (t, 1H, J=6.9 Hz, Hb), 7.11 (dd, 1H, J=8.6, 1.6 Hz, aromatic proton), 7.30 - 7.34 (m, 2H, aromatic proton), 7.41 (t, 1H, J=7.4 Hz, Hc), 7.47 (t, 2H, J=7.5 Hz, aromatic proton), 7.50 - 7.54 (m, 2H, aromatic proton), 7.65 (d, 2H, J=7.4 Hz, aromatic proton), 7.88 (s, 1H, aromatic proton), 8.13 (d, 1H, J=8.8 Hz, Hd), 8.69 (d, 1H, J=6.8 Hz, Ha), 8.82 (s, 1H, -NH). 13C-NMR (151 MHz, DMSO-d6): δ 71.5 (-OCH2Ph), 90.4 (Cf), 101.1, 110.6, 111.4, 113.1 (Cb), 114.8, 117.5 (Cd), 126.1, 127.6, 128.1, 128.2, 128.5, 128.7, 129.4, 130.6, 132.8, 136.3, 141.9 (Ce), 160.0 (Cg) * , 161.6 (Ch) * MS (ESI) 505 (M+1).

[0135] 2-(benzyloxy)-N-(1-phenyl-1H-benzo[d]imidazole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (81). Obtained from 45 using aniline 91. Flash chromatography (eluent: DCM / MeOH 95 / 5v / v). Pale pink solid (mp1 33.6-135.9℃; from grinding with diisopropyl ether). Yield 67%. 1 ¹H NMR (600 MHz, chloroform-d): δ 5.29 (s, 1H, aromatic proton), 5.59 (s, 2H, -OCH2Ph), 6.87 (t, 1H, J=6.8 Hz, Hb), 7.35 - 7.60 (m, 11H, aromatic proton), 7.63 (d, 1H, J=8.7 Hz, aromatic proton), 7.94 (s, 1H, aromatic proton), 8.10 (s, 1H, aromatic proton), 8.31 (d, 1H, J=6.8 Hz, Ha), 8.35 (d, 1H, J=8.8 Hz, Hd), 8.84 (s, 1H, -NH). 13¹¹C-NMR (151 MHz, chloroform-d): δ 72.3 (-OCH2Ph), 91.1 (Cf), 110.5, 111.4, 112.9 (Cb), 117.6, 119.0 (Cd), 124.0, 127.6, 128.1, 128.3, 128.7, 129.0, 129.1, 130.2, 130.4, 134.5, 135.9, 136.5, 142.9, 143.0 (Ce), 144.5, 161.4 (Cg) * , 162.3 (Ch) * MS (ESI) 505 (M+1).

[0136] 2-(benzyloxy)-N-(1-phenyl-1H-benzo[d][1,2,3]triazole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (82). Obtained from 45 using aniline 92. Flash chromatography (eluent: DCM / MeOH 95 / 5v / v). Pale pink solid (mp1 33.6-135.9℃; from grinding with diisopropyl ether). Yield 90%. 1 H NMR (600 MHz, chloroform-d): δ 5.61 (s, 2H, -OCH2Ph), 7.06 (t, 1H, J=6.8 Hz, Hb), 7.40 (t, 1H, J=7.3 Hz, Hc), 7.47 (t, 2H, J=7.5 Hz, aromatic proton), 7.53 - 7.72 (m, 7H, aromatic proton), 7.85 - 7.92 (m, 3H, aromatic proton), 8.12 (d, 1H, J=8.8 Hz, Hd), 8.59 (s, 1H, aromatic proton), 8.70 (d, 1H, J=6.8 Hz, Ha), 9.23 (s, 1H, -NH). 13¹¹C-NMR (151 MHz, chloroform-d): δ 71.5 (-OCH2Ph), 90.0 (Cf), 107.6, 111.3 (Cb), 113.5, 117.4 (Cd), 122.5, 128.1, 128.4, 128.5, 128.6, 128.7, 128.8, 129.6, 130.1, 135.8, 136.3, 136.4, 142.0 (Ce), 146.3, 160.6 (Cg) * , 161.9 (Ch) * MS (ESI) 505 (M+1).

[0137] General hydrogenation procedure for target compounds 19-24, 28-30, and 37. 10% palladium (Pd / C, 45 mg) supported on carbon was added to a solution of a suitable amide (compounds 73-82, 0.300 mmol) in anhydrous THF (15 mL). The resulting mixture was vigorously mixed under a hydrogen atmosphere for 3 hours. This suspension was filtered through Celite, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure. If necessary, the resulting solid was further purified by flash chromatography.

[0138] 2-Hydroxy-N-(1H-indole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (19). Obtained from 79. Flash chromatography (eluent: dichloromethane / methanol 95 / 5v / v). White solid (from grinding with diisopropyl ether at mp133.6-135.9°C). Yield 74%. 1H NMR (600 MHz, DMSO-d6): δ 6.39 (s, 1H, aromatic proton), 6.95 (t, 1H, J=6.7 Hz, Hb), 7.24 (dd, 1H, J=8.6, 1.1 Hz, aromatic proton), 7.27 - 7.38 (m, 2H, aromatic proton), 7.44 (t, 1H, J=7.8 Hz, Hc), 7.97 (d, 1H, J=1.9 Hz, aromatic proton), 8.07 (d, 1H, J=8.8 Hz, Hd), 8.55 (d, 1H, J=6.8 Hz, Ha), 9.03 (s, 1H, -NH), 11.02 (s, 1H, -NH indole), 18.84 (v br s, 1H, -OH). 13 C-NMR (151 MHz, DMSO-d6): δ 89.6 (Cf), 101.1, 110.6, 111.4, 112.5 (Cb), 115.0, 117.1 (Cd), 126.0, 127.3 (Cc), 127.7, 128.3, 130.8 (Ca), 132.7, 141.4 (Ce), 160.8 (Cg) * , 162.1 (Ch) * MS (ESI) 293 (M+1).

[0139] 2-Hydroxy-N-(1-phenyl-1H-indole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (20). Obtained from 80. Flash chromatography (eluent: DCM / methanol 95 / 5v / v). White solid (mp1 33.6-135.9℃; from grinding with diisopropyl ether). Yield 90%. 1H NMR (600 MHz, DMSO-d6): δ 6.68 (d, 1H, J=3.0 Hz, aromatic proton), 6.96 (t, 1H, J=6.7 Hz, Hb), 7.32 - 7.42 (m, 2H, aromatic proton), 7.45 (t, 1H, J=7.8 Hz, Hc), 7.49 - 7.62 (m, 5H, aromatic proton), 7.65 (d, 1H, J=3.1 Hz, aromatic proton), 8.08 (d, 1H, J=8.8 Hz, Hd), 8.13 (s, 1H, aromatic proton), 8.56 (d, 1H, J=6.7 Hz, Ha), 9.15 (s, 1H, -NH), 12.95 (s, 1H, -OH). 13 C-NMR (151 MHz, DMSO-d6): δ 89.6 (Cf), 103.6, 110.5, 111.2, 112.6 (Cb), 115.9, 117.0 (Cd), 123.5, 126.3, 127.4 (Cc), 128.9, 129.0, 129.3 (Ca), 129.9, 131.7, 132.2, 139.2, 141.4 (Ce), 160.9, 162.2. MS (ESI) 369 (M+1).

[0140] 2-Hydroxy-N-(1-phenyl-1H-benzo[d]imidazole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (21). Obtained from 81. Flash chromatography (eluent: DCM / MeOH 80 / 20v / v). Pale pink solid (mp1 33.6-135.9℃; from grinding with diisopropyl ether). Yield 90%. 1H NMR (600 MHz, DMSO-d6): δ 6.87 (t, 1H, J=6.5 Hz, Hb), 7.37 (t, 1H, J=7.7 Hz, Hc), 7.46 - 7.54 (m, 2H, aromatic proton), 7.57 (d, 1H, J=8.6 Hz, aromatic proton), 7.63 (t, 2H, J=7.8 Hz, aromatic proton), 7.69 (d, 2H, J=7.7 Hz, aromatic proton), 8.00 (d, 1H, J=8.6 Hz, Hd), 8.32 (s, 1H, aromatic proton), 8.48 (d, 1H, J=6.4 Hz, Ha), 8.54 (s, 1H, aromatic proton), 9.99 (s, 1H, -NH). 13 C-NMR (151 MHz, DMSO-d6): δ 89.6 (Cf), 109.8, 110.6, 111.8, 116.4 (Cb), 116.5, 123.4, 126.7, 127.6 (Cc), 128.4, 128.9, 130.1 134.8, 136.1, 141.4 (Ce), 141.5, 143.6, 144.2, 161.9. MS (ESI) 368 (M-1).

[0141] 2-Hydroxy-N-(1-phenyl-1H-benzo[d][1,2,3]triazole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (22). Obtained from 82. Flash chromatography (eluent: DCM / MeOH 95 / 5v / v). Gray solid (mp1 33.6-135.9℃; from grinding with diisopropyl ether). Yield 72%. 1H NMR (600 MHz, DMSO-d6): δ 6.85 (t, 1H, J=6.6 Hz, Hb), 7.35 (t, 1H, J=7.7 Hz, Hc), 7.58 (t, 1H, J=7.5 Hz, aromatic proton), 7.70 (t, 2H, J=7.9 Hz, aromatic proton), 7.78 (d, 1H, J=8.1 Hz, aromatic proton), 7.84 - 7.91 (m, 3H, aromatic proton), 7.95 (d, 1H, J=8.6 Hz, Hd), 8.44 (d, 1H, J=6.6 Hz, Ha), 8.71 (s, 1H, aromatic proton), 10.53 (s, 1H, -NH). 13 C-NMR (151 MHz, DMSO-d6): δ 89.5 (Cf), 106.8, 111.1 (Cb), 111.7, 116.1 (Cd), 122.5, 122.7, 126.6, 128.0, 128.3, 128.7, 130.1, 136.5, 136.8, 137.6, 141.5 (Ce), 146.5, 162.5. MS (ESI) 369 (M-1).

[0142] 2-Hydroxy-N-(5-phenoxypyridine-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (23). Obtained from 73. Flash chromatography (eluent: DCM / methanol 90 / 10v / v). White solid (mp1 61.1-161.9℃; from grinding with diisopropyl ether). Yield 76%. 1H NMR (600 MHz, DMSO-d6): δ 6.75 (t, 1H, J=6.7 Hz, Hb), 6.97 (d, 1H, J=8.7 Hz, aromatic proton), 7.08 (d, 2H, J=8.0 Hz, aromatic proton), 7.16 (t, 1H, J=7.4 Hz, aromatic proton), 7.26 (t, 1H, J=7.8 Hz, aromatic proton) 7.39 (t, 2H, J=7.8 Hz, aromatic proton), 7.83 (d, 1H, J=8.7 Hz, Hd), 8.21 (dd, 1H, J=8.8, 2.5 Hz, aromatic proton), 8.33 (d, 1H, J=6.6 Hz, Ha), 8.48 (d, 1H, J=2.2 Hz, aromatic proton), 10.78 (s, 1H, -NH). 13 C NMR (151 MHz, DMSO-d6): δ 89.3 (Cf), 111.1 (Cb), 111.7, 115.6 (Cd), 120.2, 123.9, 125.9 (Cc), 127.9, 129.7, 131.1 (Ca), 132.9, 137.8, 141.4 (Ce), 154.9, 157.6 (Cg), 162.8 (Ch). MS (ESI) 345 (M-1). IR (KBr) v (cm -1 ): 3061, 1653, 1636, 1534, 1476, 1379, 1248, 1205, 1124, 1023.

[0143] 2-Hydroxy-N-5-[3-(trifluoromethyl)phenoxy]pyridine-2-ylpyrazolo[1,5-a]pyridine-3-carboxamide (24). Obtained from 74. Flash chromatography (eluent: DCM / methanol 90 / 10v / v). White solid (mp2 41.2-242.0℃; from grinding with diisopropyl ether). Yield 45%. 1H NMR (600 MHz, DMSO-d6): δ 6.59 (t, 1H, J=6.7 Hz, Hb), 7.10 (t, 1H, J=7.7 Hz, Hc), 7.26 - 7.34 (m, 2H, aromatic proton), 7.46 (d, 1H, J=7.6 Hz, aromatic proton), 7.55 (dd, 1H, J=9.0, 2.8 Hz, aromatic proton), 7.61 (t, 1H, J=8.0 Hz, aromatic proton), 7.65 (d, 1H, J=8.4 Hz, aromatic proton), 8.12 (d, 1H, J=2.8 Hz, aromatic proton), 8.14 (d, 1H, J=6.5 Hz, Ha), 8.40 (d, 1H, J=9.0 Hz, Hd), 12.48 (s, 1H, -NH); 13 C NMR (151 MHz, DMSO-d6): δ 89.0 (Cf), 109.8, 113.6 (q, J=4.0 Hz), 114.3, 119.4 (q, J=3.4 Hz), 120.9, 123.8 (q, J=272.0 Hz, -CF3), 124.4, 127.0, 129.9, 130.7 (q, J=32.1 Hz), 131.5, 140.1, 140.8, 141.7, 146.0, 150.7, 158.4, 163.9, 173.1. MS (ESI) 413 (M-1). IR (KBr) v (cm -1 ): 3328, 2925, 1653, 1636, 1559, 1448, 1328, 1284, 1241, 1173, 1129, 1065.

[0144] 2-Hydroxy-N-(2-methyl-4-(p-tolyloxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (28). Obtained from 75. Flash chromatography (eluent: DCM / methanol 90 / 10v / v). White solid (mp2 38.3-239.9℃; from grinding with diisopropyl ether). Yield 87%. 1H NMR (600 MHz DMSO-d6): δ 2.28 (s, 3H, Ar-CH3), 6.88 (dd, 1H, J=8.8, 2.6 Hz, Hr), 6.94 - 7.01 (m, 4H, aromatic proton), 7.09 (t, 1H, J=7.3 Hz, Hb), 7.37 (t, 2H, J=7.9 Hz, aromatic proton), 7.47 (t, 1H, J=7.9, Hc), 8.06 (d, 1H, J=8.8 Hz, Hq), 8.20 (d, 1H, J=8.8 Hz, Hd), 8.57 (d, 1H, J=6.8 Hz, Ha), 8.93 (s, 1H, -NH), 12.99 (v br s, 1H, -OH). 13 C NMR (151 MHz, DMSO-d6): δ 17.6 (Ar-CH3), 89.5 (Cf), 112.9 (Cb), 117.0, 117.1 (Cd), 117.9, 121.0, 122.2, 122.9, 127.8 (Cc), 129.0 (Ca), 129.2, 130.0, 133.1, 141.5 (Ce), 151.6 (Cs), 157.5 (Cv), 160.8 (Cg) * , 162.1 (Ch) * ;IR (KBr) ν (cm-1): 3388, 3039, 2567, 1664, 1633, 1590, 1549, 1485, 1445, 1413, 1380, 1333, 1307, 1273, 1245, 1227, 1173, 1134; MS (ESI) 360 (M+1).

[0145] 2-Hydroxy-N-(2-ispropyl-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (29). Obtained from 76. Flash chromatography (eluent: DCM / methanol 98 / 2v / v). White solid (mp2 44.2-247.9℃; from grinding with diisopropyl ether). Yield 91%. 1¹H NMR (600 MHz, DMSO-d⁶): δ 1.17 (d, 6H, J=6.8 Hz, -CH(CH₃)₂), 2.10 (s, 3H, Ar-CH₃), 3.10 (hept, 1H, J=6.8 Hz, -CH(CH₃)₂), 6.85 (d, 2H, J=8.1 Hz, aromatic proton), 6.89 (s, 1H, Ht), 6.98 (t, 1H, J=6.9 Hz, Hb), 7.03 (t, 1H, J=7.3 Hz, aromatic proton), 7.33 (t, 2H, J=7.9 Hz, aromatic proton), 7.47 (t, 1H, J=7.9 Hz, Hc), 8.00 (s, 1H, Hq), 8.06 (d, 1H, J=8.8 Hz, Hd), 8.57 (d, 1H, J=6.8 Hz, Ha), 8.98 (s, 1H, -NH), 12.95 (v br s, 1H, -OH). 13 C NMR (151 MHz, DMSO-d6): δ 15.7 (Ar-CH3), 22.6 (-CH(CH3)2), 27.4 (-CH(CH3)2), 89.4 (Cf), 112.9 (Cb), 116.0, 117.1 (Cd), 117.5, 122.0, 125.7, 127.0, 127.8 (Cc), 129.0 (Ca), 129.9, 131.9, 138.0, 141.5 (Ce), 149.5, 158.0 (Cv), 161.0 (Ch) * , 162.1 (Cg) * IR (KBr) v (cm -1 ): 3400, 2964, 2579, 1661, 1637, 1547,1492, 1446, 1404, 1332, 1228, 1185, 1130, 887; MS (ESI) 402 (M+1).

[0146] 2-Hydroxy-N-(5-isopropyl-2-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (30). Obtained from 77. Flash chromatography (eluent: DCM / methanol 95 / 5v / v). White solid (mp2 73.9-276.5℃; from grinding with diisopropyl ether). Yield 70%. 1 H NMR (600 MHz, DMSO-d6) δ 1.16 (d, 6H, J=6.8 Hz, -CH(CH3)2), 2.23 (s, 3H, Ar-CH3), 3.09 (Hept, 1H, J=6.8 Hz, -CH(CH3)2), 6.82 (s, 1H, Ht), 6.87 (d, 2H, J=8.0 Hz, aromatic proton), 7.98 (t, 1H, J=6.6 Hz, Hb), 7.03 (t, 1H, J=7.2 Hz, aromatic proton), 7.33 (t, 2H, J=7.7 Hz, aromatic proton), 7.47 (t, 1H, J=7.8 Hz, Hc), 8.10 (d, 1H, J=8.7 Hz, Hd), 8.31 (s, 1H, Hq), 8.58 (d, 1H, J=6.6 Hz, Ha), 8.98 (s, 1H, -NH), 13.01 (v br s, 1H, -OH). 13 C NMR (151 MHz, DMSO-d6): δ 17.0 (-CH(CH3)2), 23.0 (-CH(CH3)2), 26.6 (Ar-CH3), 89.5 (Cf), 112.9 8 (Cb), 116.4, 117.1 (Cd), 119.1, 122.1, 122.2, 126.2, 127.7 (Cc), 129.0 (Ca), 129.9, 134.2, 137.6, 141.5 (Ce), 147.5, 158.5, 160.8 (Cg) * , 162.1 (Ch) * IR (KBr) v (cm -1): 3393, 2961, 2578, 1659, 1636, 1548, 1486, 1446, 1407, 1333, 1217, 1160, 1126, 1042, 978; MS (ESI) 402 (M+1).

[0147] 2-Hydroxy-N-(2-isopropyl-5-methyl-4-(4-(trifluoromethyl)phenoxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (37). Obtained from 78. Flash chromatography (eluent: DCM / methanol 95 / 5v / v). White solid (mp2 49.2-249.9℃; from grinding with diisopropyl ether). Yield 98%. 1 H NMR (600 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6.7 Hz, -CH(CH3)2), 2.08 (s, 3H, Ar-CH3), 3.08 - 3.16 (m, 1H, -CH(CH3)2), 6.95 - 7.03 (m, 4H, aromatic protons, Ht and Hb), 7.48 (t, 1H J=7.8 Hz, Hc), 7.70 (d, 2H J=8.6 Hz, aromatic protons), 8.07 (d, 1H, J=8.8 Hz, Hd), 8.10 (s, 1H, Hq), 8.58 (d, 1H, J=6.8 Hz, Ha), 9.05 (s, 1H, -NH), 13.01 (v br s, 1H, -OH). 13C NMR (151 MHz, DMSO-d6): δ 15.6 (Ar-CH3), 22.6 (CH(CH3)2), 27.4 (CH(CH3)2), 89.4 (Cf), 112.9 (Cb), 115.9, 117.0 (Cd), 118.2, 122.4 (q, J=33.1 Hz), 124.4 (q, J=271.1 Hz, -CF3), 125.5, 127.1, 127.5 (q, J=3.7 Hz), 127.8 (Cc), 129.0 (Ca), 132.8, 138.1, 141.6 (Ce), 148.1 (Cs), 161.0 (Cv), 161.1 (Cg), 162.1 (Ch); IR (KBr) ν (cm -1 ): 3402, 2948, 2576, 1665, 1640, 1615, 1550, 1515, 1482, 1446, 1404, 1334, 1250, 1214, 1183, 1156, 114, 1103; MS (ESI) 470 (M+1).

[0148] N-(2,5-dimethyl-4-(pyridine-4-ylthio)phenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (93). Oxalyl chloride (201 μL, 2.35 mmol, 3.6 eq.) and anhydrous DMF (7 μL) were added under nitrogen atmosphere to a cooled (0°C) solution of 57 (0.783 mmol, 1.2 eq.) in anhydrous THF (15 mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. This solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL). This step was repeated three times. A solution of aniline 100 (0.652 mmol, 1 eq.) and anhydrous pyridine (2.347 mmol, 3.6 eq.) in anhydrous toluene (5 mL) was added to a solution of acyl chloride under nitrogen atmosphere. Due to the partial insolubility of 100 in anhydrous toluene, 5 mL of anhydrous THF was added. The resulting mixture was stirred at room temperature for 12 hours, then overnight at 70°C. The mixture was then quenched with 0.5 M HCl (25 mL). These layers were separated, the aqueous phase was further extracted with siRNA (3 × 50 mL), and the combined organic layers were dried and evaporated under reduced pressure. This crude material was purified by flash chromatography (eluent: petroleum ether / siRNA from 70:30 v / v to DCM / methanol from 80:20 v / v), and the title compound was provided as a brown solid (melting point: unknown). Yield 80%. 1H-NMR (600 MHz, Chromo-d): δ 1.77 (s, 3H, Ar-CH3), 2.34 (s, 3H, Ar-CH3), 3.84 (s, 3H, -OCH3), 5.48 (s, 2H, -OCH2Ph), 6.81 (d, 2H, J=5.7 Hz, Aromatic Proton), 6.90 (t, 1H, J=6.9 Hz, Hb), 6.94 (d, 2H, J=8.4 Hz, Hn), 7.24 (s, 1H, Aromatic Proton), 7.40 (t, 1H, J=7.9 Hz, Hc), 7.47 (d, 2H, J=8.4 Hz, Aromatic プロトン), 8.28 (d, 2H, J=5.5 Hz, aromatic プロトン); 8.31 - 8.36 (m, 2H, aromatic プロトン), 8.51 (s, 1H, Aromatic プロトン), 8.62 (s, 1H, -NH); 13 C-NMR (151 MHz クロロホルム-d): δ 16.8 (Ar-CH3), 20.7 (Ar-CH3), 55.5 (-OCH2Ph), 72.6 (-OCH2Ph), 91.1 (Cf), 113.1 (Cb), 114.3, 118.9 (Cd), 120.1, 121.0, 122.5, 125.3, 127.4, 127.9 (Ca), 128.8 (Cc), 131.4, 138.5, 139.4, 141.9, 143.1 (Ce), 149.4, 150.9, 160.5, 161.4, 162.4; MS (ESI) 511 (M+1).

[0149] General procedure for the synthesis of pyrazolo[1,5-a]pyridine-related amides (94-99). Oxalyl chloride (1.75 mL, 1.5 mmol) and anhydrous DMF (10 μL) were added to a cooled (0°C) solution of 57 (1.2 mmol) in anhydrous THF (15 mL) maintained under a nitrogen atmosphere. This reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. This solution was concentrated under reduced pressure, the residue was dissolved in anhydrous THF (10 mL), and this step was repeated three times. A solution (5 mL) of suitable aniline (101-106, 1.00 mmol) and anhydrous pyridine (3.6 mmol) in anhydrous toluene was added to the above acyl chloride solution (10 mL) in anhydrous toluene maintained under a nitrogen atmosphere. The resulting mixture was stirred under reflux overnight and then quenched with 0.5 M HCl (25 mL). These layers were separated, the aqueous phase was further extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were dried and evaporated under reduced pressure. This crude material was purified using flash chromatography.

[0150] 2-(benzyloxy)-N-(2-isopropoxy-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (94). This was obtained from 57 using aniline 101. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA 85:15v / v), and the title compound was provided as a viscous solid. Yield 90%. 1H NMR (600 MHz, chloroform-d): δ 1.12 (d, 6H, J=6.1 Hz, -CH(CH3)2), 2.17 (s, 3H, Ar-CH3), 4.36 (h, 1H, J=6.1 Hz, -CH(CH3)2), 5.67 (s, 2H, -OCH2Ph), 6.55 (s, 1H, Ht), 6.83 (t, 1H, J=6.8 Hz, Hb), 6.88 (d, 2H, J=8.1 Hz, Hn), 7.0 (t, 1H, J=7.3 Hz, aromatic proton), 7.25 - 7.41 (m, 6H, aromatic proton), 7.53 (d, 2H, J=7.5 Hz, aromatic proton), 8.26 (d, 1H, J=6.8 Hz, Ha), 8.35 (d, 1H, J=8.9 Hz, Hd), 8.48 (s, 1H, Hq), 9.20 (s, 1H, -NH); 13 C NMR (151 MHz, Chloroform-d): δ 15.8 (Ar-CH3), 21.9 (-CH(CH3)2), 71.5 (-CH(CH3)2), 71.6 (-OCH2Ph), 91.6 (Cf), 106.7, 112.7 (Cb), 116.2, 119.0 (Cd), 121.8, 122.5, 122.9, 126.3, 127.4, 127.9, 128.4, 128.6, 128.8, 129.7, 136.4, 143.2 (Ce), 145.7, 148.6, 158.8, 161.3, 162.3. MS (ESI) 538 (M-1).

[0151] N-(2-cyclobutoxy-5-methyl-4-phenoxyphenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (95). This was obtained from 57 using aniline 102. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA 85:15v / v), and the title compound was provided as a viscous solid. Yield 79%. 1¹H NMR (600 MHz, chloroform-d): δ 1.46 - 1.56 (m, 1H, cyclobutoxyproton), 1.59 - 1.68 (m, 1H, cyclobutoxyproton), 1.80 - 1.91 (m, 2H, cyclobutoxyproton), 2.15 (s, 3H, Ar-CH3), 2.18 - 2.25 (m, 2H, cyclobutoxyproton), 3.80 (s, 3H, -OCH3), 4.46 (p, 1H, J=7.1 Hz, cyclobutoxyproton), 5.58 (s 2H, -OCH2Ph), 6.38 (s, 1H, Ht), 6.84 (t, 1H, J=6.9 Hz, Hb), 6.87 (d, 2H, J=8.0 Hz, aromatic proton), 6.91 (d, 2H, J=8.4 Hz, Hn), 7.00 (t, 1H, J=7.3 Hz, aromatic proton), 7.25 - 7.30 (m, 2H, aromatic proton), 7.35 (t, 1H, J=7.9 Hz, Hc), 7.49 (d, 2H, J=8.4 Hz, Hm), 8.28 (d, 1H, J=6.8 Hz, Ha), 8.34 (d, 1H, J=8.8 Hz, Hd), 8.44 (s, 1H, Hq), 9.16 (s, 1H, -NH); 13 ¹³C NMR (151 MHz, chloroform-d): δ 13.1, 15.8, 30.5, 55.4, 71.6, 72.2 (-OCH2Ph), 91.6 (Cf), 105.6, 112.7 (Cb), 114.1, 116.3, 118.9 (Cd), 121.9, 122.3, 122.8, 125.3, 127.4, 128.4, 128.6, 129.7, 129.8, 143.1 (Ce), 145.4, 148.6, 158.6, 159.8, 161.3, 162.4. MS (ESI) 550 (M+1).

[0152] N-(2-(Sec-butoxy)-5-methyl-4-phenoxyphenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (96). It was obtained from 57 using aniline 103. The crude product was purified by flash chromatography (eluent: petroleum ether / ethylacetate 85:15v / v), and the title compound was provided as a sticky solid. Yield 94%. 1 H NMR (600 MHz, chloroform-d): δ 0.85 (t, 3H, J=7.5 Hz, -CHCH2CH3), 1.12 (d, 3H, J=6.1 Hz, -CH3CHCH2CH3), 1.33 - 1.60 (m, 2H, -CH3CHCH2CH3), 2.16 (s, 3H, Ar-CH3), 3.79 (s, 3H, -OCH3), 4.12 (h, 1H, J=6.1 Hz, -CH3CHCH2CH3), 5.56 (d, 1H, J=12.1 Hz, -OCH2Ph), 5.59 (d, 1H, J=12.1 Hz, -OCH2Ph), 6.54 (s, 1H, Ht), 6.83 (t, 1H, J=6.8 Hz, Hb), 6.86 - 6.92 (m, 4H, aromatic proton), 7.0 (t, 1H, J=7.3 Hz, aromatic proton), 7.25 - 7.31 (m, 2H, aromatic proton), 7.34 (t, 1H, J=7.9 Hz, Hc), 7.47 (d, 2H, J=8.5 Hz, Hm), 8.27 (d, 1H, J=6.8 Hz, Ha), 8.34 (d, 1H, J=8.9 Hz, Hd), 8.46 (s, 1H, Hq), 9.17 (s, 1H, -NH); 13C NMR (151 MHz, Chloroform-d): δ 10.1 (-CH3CHCH2CH3) 15.8 (Ar-CH3), 19.3 (-CH3CHCH2CH3), 29.1 (-CH3CHCH2CH3), 55.4 (-OCH3), 71.5 (-CH3CHCH2CH3), 76.8 (-OCH2Ph), 91.6 (Cf), 106.7, 112.6 (Cb), 114.1, 116.2, 119.0 (Cd), 121.8, 122.4, 123.0, 126.3, 127.3, 128.4, 128.6, 129.7, 129.9, 143.2 (Ce), 146.0, 148.6, 158.8, 159.8, 161.4, 162.3. MS (ESI) 552 (M+1).

[0153] 2-((4-methoxybenzyl)oxy)-N-(5-methyl-2-(pentan-2-yloxy)-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (97). This was obtained from 57 using aniline 104. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA 85:15v / v), and the title compound was provided as a sticky solid. Yield 89%. 1 H NMR (600 MHz, chloroform-d): δ 0.82 (t, 3H, J=6.9 Hz, -CH2CH2CH3), 1.11 (d, 2H, J=6.0 Hz, -CH3CHCH2CH2CH3)1.21 - 1.40 (m, 3H, --CH3CHCH2CH2CH3), 1.47 - 1.57 (m, 1H, -CH3CHCH2CH2CH3) ,2.16 (s, 3H, Ar-CH3), 3.79 (s, 3H, -OCH3), 4.16 - 4.23 (m, 1H, -CH3CHCH2CH2CH3), 5.56 (d, 1H, J=12.1 Hz, -OCH2Ph), 5.60 (d, 1H, J=12.1 Hz, -OCH2Ph), 6.54 (s, 1H, Ht), 6.83 (t, 1H, J=6.7 Hz, Hb), 6.85 - 6.92 (m, 4H, aromatic protons), 7.0 (t, 1H, J=7.3 Hz, aromatic protons), 7.24 - 7.31 (m, 2H, aromatic protons). 7.34 (t, 1H, J=7.9 Hz, Hc), 7.47 (d, 2H, J=8.5 Hz, Hm), 8.27 (d, 1H, J=6.8 Hz, Ha), 8.34 (d, 1H, J=8.8 Hz, Hd), 8.47 (s, 1H, Hq), 9.17 (s, 1H, -NH); 13 C NMR (151 MHz, クロロホルム-d): δ 14.1 (-CH3CHCH2CH2CH3) 15.8 (Ar-CH3), 18.9 (-CH3CHCH2CH2CH3), 19.8 (-CH3CHCH2CH2CH3), 38.4 (-CH3CHCH2CH2CH3), 55.4 (-OCH3), 71.5 (-OCH2Ph), 75.3 (-CH3CHCH2CH2CH3), 91.6 (Cf), 106.6, 112.6 (Cb), 114.1, 116.2, 118.9 (Cd), 121.8, 122.4, 122.9, 126.3, 127.3, 128.4, 128.6, 129.7, 129.8, 143.2 (Ce), 146.0, 148.6, 158.7, 159.8, 161.4, 162.3. MS (ESI) 566 (M+1).

[0154] 2-((4-methoxybenzyl)oxy)-N-(5-methyl-2-(pentan-3-yloxy)-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (98). This was obtained from 57 using aniline 105. The crude product was purified by flash chromatography (eluent: petroleum ether / ethylacetate 85:15v / v), and the title compound was provided as a viscous solid (melting point from XXX). Yield 61%. 1 H NMR (600 MHz, chloroform-d): δ 0.84 (t, 6H, J=7.4 Hz, -CHCH2CH3), 1.43 - 1.54 (m, 4H, -CHCH2CH3), 2.15 (s, 3H, Ar-CH3), 3.79 (s, 3H, -OCH3), 3.97 (p, 1H, J=5.8 Hz, -CHCH2CH3), 5.58 (s, 2H, -OCH2Ph), 6.54 (s, 1H, Ht), 6.83 (t, 1H, J=6.8 Hz, Hb), 6.85 - 6.92 (m, 4H, aromatic proton), 7.0 (t, 1H, J=7.3 Hz, aromatic proton), 7.25 - 7.31 (m, 2H, aromatic proton), 7.34 (t, 1H, J=7.9 Hz, Hc), 7.46 (d, 2H, J=8.5 Hz, Hm), 8.27 (d, 1H, J=6.8 Hz, Ha), 8.34 (d, 1H, J=8.9 Hz, Hd), 8.47 (s, 1H, Hq), 9.20 (s, 1H, -NH); 13C NMR (151 MHz, Chloroform-d): δ 9.8 (-CHCH2CH3) 15.8 (Ar-CH3), 26.3 (-CHCH2CH3), 55.4 (-OCH3), 71.5 (-OCH2Ph), 81.9 (-CHCH2CH3), 91.6 (Cf), 106.5, 112.6 (Cb), 114.1, 116.2, 119.0 (Cd), 121.8, 122.3, 122.9, 126.3, 127.3, 128.5, 128.6, 129.7, 129.8, 143.2 (Ce), 146.5, 148.5, 158.7, 159.8, 161.4, 162.3. MS (ESI) 566 (M+1).

[0155] N-(2-isopropyl-5-methyl-4-(pyridine-4-yloxy)phenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (99). Oxalyl chloride (198 μL, 2.23 mmol, 3.6 eq.) and anhydrous DMF (7 μL) were added under nitrogen atmosphere to a cooled (0°C) solution of 57 (0.743 mmol, 1.2 eq.) in anhydrous THF (15 mL). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. This solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL; this step was repeated 3 times). The resulting acyl chloride was dissolved in anhydrous toluene (10 mL). A solution of aniline 106 (0.619 mmol, 1 eq.) and anhydrous pyridine (2.228 mmol, 3.6 eq.) in anhydrous toluene (5 mL) was added to a solution of acyl chloride under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. This mixture was quenched with water (80 mL) and partially concentrated under reduced pressure. The aqueous phase was extracted with toluene (3 × 50 mL). The combined organic layers were dried and evaporated under reduced pressure. The crude material was purified by flash chromatography (eluent: petroleum ether / toluene 50:50 v / v), and the title compound was provided as a brown solid (melting point: unknown). Yield 80%. 1H NMR (600 MHz, Chroloholm-d): δ 0.94 (d, 6H, J=6.7 Hz, CH(CH3)2), 2.11 (s, 3H, -CH3), 2.70 (hept, 1H, J=6.7 Hz, -CH(CH3)2), 3.82 (s, 3H, -OCH3), 5.49 (s, 2H, -OCH2Ph), 6.74 (d, 2H, J=4.3 Hz, aromatic protons), 6.83 (s, 1H, aromatic protons), 6.88 (t, 1H, J=6.8 Hz, Hb), 6.95 (d, 2H, J=8.4 Hz, Hn), 7.38 (t, 1H, J=7.9 Hz, Hc), 7.47 (d 2H, J=8.4 Hz, Hm), 8.13 (s, 1H, aromatic proton), 8.31 - 8.36 (m, 2H, aromatic proton), 8.41 (d, 2H, J=4.7 Hz, aromatic proton), 8.55 (s, 1H, -NH). 13 C NMR (151 MHz, クロロホルム-d): δ 15.9 (Ar-CH3), 22.6 (-CH(CH3)2), 27.8 (-CH(CH3)2), 55.5 (-OCH3), 72.4 (-OCH2Ph), 91.0 (Cf), 111.3, 112.9 (Cb), 114.3, 118.3, 119.0 (Cd), 126.1, 127.6, 127.7 (Ca), 128.3, 128.7 (Cc), 131.1, 132.9, 138.3, 143.2 (Ce), 148.1, 151.4, 160.4, 161.6, 162.5, 165.2. MS (ESI) 523 (M+1).

[0156] General procedure for the synthesis of compounds 26, 31-36. Thianisole (10.0 eq.) was added to solutions of protected amides 93-99 (1.0 eq.) in TFA (4 mL). This mixture was heated at 70°C for 4 hours and then cooled to rt. This mixture was concentrated to some extent, and the resulting biomass was dissolved in phosphate-buffered saline (pH=5) to obtain a suspension, which was filtered. The resulting solid was then ground with hexane to provide the title compound in its pure form.

[0157] 2-Hydroxy-N-(2,5-dimethyl-4-(pyridine-4-ylthio)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (26). White solid. Yield 80%. 1 H-NMR (600 MHz, DMSO-d6): δ 2.31 (s, 3H, Ar-CH3), 2.32 (s, 3H, Ar-CH3), 7.02 (t, 1H, J=6.9 Hz, Hb), 7.28 (d, 2H, J=6.1 Hz, aromatic proton), 7.48 - 7.56 (m, 2H, aromatic proton), 8.08 (d, 1H, J=8.8 Hz, Hd); 8.50 (d, 2H, J=5.0 Hz, aromatic proton), 8.58 - 8.65 (m, 2H, aromatic proton), 9.20 (s, 1H, -NH); 13 C-NMR (151 MHz DMSO-d6): δ 16.6 (Ar-CH3), 20.2 (Ar-CH3), 89.4 (Cf), 113.2 (Cb), 117.0, 118.1 (Cd), 120.8, 121.7, 125.5, 128.2 (Ca), 129.1 (Cc), 138.1, 140.2, 140.9, 141.6, 143.8 (Ce), 160.9, 162.2. MS (ESI) 389 (M-1).

[0158] 2-Hydroxy-N-(2-isopropoxy-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (31). White solid. Yield 89%. 1H NMR (600 MHz, chloroform-d): δ 1.40 (d, 6H, J=6.0 Hz, -CH(CH3)2), 2.19 (s, 3H, Ar-CH3), 4.51 (h, 1H, J=6.0 Hz, -CH(CH3)2), 6.63 (s, 1H, Ht), 6.88 - 6.92 (m, 3H, Hb and aromatic protons), 7.0 (t, 1H, J=7.3 Hz, aromatic protons), 7.30 (t, 2H, J=7.9 Hz, aromatic protons), 7.43 (t, 1H, J=7.9 Hz, Hc), 8.27 (d, 1H, J=6.8 Hz, Ha), 8.35 (d, 1H, J=8.8 Hz, Hd), 8.52 (s, 1H, Hq), 9.32 (s, 1H, -NH); 13 C NMR (151 MHz, Chloroform-d): δ 15.9 (Ar-CH3), 22.4 (-CH(CH3)2), 72.0 (-CH(CH3)2), 91.1 (Cf), 107.3, 113.2 (Cb), 116.3, 118.8 (Cd), 122.0, 122.5, 123.1, 126.6, 127.4, 128.2, 129.8, 136.4, 141.9 (Ce), 145.4, 148.7, 158.7, 161.4, 162.8. MS (ESI) 418 (M-1).

[0159] N-(2-cyclobutoxy-5-methyl-4-phenoxyphenyl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide (32). White solid. Yield 75%. 1¹H NMR (600 MHz, DMSO-d6): δ 1.55 - 1.65 (m, 1H, cyclobutoxyproton), 1.73 - 1.82 (m, 1H, cyclobutoxyproton), 2.00 - 2.14 (m, 2H, cyclobutoxyproton), 2.06 (s, 3H, Ar-CH3), 2.30 - 2.39 (m, 2H, cyclobutoxyproton), 4.70 (p, 1H, J=7.0 Hz, cyclobutoxyproton), 6.53 (s, 1H, Ht), 6.85 (d, 2H, J=8.1 Hz, aromatic proton), 6.98 (t, 1H, J=6.8 Hz, Hb), 7.03 (t, 1H, J=7.3 Hz, aromatic proton), 7.32 (t, 2H, J=7.8 Hz, aromatic proton), 7.47 (t, 1H, J=7.8 Hz, Hc), 8.09 (d, 1H, J=8.7 Hz, Hd), 8.46 (s, 1H, Hq), 8.58 (d, 1H, J=6.7 Hz, Ha), 9.62 (s, 1H, -NH), 12.85 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 12.7, 15.5, 29.8, 71.8, 89.7 (Cf), 105.9, 112.8 (Cb), 115.9, 117.0 (Cd), 120.8, 121.0, 122.0, 125.8, 127.7, 129.0, 129.9, 141.5 (Ce), 144.3, 147.4, 158.0, 160.6, 162.0. MS (ESI) 430 (M+1).

[0160] N-(2-(Sec-butoxy)-5-methyl-4-phenoxyphenyl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide (33). White solid. Yield 76%. 1¹H NMR (600 MHz, DMSO-d⁶): δ 0.91 (t, 3H, J=7.4 Hz, -CHCH₂CH₃), 1.22 (d, 3H, J=6.0 Hz, -CH₃CHCH₂CH₃), 1.56 - 1.75 (m, 2H, -CH₃CHCH₂CH₃), 2.06 (s, 3H, Ar-CH₃), 4.36 (h, 1H, J=5.8 Hz, -CH₃CHCH₂CH₃), 6.73 (s, 1H, Ht), 6.85 (d, 2H, J=8.1 Hz, aromatic protons), 6.98 (t, 1H, J=6.8 Hz, Hb), 7.02 (t, 1H, J=7.3 Hz, aromatic protons). 7.32 (t, 2H, J=7.9 Hz, aromatic proton), 7.34 (m, 1H, Hc), 8.09 (d, 1H, J=8.8 Hz, Hd), 8.47 (s, 1H, Hq), 8.57 (d, 1H, J=6.8 Hz, Ha), 9.63 (s, 1H, -NH), 12.79 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 9.4 (-CH3CHCH2CH3) 15.5 (Ar-CH3), 18.9 (-CH3CHCH2CH3), 28.4 (-CH3CHCH2CH3), 76.1 (-CH3CHCH2CH3), 89.7 (Cf), 107.0, 112.8 (Cb), 115.8, 117.1 (Cd), 120.9, 121.1, 121.9, 126.8, 127.7, 129.0, 129.9, 141.5 (Ce), 144.9, 147.4, 158.1, 160.6, 162.0. MS (ESI) 432 (M+1).

[0161] 2-ヒドロキシ-N-(5-メチル-2-(ペンタン-2-イルオキシ)-4-フェノキシフェニル)ピラゾロ[1,5-a]ピリジン-3-カルボキサミド(34). White solid matter. The yield is 89%. 1H NMR (600 MHz, DMSO-d6): δ 0.84 (t, 3H, J=7.3 Hz, -CH2CH2CH3), 1.22 (d, 2H, J=6.0 Hz, -CH3CHCH2CH2CH3), 1.27 - 1.44 (m, 2H, -CH3CHCH2CH2CH3), 1.47 - 1.57 (m, 1H, -CH3CHCH2CH2CH3) , 1.63 - 1.74 (m, 1H, -CH3CHCH2CH2CH3) , 2.06 (s, 3H, Ar-CH3), 4.37 - 4.43 (m, 1H, -CH3CHCH2CH2CH3), 6.72 (s, 1H, Ht), 6.85 (d, 2H, J=8.1 Hz, aromatic proton), 6.96 (t, 1H, J=6.7 Hz, Hb), 7.02 (t, 1H, J=7.3 Hz, aromatic proton), 7.32 (t, 1H, J=7.8 Hz, aromatic proton), 7.45 (t, 1H, J=7.8 Hz, Hc), 8.08 (d, 1H, J=8.7 Hz, Hd), 8.47 (s, 1H, Hq), 8.55 (d, 1H, J=6.7 Hz, Ha), 9.71 (s, 1H, -NH), 12.84 (s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6): δ 13.9 (-CH3CHCH2CH2CH3) 15.5 (Ar-CH3), 18.1 (-CH3CHCH2CH2CH3), 19.4 (-CH3CHCH2CH2CH3), 37.8 (-CH3CHCH2CH2CH3), 74.9 (-CH3CHCH2CH2CH3), 89.7 (Cf), 106.9, 112.6 (Cb), 115.8, 116.9 (Cd), 120.9, 121.0, 121.9, 126.8, 127.5, 128.9, 129.9, 141.5 (Ce), 144.9, 147.4, 158.1, 160.7. MS (ESI) 446 (M+1).

[0162] 2-Hydroxy-N-(5-methyl-2-(pentan-3-yloxy)-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (35). White solid. Yield 30%. 1 H NMR (600 MHz, DMSO-d6): δ 0.96 (t, 6H, J=7.4 Hz, -CHCH2CH3), 1.70 - 1.77 (m, 4H, -CHCH2CH3), 2.18 (s, 3H, Ar-CH3), 4.12 (p, 1H, J=5.6 Hz, -CHCH2CH3), 6.59 (s, 1H, Ht), 6.89 (d, 2H, J=8.1 Hz, aromatic proton), 6.93 (t, 1H, J=6.7 Hz, Hb), 7.02 (t, 1H, J=7.3 Hz, aromatic proton), 7.30 (t, 2H, J=7.8 Hz, aromatic proton), 7.47 (t, 1H, J=7.9 Hz, Hc), 8.27 - 8.41 (m, 2H, Ha and Hd), 8.49 (s, 1H, Hq), 9.25 (s, 1H, -NH); 13 C NMR (151 MHz, DMSO-d6): δ 9.7 (-CHCH2CH3) 15.9 (Ar-CH3), 26.2 (-CHCH2CH3), 81.7 (-CHCH2CH3), 91.0 (Cf), 106.5, 113.4 (Cb), 116.3, 118.6 (Cd), 122.0, 122.5, 122.6, 126.1, 127.6, 128.6, 129.8, 141.7 (Ce), 146.0, 148.9, 153.2, 158.7, 161.4. MS (ESI) 446 (M+1).

[0163] 2-Hydroxy-N-(2-isopropyl-5-methyl-4-(pyridine-4-yloxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (36). White solid. Yield 74%. 1H NMR (600 MHz, DMSO-d6): δ 1.22 (d, 6H, J=6.8 Hz, CH(CH3)2), 2.01 (s, 3H, -CH3), 3.14 (Hept, 1H, J=6.8 Hz, -CH(CH3)2), 6.96 - 7.04 (m, 1H, Hb), 7.09 - 7.16 (m, 3H, aromatic proton), 7.49 (t, 1H, J=7.9 Hz, Hc), 8.07 (d, 1H, J=8.8 Hz, Hd), 8.18 (s, 1H, aromatic proton), 8.59 (d, 1H, J=6.8 Hz, Ha), 8.60 - 8.70 (m, 2H, aromatic proton), 9.10 (s, 1H, -NH). 13 C NMR (151 MHz, DMSO-d6): δ 15.4 (Ar-CH3), 22.5 (-CH(CH3)2), 27.4 (-CH(CH3)2), 89.4 (Cf), 112.3, 112.9 (Cb), 117.0, 118.3 (Cd), 125.3 (Ca), 127.1, 127.9 (Cc), 129.0, 133.7, 138.1, 141.6, (Ce), 146.6, 146.7, 147.7, 161.0, 162.1. MS (ESI) 403 (M+1).

[0164] 2-Hydroxypyrazolo[1,5-a]pyridine-3-carboxylic acid (107). 5 M NaOH solution (5 eq.) was added to a solution of 44 (1 g, 4.84 mmol) in EtOH (20 mL), and the reaction mixture was stirred under reflux for 6 hours. The EtOH was then evaporated under vacuum, and the residue was dissolved in distilled water (20 mL). To obtain the product as a precipitate, this suspension was acidified to pH=2 with 6 M HCl. The white solid was filtered and washed with distilled water until neutral. Yield: 98%.

[0165] Pyrazolo[1,5-a]pyridine-2-ol (108). 10 eq. of 6M NaOH solution was added to a suspension of 2-hydroxypyrazolo[1,5-a]pyridine-3-carboxylic acid (107, 1.4 g, 7.86 mmol) in EtOH (25 mL). The reaction mixture was stirred and refluxed at 85°C until compound 107 was completely dissolved. Then, 12M HCl (2.38 mL) was added dropwise at 85°C. The reaction mixture was stirred for 20 minutes. The reaction was quenched with distilled water (30 mL) and extracted with ELISA (3 × 15 mL). The organic phase was collected, washed with saturated NaHCO3 solution (3 × 20 mL) and saturated brine solution, dried over Na2SO4, and concentrated under reduced pressure. This was purified by flash chromatography (eluent: petroleum ether / ethyl acetate 9 / 1 v / v). Yield: 90%.

[0166] 2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-amine (46). K2CO3 (0.33 g, 3.0 eq.) and Pd(PPh3)4 (0.187 g, 0.2 eq.) were added to a solution of 4-bromo-2,3,5,6-tetrafluoroaniline (0.2 g, 0.81 mmol) in dioxane / H2O (30 mL, 9 / 1 v / v) under inert air, and the reaction mixture was stirred for 1 hour. Then phenylboronic acid (0.296 g, 3.0 eq.) was added, and the reaction mixture was stirred overnight at 90°C. This reaction was quenched with distilled water (30 mL) and extracted with RINKAN (3 × 15 mL). The organic layer was collected, washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. This was purified by flash chromatography (eluent: petroleum ether / ethyl acetate 95 / 5v / v). Yield: 90%. 1 ¹H NMR (300 MHz, chloroform-d): δ 4.04 (s, 2H, -NH2), 7.35 - 7.51 (m, 5H, aromatic proton); 13¹³C NMR (75 MHz, chloroform-d): δ 108.4 (t, J=17.1 Hz), 125.5 (tt, J=13.8, 3.6 Hz), 128.2 (t, J=2.2 Hz), 128.4, 128.6, 130.5 (t, J=2.0 Hz), 136.9 (d, J=238.4 Hz), 144.2 (d, J=242.0 Hz). MS (ESI) 242 (M+1).

[0167] (E)-3-((2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)diadinyl)pyrazolo[1,5-a]pyridine-2-ol (25). A solution of NaNO2 (51 mg, 0.74 mmol.) in water (5 mL) was added dropwise to a chilled (0°C) solution of 2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-amine (46, 150 mg, 0.62 mmol.) in nitric acid (1.55 mL); the resulting mixture was stirred for 10 minutes. The resulting solution was added dropwise to a chilled solution of 108 (83 mg, 0.62 mmol.) in water (5 mL) at pH ~10. The resulting mixture was stirred for 5 minutes, and an orange precipitate was observed. This precipitate was filtered on a Buchner filter, and the title compound was provided as an orange solid (ground with diisopropyl ether). Yield: 48%. 1 H NMR (600 MHz, DMSO-d6): δ 7.27 (t, 1H, J=6.5 Hz, Hb), 7.50 - 7.60 (m, 5H, aromatic proton), 7.80 (t, 1H, J=7.7 Hz, Hc), 8.19 (d, 1H, J=8.2 Hz, Hd), 8.75 (d, 1H, J=6.6 Hz, Ha). 13 C NMR (151 MHz, DMSO-d6): δ 117.0, 117.2, 118.4, 127.4, 129.1, 129.3, 129.9, 130.7, 130.8, 130.9, 133.3, 133.4, 140.3 (d, MS (ESI) 387 (M+1).

[0168] (E)-3-((4-phenoxyphenyl)diadinyl)pyrazolo[1,5-a]pyridin-2-ol (38). A solution of NaNO2 (51 mg, 0.74 mmol, 1.2 eq.) in water (5 mL) was added dropwise to a chilled (0°C) solution of 4-phenoxyaniline (46) (150 mg) in nitric acid (1.55 mL); the resulting mixture was stirred for 10 minutes. The resulting solution was added dropwise to a chilled solution (108 mg, 83 mg, 1 eq.) in water (5 mL) at pH ~10. The resulting mixture was stirred for 5 minutes, and precipitation was observed. The precipitate was filtered on a Buchner filter, and the title compound was provided as an orange solid (ground with diisopropyl ether). Yield 60%. 1 H NMR (600 MHz, DMSO-d6): δ 7.04 - 7.13 (m, 4H, aromatic proton), 7.13 - 7.20 (m, 2H, aromatic proton, Hb), 7.42 (t, 2H, J=8.0 Hz, aromatic proton), 7.63 (t, 1H, J=7.8 Hz, Hc), 7.76 (d, 2H, J=8.8 Hz, aromatic proton), 8.15 (d, 1H, J=8.5 Hz, Hd), 8.61 (d, 1H, J=6.5 Hz, Ha). 13 C NMR (151 MHz, DMSO-d6): δ 116.2, 117.2, 117.7, 119.0, 119.0, 121.6, 123.8, 130.0 130.2, 130.7, 132.8, 145.5, 156.39, 156.42, 164.5. MS (ESI) 331 (M+1).

[0169] Ethyl 2-methyloxypyrazolo[1,5a]pyridine-3-carboxylate (110a) and ethyl N-methyl-2-oxopyrazolo[1,5a]pyridine-3-carboxylate (110b) from (44). Cs2CO3 (3 eq.) was added to a solution of 44 (5.0 g, 24.24 mmol) in anhydrous DMF (50 mL), and the resulting mixture was stirred at room temperature for 30 minutes, after which iodomethane (29.1 mmol, 1.81 mL) was added dropwise to the mixture. This reaction was quenched with distilled water (300 mL) and extracted with ethyl acetate (6 × 70 mL). The organic phase was collected, washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a pale yellow crude solid containing the two isomers. This was separated by flash chromatography (eluent: petroleum ether / ethyl acetate 6 / 4v / v, followed by DCM / MeOH 95 / 5v / v). Yield: 77% (110a) and 13% (110b).

[0170] (110a) mp142.4-143.5℃; 1 H NMR (600 MHz, chloroform-d): δ 1.40 (t, 3H, J=7.1 Hz, -OCH2CH3), 4.12 (s, 3H-OCH3), 4.37 (q, 2H, J=7.1 Hz, -OCH2CH3), 6.83 (t, 1H J=6.8 Hz, Hb), 7.35 (t, 1H, J=7.9 Hz, Hc), 7.97 (d, 1H, J=8.9 Hz, Hd), 8.28 (d, 1H, J=6.8 Hz, Ha). 13 ¹³C NMR (151 MHz, chloroform-d): δ 14.7 (-OCH2CH3), 57.0 (-OCH3), 59.9 (-OCH2CH3), 88.1 (Cf), 112.6 (Cb), 118.4 (Cd), 127.9 (Cc) * , 128.9 (Ca) * , 142.9 (Ce), 163.3 (Cg) ** , 166.0 (Ch) ** (ESI) 221 (M+1).

[0171] (110b) mp234.4-235.8℃; 1 H NMR (600 MHz, chloroform-d): δ 1.28 (t, 3H, J=7.1 Hz, -OCH2CH3), 3.58 (s, 3H-OCH3), 4.21 (q, 2H, J=7.1 Hz, -OCH2CH3), 7.10 (t, 1H J=6.9 Hz, Hb), 7.66 (t, 1H, J=7.9 Hz, Hc), 7.90 (d, 1H, J=8.9 Hz, Hd), 8.57 (d, 1H, J=6.8 Hz, Ha). 13 ¹³C NMR (151 MHz, chloroform-d): δ 15.5 (-OCH2CH3), 28.9 (-NCH3), 59.3 (-OCH2CH3), 84.2 (Cf), 113.3 (Cb), 116.7 (Cd), 125.8 (Cc) * , 132.9 (Ca) * , 142.6 (Ce), 160.6 (Cg) ** , 164.1 (Ch) ** (ESI) 221 (M+1).

[0172] 2-Methoxypyrazolo[1,5-a]pyridine-3-carbohradazide (111). 20 eq. (0.273 g, 20 eq.) of hydrazine monohydrate were added to a solution of 110a (0.6 g, 2.73 mmol) in EtOH (3 mL), and the reaction mixture was stirred under reflux overnight. The reaction product was cooled to room temperature, the solid was filtered, washed with distilled water, and the title compound was provided as a white solid. Yield: 68.7%. 1 ¹H NMR (600 MHz, chloroform-d): δ 4.03 (s, 2H, -CONHNH2), 4.13 (s, 3H, -OCH3), 6.81 (t, 1H, J=6.7 Hz, Hb), 7.32 (t, 1H, J=7.9 Hz, Hc), 7.87 (s, 1H, -CONHNH2), 8.19 (d, 1H, J=8.9 Hz, Hd), 8.24 (d, 1H, J=6.9 Hz, Ha).13 ¹³C NMR (151 MHz, chloroform-d): δ 57.2 (-OCH3), 88.8 (Cf), 112.6 (Cb), 118.5 (Cd), 127.5 (Cc) * , 128.6 (Ca) * , 142.7 (Ce), 163.2 (Cg) * , 164.6 (Ch) * (ESI) 207 (M+1).

[0173] 2-(4-bromo-2,3,5,6-tetrafluorophenyl)-5-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3,4-oxadiazole (112). Compound 111 (0.3 g, 1.52 mmol) and 4-bromo-2,3,5,6-tetrafluorobenzoic acid (0.414 g, 1.52 mmol) were dissolved in POCl3 (5 mL). The reaction mixture was stirred at 50°C for 4 hours. This mixture was concentrated under vacuum, and the solid was dissolved in distilled water (80 mL) and extracted with ELISA (3 × 50 mL). The organic layer was collected, washed with saturated brine, dried over Na2SO4, concentrated under reduced pressure, and a pale yellow biomass was provided. This was purified by flash chromatography (eluent: petroleum ether / ethyl acetate 7 / 3 v / v), and the title compound was provided as a pale yellow solid. Yield: 52%. 1 ¹H NMR (600 MHz, chloroform-d): δ 4.21 (s, 3H, -OCH3), 6.92 (t, 1H, J=6.9 Hz, Hb), 7.45 (m, 1H, Hc), 8.10 (d, 1H, J=8.8 Hz, Hd), 8.36 (d, 1H, J=6.8 Hz, Ha). 13 ¹³C NMR (151 MHz, chloroform-d): δ 57.3 (-OCH3), 81.1 (Cf), 103.5 (t, J=17.9 Hz), 105.1 (t, J=14.4 Hz), 112.9 (Cb), 117.6 (Cd), 128.3 (Cc) * , 129.2 (Ca) *, 140.8 (Ce), 144.7 (d, J=246.0 Hz), 145.6 (d, J=249.7 Hz), 153.1, 161.2 (Cg), 164.2. (ESI) 443-445 (M+1).

[0174] 2-(2-methoxypyrazolo[1,5-a]pyridine-3-yl)-5-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazole (113). K2CO3 (0.187 g, 3.0 eq) and Pd(PPh3)4 (0.053 g, 0.1 eq) were added to a solution of 112 (0.2 g, 0.45 mmol) in dioxane / H2O (30 mL, 9 / 1 v / v) under inert air and stirred for 1 hour. Phenylboronic acid (0.165 g, 3.0 eq.) was then added, and the reaction mixture was stirred overnight at 90°C. This reaction mixture was quenched with distilled water (150 mL) and extracted with ELISA (3 × 60 mL). The organic layer was collected, washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure to yield a pale yellow solid. Yield: 100%. 19 F NMR (565 MHz, DMSO-d6): δ -137.74 (d, 2F, J=21.5 Hz), -142.75 (d, 2F, J=30.2 Hz). 1 H NMR (600 MHz, DMSO-d6): δ 4.12 (s, 3H, -OCH3), 7.11 (t, 1H, J=6.8 Hz, Hb), 7.55 - 7.62 (m, 6H, Hc and aromatic protons), 8.00 (d, 1H, J=8.8 Hz, Hd), 8.78 (d, 1H, J=6.8 Hz, Ha). 13 C NMR (151 MHz, DMSO-d6): δ 57.1 (-OCH3), 79.7 (Cf), 103.5, 113.5 (Cb), 116.4 (Cd), 126.1 (Cc) * , 127.3, 127.4, 128.9, 129.3 (Ca) *, 130.0, 134.1, 139.9 (Ce), 144.7 (d, J=246.0 Hz), 145.6 (d, J=249.7 Hz), 153.0, 160.0 (Cg), 163.3.

[0175] 3-(5-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazole-2-yl)pyrazolo[1,5-a]pyridine-2-ol (39). A 1M solution of BBr3 in DCM (650 μL, 0.69 mmol) was dissolved in anhydrous DCM (5 mL) under inert air. This solution was cooled to -10°C, compound 119 (0.12 g, 0.273 mmol) was added, and the reaction mixture was stirred at 0°C for 30 minutes. This reaction was quenched with distilled water (150 mL) and extracted with DCM (3 × 60 mL). The organic layer was collected, washed with saturated brine, dried over Na₂SO₄, concentrated under reduced pressure, and a pale yellow solid was provided. This crude solid was ground with diisopropyl ether, and the title compound was provided as a pale yellow solid. Yield 90%. Decomposition temperature: 272-273℃. 1 H NMR (600 MHz, DMSO-d6): δ 7.06 (t, 1H, J=6.7 Hz, Hb), 7.52-7.65 (m, 6H, Hc and aromatic protons), 7.98 (d, 1H, J=8.7 Hz, Hd), 8.67 (d, 1H, J=6.7 Hz, Ha), 12.05 (s, 1H, -OH). 13 C NMR (151 MHz, DMSO-d6): δ 79.5 (Cf), 103.8 (t, J=12.9 Hz), 113.2 (Cb), 116.1 (Cd), 122.6 (t, J=17.1 Hz), 126.1 (Cc) * , 128.52, 128.92, 129.5, 129.9 (Ca) * , 130.0, 139.6 (Ce), 144.7 (d, J=246.0 Hz), 145.6 (d, J=249.7 Hz), 152.8, 160.6 (Cg), 162.8. (ESI) 427 (M+1).

[0176] N-(4-bromo-2,3,5,6-tetrafluorophenyl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide (114). Oxalyl chloride (811 mg, 6.39 mmol, 3.0 eq.) and anhydrous DMF (10 mL) were added to a cooled (0°C) solution of 57 (635 mg, 2.13 mmol) in anhydrous THF (49 mL) maintained under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. In parallel, a 1 M solution of LiHMDS in THF (3.62 mL, 3.62 mmol, 1.7 eq.) was added to a solution of 4-bromo-2,3,5,6-tetrafluoroaniline (883 mg, 3.62 mmol, 1.7 eq.) in anhydrous THF (10 mL) under nitrogen atmosphere. The resulting suspension was stirred at room temperature for 30 minutes. The acilcloride solution was then concentrated under reduced pressure, and the residue was dissolved in anhydrous THF (25 mL); this process was repeated three times to remove all gaseous residue. Acilcloride was dissolved in anhydrous THF (15 mL), and this solution was added to the previously described solution. This reaction mixture was stirred overnight at 70°C, then cooled to room temperature and evaporated. The residue was dissolved in HCl (40 mL), then 0.5 M HCl (50 mL) was added, and these layers were separated. The aqueous phase was extracted twice with HCl, and the combined organic layers were washed with brine, dried, and evaporated under reduced pressure. This crude material was purified by flash chromatography (eluent: petroleum ether / HCl 8 / 2 v / v, then 7 / 3 v / v), and the title compound was provided as a white solid (melting point = 157.9–161.9°C, ground with diisopropyl ether). Yield: 78%. 1H-NMR (600 MHz, クロロホルム-d) δ: 3.82 (s, 3H, -OCH3), 5.50 (s, 2H, -OCH2Ar), 6.91 (t, 1H, J=6.9 Hz, Hb), 6.94 (d, 2H, J=8.5 Hz, Hn), 7.41 (d, 1H, J=7.8 Hz, Hc), 7.46 (d, 2H, J=8.5 Hz, Hm), 8.21 (d, 1H, J=8.8 Hz, Hd), 8.26 (s, 1H, -NH), 8.33 (d, 1H, J=6.8 Hz, Ha)。 13 C NMR (151 MHz, クロロホルム-d) δ: 55.5 (-OCH3), 72.3 (-OCH2Ar), 89.8 (Cf), 94.6 (t, J=22.5 Hz, Cs), 113.4 (Cb), 114.3 (Cn), 116.6 (t, J=14.6 Hz, Cp), 118.9 (Cd), 127.6 (Cl), 128.4 (Ca) * , 128.8 (Cc) * , 130.3 (Cm), 142.6 (d, J=251.6 Hz, Cr) ** , 143.1 (Ce), 145.2 (d, J=246.5 Hz, Cq) ** , 160.19 (Co) *** , 160.24 (Ch) *** , 162.9 (Cg) *** 。 19 F NMR (565 MHz, クロロホルム-d) -143.55 (d, 2F, J=19.6 Hz, Fp), -133.93 (d, 2F, J=16.6 Hz, Fr)。MS (ES + ): 524 / 526 (M + 1)。

[0177] 1-(3-Boromofenoxy)propan-2-one (116). 3-Chloroacetone (7.70 g, 83.2 mmol, 3.0 eq.) was added dropwise to a mixture of 3-bromophenol (4.80 g, 27.7 mmol) and DBU (16.9 g, 111 mmol, 4.0 eq.) in anhydrous DMF (50 mL). The reaction mixture was stirred overnight at room temperature and then quenched in 2 M HCl (250 mL). This mixture was extracted with SiO2 (3 × 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / SiO2 from 9 / 1 v / v to petroleum ether / SiO2 from 8 / 2 v / v), and the title compound was provided as a yellow oil. Yield: 98%. 1 ¹H NMR (600 MHz, chloroform-d) δ: 2.28 (s, 3H, -CH3), 4.53 (s, 2H, -OCH2), 6.82 (ddd, 1H, J=7.9, 2.5, 1.4 Hz, aromatic proton), 7.04 - 7.06 (m, 1H, aromatic proton), 7.13 (dt, 1H, J=7.9, 1.5 Hz, aromatic proton), 7.16 (d, 1H, J=7.9 Hz, aromatic proton). 13 ¹³C NMR (151 MHz, chloroform-d) δ: 26.8 (-CH3), 72.9 (-OCH2), 113.6, 118.2, 123.1, 125.1, 130.9, 158.6, 204.9 (-OCH2COCH3). MS (ES + ): 227 / 229 (M+1).

[0178] 1-Bromo-3-(2,2-difluoropropoxy)benzene (117). DAST (1.40 g, 8.70 mmol, 5.0 eq.) was added dropwise at 0°C to a solution of 116 (437 mg, 1.74 mmol) in anhydrous DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours, then quenched in saturated Na2CO3 solution (30 mL). The mixture was extracted by DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA 8 / 2v / v), and the title compound was provided as a yellow oil. Yield: 78%. 1 ¹H NMR (600 MHz, chloroform-d) δ: 1.77 (t, 3H, J=18.8 Hz, -CH3), 4.09 (t, 2H, J=11.3 Hz, -OCH2), 6.87 (ddd, 1H, J=7.8, 2.4, 1.5 Hz, aromatic proton), 7.09 - 7.10 (m, 1H, aromatic proton), 7.15 (dt, 1H, J=7.9, 1.5 Hz, aromatic proton); 7.17 (t, 1H, J=7.8 Hz, aromatic proton). 13 ¹³C NMR (151 MHz, chloroform-d) δ: 21.0 (t, J= 25.7 Hz, -CH3), 69.9 (t, J= 34.8 Hz, -OCH2), 113.7, 118.3, 121.4 (t, J= 239.3 Hz, -CF2), 123.0, 125.1, 130.9, 158.7. MS (ES + ): 183 / 185 (M - 67). Mass spectrometry was redone (Massa da rifare).

[0179] 3-(3-boromofenoxy)propan-1-ol (122).PPh3 (1.80 g, 6.87 mmol, 1.4 eq.) was added to a solution of 3-bromophenol (1.34 g, 4.91 mmol, 1.0 eq.) and 1,3-propanediol (523 mg, 6.87 mmol, 1.4 eq.) in anhydrous THF (20 mL). The resulting mixture was stirred under nitrogen atmosphere at rt for 30 minutes, and then DIAD (1.19 g, 6.87 mmol, 1.4 eq.) was added dropwise. The reaction mixture was then stirred under nitrogen atmosphere at rt for 2 days. This mixture was concentrated under reduced pressure and dissolved in 0.1 M NaOH (50 mL). The mixture was extracted with SiO2 (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / siRNA in 8 / 2v / v, followed by 7 / 3v / v). The white solid product was washed with hexane / diisopropyl ether in 8 / 2v / v, the supernatant was filtered, and concentrated under vacuum to obtain a colorless oil (this procedure was repeated three times). Yield: 69%. 1 H NMR (600 MHz, chloroform-d) δ: 1.83 (br s,-OCH2CH2CH2OH), 2.00 - 2.06 (m, 2H, -OCH2CH2CH2OH), 3.84 (t, 2H, J=6.0 Hz, -OCH2CH2CH2OH), 4.09 (t, 2H, J=6.0 Hz, -OCH2CH2CH2OH), 6.83 (ddd, 1H, J= 8.3, 2.3, 1.0 Hz, aromatic proton), 7.05-7.09 (m, 2H, aromatic proton), 7.13 (t, 1H, J= 7.9 Hz, aromatic proton); 13 ¹³C NMR (151 MHz, chloroform-d) δ: 32.0 (-OCH2CH2CH2OH), 60.2 (-OCH2CH2CH2OH), 65.8 (-OCH2CH2CH2OH), 113.6, 117.9, 122.9, 124.0, 130.7, 159.7; MS (ES+): 271 / 273 (M + 40).

[0180] 3-(3-boromophenoxy)propyl tert-butyl carbonate (123). A solution of di tert-butyl dicarbonate (827 mg, 4.26 mmol, 2.0 eq.) in anhydrous THF (5 mL) was added dropwise to a mixture of 122 (705 mg, 2.13 mmol) and NaH (98.0 mg, 4.26 mmol, 2.0 eq.) in anhydrous THF (10 mL). The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The crude product was dissolved in water (50 mL), and the mixture was extracted with SiO2 (3 × 40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: petroleum ether / SiO2 9 / 1 v / v), and the title compound was provided as a yellow oil. Yield: 96%. 1 H NMR (600 MHz, chloroform-d) δ: 1.49 (s, 9H, -C(CH3)3), 2.10 - 2.16 (m, 2H, -OCH2CH2CH2O-), 4.04 (t, 2H, J=6.1 Hz, -OCH2CH2CH2O-), 4.25 (t, 2H, J=6.3 Hz, -OCH2CH2CH2O-), 6.82 (ddd, 1H, J=8.2, 2.4. 0.9 Hz, aromatic proton), 7.04 - 7.09 (m, 2H, aromatic proton), 7.13 (t, 1H, J=8.0 Hz, aromatic proton). 13 ¹³C NMR (151 MHz, chloroform-d) δ: 27.9 (-C(CH3)3), 28.7 (-OCH2CH2CH2O-), 63.7 (-OCH2CH2CH2O-) * , 64.6 (-OCH2CH2CH2O-) * , 82.3, 85.3 (-C(CH3)3), 113.7, 117.9, 122.9, 124.1, 130.7, 146.9, 153.6, 159.7 (CO);MS (ES + ): 353 / 355 (M + 23).

[0181] General Procedure: Synthesis of pinacolatoborone compounds 117, 120, and 124. PdCl2(dppf)(36.0 mg, 0.0495 mmol, 0.03 eq.) was added to the corresponding starting material in dioxane (15 mL) and a solution of (415 mg, 1.65 mmol) and K2CO3 (684 mg, 4.95 mmol, 3.0 eq.). The resulting mixture was stirred at rt under nitrogen atmosphere for 1 hour, and then bis(pinacolato)diborone (626 mg, 5.94 mmol, 3.60 eq.) was added. The reaction mixture was then refluxed under nitrogen atmosphere overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude substance was dissolved in 9 / 1v / v petroleum ether / siRNA (20 mL) and purified by flash chromatography (see conditions below).

[0182] 2-(3-(2,2-difluoropropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117). This crude product was purified by flash chromatography (eluent: petroleum ether / SiO₂ 9 / 1v / v) to obtain a pale yellow oily substance. Yield: 97%. 1 ¹H NMR (600 MHz, chloroform-d) δ: 1.35 (s, 12H, -OC(CH3)2), 1.77 (t, 3H, J= 18.8 Hz, -OCH2CF2CH3), 4.14 (t, 2H, J=11.4 Hz, -OCH2CF2CH3), 7.04 (ddd, 1H, J=8.2, 2.8, 1.0 Hz, aromatic proton), 7.29 - 7.35 (m, 2H, aromatic proton), 7.44 - 7.47 (m, 1H, aromatic proton); 13C NMR (151 MHz, chloroform-d) δ: 21.1 (t, J= 26.0 Hz, -OCH2CF2CH3), 25.2 (-OC(CH3)2), 25.2 (-OC(CH3)2), 69.7 (t, J= 34.6 Hz, -OCH2CF2CH3), 83.6 (-BOC(CH3)2C(CH3)2O), 84.1 (-B(OC(CH3)2C(CH3)2O), 118.3 (t, J= 109.9 Hz, OCH2CF2CH3), 118.5, 119.7, 121.7, 128.3, 129.3, 157.5;MS (ES+): 299 (M +1).

[0183] 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-one (120). This crude product was filtered over silica gel (eluent: petroleum ether / SiO₂ 9 / 1v / v) to obtain a yellow oily substance. Yield: 96%. 1 ¹H NMR (600 MHz, chloroform-d) δ: 1.24 (s, 6H, -OC(CH3)2),), 1.34 (s, 6H, -OC(CH3)2),, 2.31 (s, 3H, -OCH2COCH3), 4.60 (s, 2H, -OCH2COCH3), 6.86 (dd, 1H, J=8.2, 2.5 Hz, aromatic proton), 7.09 - 7.11 (m, 1H, aromatic proton), 7.21 (dd, 1H, J= 7.6, 0.5 Hz, aromatic proton), 7.36 (t, 1H, J= 7.9 aromatic proton); 13 C NMR (151 MHz, Chloroform-d) δ: 25.0 (-OC(CH3)2)), 26.8 (-OCH2COCH3), 73.2 (-OCH2COCH3), 84.1 (-OC(CH3)2), 113.5, 113.8, 118.2, 120.8, 128.3, 130.2, 158.2, 205.8 (-OCH2COCH3). MS (ES+): 277 (M + 1).

[0184] tert-butyl (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl) carbonate (124). This crude product was filtered over silica gel (eluent: petroleum ether / ethyl phosphate 9 / 1v / v) to obtain a colorless oil. Yield: 96%. 1 H NMR (600 MHz, chloroform-d) δ: 1.34 (s, 12H, -OC(CH3)2),, 1.47 (s, 9H, -C(CH3)3), 2.10-2.14 (m, 2H, -OCH2CH2CH2OC-), 4.08 (t, 2H, J= 6.1 Hz, -OCH2CH2CH2OC-), 4.25 (t, 2H, J=6.3 Hz, -OCH2CH2CH2OC-), 6.98 (ddd, 1H, J= 8.2, 2.7, 0.8 Hz, aromatic proton), 7.27 (t, 1H, J= 7.5 Hz, aromatic proton), 7.32 (s, 1H, aromatic proton), 7.38 (d, 1H, J = 6.5 Hz, aromatic proton; 13 C NMR (151 MHz, chloroform-d) δ: 24.9 (-OC(CH3)2), 27.9 (-C(CH3)3), 28.9 (-OCH2CH2CH2OC-), 64.0 (-OCH2CH2CH2OC-), 64.2 ((-OCH2CH2CH2OC-), 82.1 (-C(CH3)3), 83.6, 83.9 (-OC(CH3)2), 114.6, 118.3, 119.7, 127.3, 129.0, 153.6, 158.3 (-COOC(CH3)3) MS (ES+): 401 (M + 40).

[0185] General procedure for the synthesis of compounds 119, 121, and 125. Pd(PPh3)4 (63.8 mg, 0.0552 mmol, 0.20 eq.) was added to a solution of 114 (145 mg, 0.276 mmol) and K2CO3 (114 mg, 0.579 mmol, 3.00 eq.) in a dioxane / water mixture (10 mL, 9:1 v / v). The resulting mixture was stirred under nitrogen atmosphere at rt for 1 hour, and then the corresponding pinacol boronic acid ester (262 mg, 0.579 mmol, 3.0 eq.) was added. The reaction mixture was then heated under reflux under nitrogen atmosphere. After 5-6 hours, it was cooled to room temperature and concentrated under reduced pressure. The crude substance was dissolved in water (50 mL), and the mixture was extracted with RINKAN (3 × 40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (see conditions below).

[0186] N-(3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-((4-methoxybenzyl)oxy)pyrazolo[1,5a]pyridine-3-carboxamide (119). This crude product was purified by flash chromatography (eluent: petroleum ether / SiO2, then 7:3 v / v) to obtain a solid. This solid was then ground with diisopropyl ether to obtain the title compound as a yellow solid (melting point = 117.0-114.6°C). Yield: 79%. 1H NMR (600 MHz, Chromo-d) δ: 1.80 (t, 3H, J= 6.9 Hz, -OCH2CF2CH3), 3.83 (s, 3H, -OCH3), 4.15 (t, 2H, J=11.3 Hz, -OCH2CF2CH3), 5.52 (s, 2H, -CH2Ar), 6.92 (td, 1H, J= 6.9, 1.2 Hz, Hb), 6.96 (d, 2H, J= 8.6 Hz, Hn), 7.02-7.05 (m, 2H, J= 8.0 Hz, aromatic protons and Hc), 7.10 (d, 1H, J= 7.6 Hz, Aromatic protons), 7.42 (td, 2H, J= 5.21, 8.34, 5.2 Hz, Aromatic protons), 7.48 (d, 2H, J= 8.6 Hz, Hm), 8.25 (d, 1H, J= 8.8 Hz, Ha), 8.32 (s, 1H, NH), 8.34 (d, 1H, J=6.9 Hz, Hd); 13 C NMR (151 MHz, クロロホルム-d) δ: 21.1 (t, J= 25.7 Hz, -OCH2CF2CH3), 55.4 (-OCH3), 69.8 (t, J= 35.0 Hz, -OCH2CF2CH3), 72.3 (-CH2Ar), 89.9 (Cf), 113.3 (Cb), 114.3 (Cn), 115.5, 116.2 (t, J=14.6 Hz, Cs) * , 116.7, 117.4 (t, J= 17.1 Hz, Cp) * , 118.8 (Cd), 121.5 (t, J= 239.6 Hz, -OCH2CF2CH3), 123.8, 127.7. 128.3 (Ca), 128.8 (Ce), 128.9 (Cl) 129.9 (Cc), 130.3 (Cm), 142.6 (d, J=237.4 Cr) ** , 143.2, 144.13 (d, J=237.4, Cq) **, 158.06 (Co), 160.18 (Ch), 160.54, 162.96 (Cg);MS (ES+): 616 [M+1], 638 (M+22), 654 (M+39).

[0187] 2-((4-methoxybenzyl)oxy)-N-(2,3,5,6-tetrafluoro-3'-(2-oxopropoxy)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (121). This crude product was purified by flash chromatography (eluent: petroleum ether / SiO2, then 7:3 v / v) to obtain a solid. This solid was then ground with diisopropyl ether to obtain the title compound as a pale yellow solid (melting point = 78.4-81.5°C). Yield: 70%. 1 H NMR (600 MHz, chloroform-d) δ: 2.31 (s, 3H, -OCH2COCH3), 3.83 (s, 3H, -OCH3), 4.58 (s, 2H, -OCH2COCH3), 5.52 (s, 2H, -CH2Ar), 6.92 (td, 1H, J= 7.0 Hz, Hb), 6.93-6.98 (m, 4H, aromatic protons and Hn), 7.09 (d, 1H, J= 7.6 Hz, Hc), 7.40-7.43 (m, 1H, aromatic protons), 7.48 (d, 2H, J= 7.6 Hz, Hm), 7.48 (d, 2H, J= 8.6 Hz, Hn), 8.25 (d, 1H, J= 8.8 Hz, Ha), 8.31 (s, 1H, -NH), 8.34 (d, 1H, J=6.9 Hz, Hd); 13 ¹³C NMR (151 MHz, chloroform-d) δ: 25.8 (-OCH2COCH3), 55.5 (-OCH3), 72.3 (-OCH2COCH3), 73.2 (-CH2Ar), 89.9 (Cf), 113.3 (Cb), 114.3 (Cn), 115.3, 116.1 (t, J=16.8 Hz, Cs) *, 116.6, 117.3 (t, J=16.3 Hz, Cp) * , 118.8 (Cd), 123.8, 127.7, 128.3 (Ca), 128.8 (Ce), 128.9 (Cl), 130.0 (Cc), 130.3 (Cm), 142.6 (d, J=233.2 Hz, Cr) ** , 143.2, 144.2 (d, J=221.7 Hz, Cq) ** , 157.9 (Co), 160.17 (Ch), 160.55, 162.96 (Cg), 205.40 (-OCH2COCH3);MS (ES-): 592 (M-1).

[0188] Tert-butyl (3-((2',3',5',6'-tetrafluoro-4'-(2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide)-[1,1'-biphenyl]-3-yl)oxy)propyl)carbonate (125). This crude product was purified by flash chromatography (eluent: petroleum ether / ethyl phosphate 75 / 25v / v) to obtain a solid. This solid was then ground with diisopropyl ether to obtain the title compound as a pale yellow solid (melting point = 65.3-67.1°C). Yield: 67%. 1H NMR (600 MHz, Chroloholm-d) δ: 21.48 (s, 9H, -C(CH3)3), 2.14-2.18 (m, 2H-OCH2CH2CH2OCOC(CH3)3), 3.82 (s, 3H, -OCH3), 4.09 (t, 2H, J=2.1 Hz, -OCH2CH2CH2OCOC(CH3)3), 4.27 (t, 2H, J= 6.3 Hz, -OCH2CH2CH2OCOC(CH3)3), 5.52 (s, 2H, -CH2Ar), 6.91 (t, 1H, J= 6.91 Hz, Hc), 6.94-6.99 (m, 4H, Hm and aromatic protons). 7.02 (d, 1H, J= 7.5 Hz, aromatic プロトン), 7.37-7.42 (m, Hz, Hb and aromatic プロトン), 7.48 (d, 2H, J= 8.6 Hz, Hn), 8.25 (d, 1H, J= 8.8 Hz, Ha), 8.30 (s, 1H, -NH), 8.34 (d, 1H, J=6.9 Hz, Hd); 13 C NMR (151 MHz, クロロホルム-d) δ: 27.9 (-C(CH3)3), 55.5 (-OCH3), 63.9 (OCH2CH2CH2OCOC(CH3)3), 64.5 (-OCH2CH2CH2OCOC(CH3)3), 72.3 (-CH2Ar), 75.2 (-OCH2CH2CH2OCOC(CH3)3) 82.3(-C(CH3)3), 90.0 (Cf), 113.3 (Cb), 114.3 (Cn), 115.4, 116.3 (Cs) * , 116.3, 115.86 Cp) * , 118.8 (Cd), 122.8, 127.7, 128.3 (Ca), 128.6 (Cl), 128.8 (Ce), 129.7 (Cc), 130.3 (Cm), 144.2 (d, J=235.3 Hz, Cr) ** , 145.5 (d, J=221.4 Hz, Cq) **, 153.56, 158.9 (Co), 160.2 (Ch), 160.6, 163.0 (Cg), 200.7 (-OCH2CH2CH2OCOC(CH3)3). MS (ES-): 640 (M-58).

[0189] General procedure: Removal of the 4-methoxybenzyloxy moiety to produce the final compounds 40-42. Thianisole (187 mg, 1.51 mmol, 10 eq.) was added to the solution of the corresponding starting material (94.8 mg, 0.151 mmol, 1.0 eq.) in TFA (2 mL). This mixture was stirred at room temperature for 30 minutes to 1 hour. The mixture was concentrated to some extent, and this crude product was dissolved in water (20 mL), and the mixture was extracted with SiO2 (3 × 20 mL). This crude product was purified by flash chromatography (see conditions below).

[0190] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-(3-hydroxypropoxy)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (42). This crude product was purified by flash chromatography (eluent: DCM to DCM / MeOH 98 / 2v / v) to obtain a solid. This solid was subjected to reverse-phase purification using Combiflash® Rf 200 (eluent: MeOH / water 35 / 75v / v to water, 13 times the column volume). The title product was obtained as a white solid (melting point = X). Yield: 34%. 1H NMR (600 MHz, DMSO-d6) δ: 1.86-1.90 (m, 2H, -OCH2CH2CH2OH), 3.57 (dd, 2H, J=10.2, 5.4 Hz, -OCH2CH2CH2OH), 4.09 (t, 2H, J=6.3 Hz, -OCH2CH2CH2OH), 4.57 (br t, 1H, J=3.8, -OCH2CH2CH2OH), 6.96 (t, 1H, J=7.0 Hz, Hb), 7.08-7.11 (m, 3H, aromatic proton), 7.45-7.48 (m, 2H, Hc, aromatic proton), 7.91 (d, 1H, J=7.0 Hz, Hd), 8.55 (d, 1H, J=8.7 Hz, Hd), 9.37 (br s, 1H, -NH), 12.92 (br s, 1H, -OH); NMR was repeated. MS (ES-): 474 (M-1).

[0191] N-(3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide (40). This crude product was purified by flash chromatography (eluent: DCM to DCM / ELISA 95 / 5v / v) to obtain a solid. This solid was then ground with diisopropyl ether to obtain the title compound as a white solid (melting point = 229.6-231.7°C). Yield: 43%. MS (ES+): 494 (M-1). 1¹H NMR (600 MHz, DMSO-d⁶) δ: 1.76 (t, 3H, J=19.2 Hz, -OCH₂CF₂CH₃), 4.36 (t, 2H, J=12.7 Hz, -OCH₂CF₂CH₃), 7.03 (t, 1H, J=6.8 Hz, Hb), 7.17–7.20 (m, 2H, aromatic protons), 7.24 (s, 1H, aromatic protons), 7.50–7.52 (m, 2H, Hc and aromatic protons), 7.98 (d, 1H, J=8.7 Hz, aromatic protons), 8.62 (d, 1H, J=6.7 Hz, Ha), 8.94 (br s, 1H, -NH), 12.83 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6) δ: 21,38 (t, J=24.9 Hz, -OCH2CF2CH3), 68.9 (t, J= 31.5 Hz, -OCH2CF2CH3), 88.2 (Cf), 113.2 (Cb), 115.8, 116.5 (Cd), 116.8 (t, J= 10.6 Hz, Cs) * , 117.8 (Cp) * , 119.9 (t, J=243.5 Hz, -OCH2CF2CH3), 123.3, 128.0, 128.3, 129.1 (Ca), 130.1 (Cc), 141.6 (d, J= 269.4 Hz, Cq) ** , 141.7 (Ce), 142.8 (d, J=244.7 Hz, Cr) ** , 152.6, 157.6 (Ch), 160.4, 170.6 (Cg); 19 F NMR (565 MHz, DMSO-d6) -145.3 (s, 2F, -OCH2CF2CH3), -97.0 (d, 2F, J=14.7 Hz), -96.9 (d, 2F, J=15.0 Hz); MS (ES-): 494 [M-1].

[0192] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-(2-oxopropoxy)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (41). This crude product was purified by flash chromatography (eluent: DCM to DCM / MeOH 95 / 5v / v) to obtain a solid. This solid was then ground with diisopropyl ether to obtain the title compound as a white solid (melting point = 218.2-220.3°C). Yield: 43%. 1 H NMR (600 MHz, DMSO-d6) δ: 2.17 (s, 3H, -OCH2COCH3), 4.90 (s, 2H, -OCH2COCH3), 7.02 (t, 1H, J= 6.6 Hz, Hb), 7.06 (d, 1H, J= 8.5 Hz, aromatic proton), 7.11-7.12 (m, 2H, aromatic proton), 7.46 (t, 1H, J= 7.9 Hz, Hc), 7.50 (t, 1H, J= 7.8 Hz, aromatic proton), 7.97 (d, 1H, J= 8.7 Hz, Hd), 8.60 (d, 1H, J=8.7 Hz, Ha), 8.99 (s, 1H, -NH), 12.90 (br s, 1H, -OH); 13 C NMR (151 MHz, DMSO-d6) δ: 26.2 (-OCH2COCH3), 72.1 (-OCH2COCH3), 88.2 (Cf), 113.2 (Cb), 115.5, 116.2 (Cd), 116.8, 116.9 (Cs) * , 118.1 (Cp) * , 122.7, 127.8, 128.3, 129.1 (Ca), 129.9 (Cc), 140.0 (d, J=246.7 Hz, Cq) ** , 141.7 (Ce), 143.80 (d, J= 252.7 Hz Cr) ** , 157.9, 160.5 (Ch), 162.6 (Cg); 203.8 (-OCH2COCH3). MS (ES-): 472 [M-1].

[0193] 2-Hydroxy-N-(2,3,5,6-tetrafluoro-3'-(2-hydroxypropoxy)-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (43). NaBH4 (8.00 mg, 0.210 mmol, 2 eq) (5 mL) was added to a mixture of 41 (50.0 mg, 0.105 mmol) in EtOH (5 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was dissolved in water (10 mL), and the mixture was extracted with ELISA (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by grinding with diisopropyl ether to provide a white solid (melting point = 175.7–177.6 °C). Yield: 90%. 1 H NMR (600 MHz, DMSO-d6) δ: 1.16 (d, 3H, J=6.2 Hz, -OCH2CH(OH)CH3), 3.86 (td, 2H, J=9.2, 5.7 Hz, -OCH2CH(OH)CH3), 3.94-4.05 (m, 1H, -OCH2CH(OH)CH3), 4.90 (s, 1H, -OCH2CH(OH)CH3), 7.03 (t, 1H, J= 6.6 Hz, Hb), 7.09-7.12 (m, 3H, aromatic proton), 7.46 (t, 1H, J= 7.9 Hz, Hc), 7.51 (t, 1H, J= 7.8 Hz, aromatic proton), 7.98 (d, 1H, J= 8.7 Hz, Hd), 8.62 (d, 1H, J=6.7 Hz, Ha), 8.92 (s, 1H, -NH), 12.86 (br s, 1H, acid-OH); 13 C NMR (151 MHz, DMSO-d6) δ: 20.10 (-OCH2CH(OH)CH3), 64.5 (-OCH2CH(OH)CH3), 73.4 (-OCH2CH(OH)CH3), 88.2 (Cf), 113.2 (Cb), 114.4, 115.6, 116.3 (Cd), 116.9 (Cs) * , 117.5 (Cp) *, 122.3, 127.8, 128.3, 129.2 (Ca), 130.0 (Cc), 141.68 (d, J=242.9 Hz, Cq) ** , 141.72 (Ce), 142.8 (d, J=25.3 Hz, Cr) ** , 158.7, 160.4 (Ch), 162.7 (Cg);MS (ES-): 474 [M-1].

[0194] Protein expression and purification. BL21DE3 PyrD E. coli cells were transformed using the plasmid construct pFN2A-hDHODH (obtained courtesy of the Department of Drug Science and Technology, University of Turin, Turin). This vector produces hDHODH as the N-terminal GST-fusion protein. The cells were grown at 37°C in LB medium supplemented with 0.1 mM flavin mononucleotide (Cayman Chemical). After 20 hours of growth, the cells were further induced with 0.8 mM isopropyl-D-thiogalactopyranoside for 6 hours at 28°C until the OD600 reached 0.5-0.7. A cell pellet from 250 mL of culture was dissolved in 20 mL of PBS (50 mM Na2HPO4, 50 mM NaH2PO4, 500 mM NaCl) supplemented with a cocktail of 24 mg lysozyme and 0.2% v / v protease inhibitor. This solution was incubated on ice for 30 minutes and then destroyed by sonication (total sonication time: 8 minutes with 10" / 50" on / off cycles). Triton X-100 was added to this solution to a final concentration of 1%, and then the mixture was centrifuged at 14000 g for 40 minutes at 4°C. 6As described, the cleared supernatant was incubated with DNase I at room temperature for 30 minutes, supplemented with 2 mM dithiothreitol (DTT), and filtered through a 0.45 μm syringe filter. The GST-fused enzyme was purified from this bacterial lysate using affinity chromatography on a fixed glutathione-Sepharose column (GE-HiTrap Protein G HP 1 ml). The GST tag was not cleaved for further analysis. Unless otherwise specified, all reagents used for the expression and purification of this protein were supplied by Merck / Sigma-Aldrich.

[0195] hDHODH Inhibition Assay. The enzyme inhibition assay was performed on a 96-well plate and optimized to achieve higher throughput. For each well of the plate, a total volume of 200 μL was used: 5 μL of purified GST-hDHODH; 60 μL of 500 μM 2,6-dichloroindophenol (DCIP); 20 μL of 100 μM coenzyme Q10 enzyme; 20 μL of 500 μM dihydroorotic acid (DHO); and Tris-HCl (pH 8) to a final volume of 200 μL. Inhibitory activity was assayed by monitoring the decrease in DCIP, which is related to the oxidation of dihydroorotic acid catalyzed by the DHODH enzyme. This enzyme was pre-incubated at 37°C for 5 minutes in Tris-HCl (pH 8) containing coenzyme Q10, DCIP (50 μM), and the test compound used at different concentrations (final DMSO concentration 0.1% v / v). This reaction was initiated by the addition of DHO (500 μM), and the kinetic decrease in absorbance was monitored at λ = 650 nm using a multi-plate reader (Tecan, M1000Pro). To evaluate the minimum and maximum absorbance of this enzymatic reaction, the Min control value was obtained by measuring the absorbance without DHO. Similarly, the Max value was obtained by measuring the absorbance with DHO but without the inhibitor. Blank reduction calculations were also performed by measuring the absorbance using 180 μL of Tris-HCl and 20 μL of coenzyme Q10. The instrument was set to read absorbance every 10 seconds over a total measurement time of 10 minutes at 37°C. The initial velocity was measured during the first 5 minutes (ε = 10⁴⁰ / M·cm) and recorded using GraphPad Prism 7 software. 19 Using IC 50 The value was calculated. The value is the mean ± SE of three independent experiments.

[0196] Statistical analysis. Statistical analysis was performed using Prism software, version 5.0 (GraphPad Software, San Diego, CA). Data are reported as mean ± SE. A two-tailed paired Student's t-test was calculated to evaluate the difference between means, with P < 0.05 considered significant. EC 50A nonlinear regression model was applied to determine this.

[0197] Preliminary ADME and physicochemical profiling Solubility assay at pH 7.4. Solubility was assayed in phosphate-buffered saline (PBS: 12 mM, containing 137 mM NaCl and 2.7 mM KCl, pH 7.4). Each solid compound (1 mg) was added to 1 mL of PBS. These samples were shaken in an orbital shaker at 25°C for 24 hours. These suspensions were filtered through a PTFE 0.45 μm filter (VWR), and the solutions were analyzed by chromatography using a Perkin Elmer ultra-high-performance liquid chromatography (UHPLC) system equipped with a reverse-phase (RP) C18 Phenomenex column (2.1 × 100 mm, particle size 1.7 μm). Elution gradient: The ratio of eluents A and B (0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, respectively) was linearly changed over 12 minutes from 60% A-40% B to 0% A-100% B. Then, a 5-minute elution with 100% eluent B was performed to determine the final composition, followed by a 4-minute equilibrium elution to reset the starting conditions. The flow rate was 0.5 mL / min. The standard injection volume for poorly soluble compounds was either 2 or 4 μl. The detection system was a Perkin Elmer diode-array-detector. The wavelength monitored for each compound was determined according to the compound's own absorption spectrum. Solubility, expressed as the concentration of the saturated solution in μM, was calculated by interpolation using external calibration curves obtained from solutions of each compound in acetonitrile.

[0198] ClogP and logD (pH 7.4). The ClogP value was calculated using the Bio-Loom program for Windows, version 1.5 (BioByte). The partition coefficient (logD) between n-octanol and PBS (pH 7.4). 7.4The compounds were obtained at room temperature using the shake-flask technique. In this shake-flask experiment, 50 mM phosphate-buffered saline (pH 7.4) was used as the aqueous phase. The organic phase (n-octanol) and the aqueous phase were saturated with each other by shaking for 4 hours. These compounds were solubilized in the buffered aqueous phase at the highest concentration compatible with solubility, and an appropriate amount of n-octanol was added. These two phases were shaken for approximately 20 minutes to reach the solute distribution equilibrium by this time, and then centrifuged (10000 rpm, 10 minutes). The solute concentrations were measured in the aqueous phase using a UV spectrophotometer (Varian Cary 50BIO); absorbance (recorded for each compound at the maximum absorption wavelength) was interpolated into calibration curves obtained using standard solutions of these compounds (r 2 (>0.99). Each logD value is the average of at least six measurements.

[0199] In vitro protein binding was achieved by ultrafiltration using a commercially available membrane system (Centrifree ultrafiltration system, Merck, equipped with an UltraCell YM-T membrane). A solution of the selected compound in DMSO solvent was added to human serum (Sigma-Aldrich, sterile filtered from human male AB plasma) and diluted to a final concentration of 50 μM with 2% co-solvent. 1 mL of the resulting solution in the sample storage chamber of the ultrafiltration system was gently shaken in an orbital shaker at 37°C for 1 hour. The tube was then centrifuged at 1000 × g for 15 minutes. The concentrations of these compounds in the ultrafiltrate and filtrate were determined using reverse-phase UHPLC, and the chromatographic conditions were those described previously, although with different injection volumes; 20 μL ultrafiltrate sample and 2 μL filtrate sample. The quantitative determination of these compounds in the filtrate and ultrafiltrate was performed using two different calibration curves of standard solutions of the compounds (linearity was determined for the ultrafiltrate with an injection volume of 20 μL and a concentration range of 0.5–25 μM, and for the filtrate with an injection volume of 2 μL and a concentration range of 10–100 μM). 2 (>0.99). Considering the limited solubility of the test compounds, the recovery rate of the ultrafiltration process was calculated to determine whether any of the compounds were lost during ultrafiltration. Recovery rate = 100 × [(capacity) 結合 ×Concentration 結合 )+(capacity 未結合 ×Concentration 未結合 )] / capacity 初期血清 ×Concentration 初期 capacity 結合 The density was calculated by dividing the weight of the combined fraction (the difference between the weight after ultrafiltration and the weight of the empty sample storage container) by its density (0.991 g / mL, as assessed by weighing five reproducible samples of a known volume of the combined fraction). capacity 未結合 The density was calculated by dividing the weight of the unbound fraction (the difference between the ultrafiltrate cups before and after ultrafiltration) by its density (0.999 g / mL, assessed by weighing five reproducible samples of a known volume of the unbound fraction). concentration 結合 Calculations were performed using the RP-HPLC method. concentration 未結合 Calculations were performed using the RP-HPLC method (calibration of standard additives). The average recovery rate was 90% for all test compounds.

[0200] Virological methods Herpes simplex virus types 1 and 2 (HSV-1 / 2) Cells, culture conditions, and viruses - African green monkey kidney cells (Vero) (ATCC CCL-81) were cultured in Dulbecco's modified Eagle medium (DMEM; Euroclone) supplemented with 10% fetal bovine serum (FBS; Euroclone), 2 mM L-glutamine, 1 mM sodium pyruvate, 100 U / ml penicillin, and 100 mg / ml streptomycin sulfate.

[0201] Clinical isolates of acyclovir-sensitive HSV-1 and HSV-2 were kindly provided by Dr. V. Ghisetti (Amedeo di Savoia Hospital, Turin, Italy). HSV-1 and HSV-2 were grown and their titers were determined by a plaque assay in Vero cells, as previously described (Terlizzi et al., Antiviral Research 132, 154-164, 2016).

[0202] Antiviral assay – To determine cell viability, Vero cells were exposed to 17, 1, or Blechnal at increasing concentrations. After 3 days of incubation, the number of viable cells was determined using the Cell Titer Glo(R) luminescent cell viability assay (Promega).

[0203] To evaluate the anti-HSV activity of 1, 17, or Brechinal cells by plaque reduction assay (PRA), Vero cells were placed in 24-well plates at a density of 70 × 10⁶. 3 Individual cells were seeded. After 24 hours, cells were treated with different concentrations of 17, 1, or Brekinal 1 hour prior to infection, and then infected with HSV-1 or HSV-2 (50 PFU / well). After viral adsorption (2 hours at 37°C), cultures were maintained in a medium containing 0.8% methylcellulose (Sigma) and the compound. 48 hours after infection (hpi), cells were fixed and stained with 20% ethanol and 1% crystal violet. Plaques were counted microscopically, and the average plaque count for each concentration was expressed as a percentage of the average plaque count for the control virus. Plaque count was plotted as a function of drug concentration; the concentration (EC) that produced a 50% reduction in plaque formation was plotted. 50 We determined that this was as explained by Terlizzi et al. (Antiviral Research 132, 154-164, 2016).

[0204] Influenza virus Cells, culture conditions, and viruses – Maiden Derby canine kidney cells (MDCK, ATCC CCL-34™) were grown in DMEM supplemented with 10% fetal bovine serum (FBS; Euroclone), 2 mM L-glutamine, 1 mM sodium pyruvate, 100 U / ml penicillin, and 100 μg / ml streptomycin sulfate. Infection was performed in the presence of 1 μg / ml trypsin TPCK treated with bovine pancreas (Sigma-Aldrich) and 0.14% bovine serum albumin (Sigma-Aldrich). Influenza virus strains A / Puerto Rico / 8 / 34(IAV)(VR-1469) and BB / Lee / 40(IBV)(VR-101) were obtained from ATCC. IAV and IBV were cultured and their titers were determined by a plaque assay in MDCK cells, as described in Luganini et al.'s paper, Front. Microbiol. 9:1826, 2018.

[0205] The cytotoxicity of antiviral assay-1 and Brechnal was determined in MDCK cells 72 hours after treatment using the Cell Titer Glo(R) luminescent cell viability assay (Promega).

[0206] The antiviral activity of 1 and Brechnal was determined by PRA. For this purpose, MDCK cells were seeded in 24-well plates (3 × 10⁻¹⁶). 5 Individual cells (per well) were exposed to gradually increasing concentrations of 1 or Blekinal 1 hour before infection, and then infected with IAV or IBV (40 PFU / well). After viral adsorption (1 hour at 37°C), the cultures were incubated in a medium containing 0.7% Avicel (FMC Biopolymer) and 1 or Blekinal. 48 hours post-infection (hpi), the cells were fixed at room temperature (RT) for 1 hour with a 4% formaldehyde solution in 1× phosphate-buffered saline (PBS) and stained with 1% crystal violet solution. Subsequent microscopic plaque counts were measured at either concentration of 1 (EC) that resulted in a 50% reduction in plaque formation. 50This made it possible to determine (Luganini et al., Front. Microbiol. 9:1826, 2018).

[0207] Respiratory syncytial virus (RSV) Cells, culture conditions, and virus-HEp-2 cells (ATCC CCL-23) were maintained in Dulbecco's modified Eagle medium (DMEM; Euroclone) supplemented with 10% fetal bovine serum (FBS; Euroclone), 2 mM L-glutamine, 1 mM sodium pyruvate, 100 U / ml penicillin, and 100 mg / ml streptomycin sulfate.

[0208] Respiratory syncytial virus (RSV) strains A-Long (VR-26) and B-Washington (RSV-9320 VR-955) were obtained from ATCC, propagated, and titrated in HEp-2 cells as described by Rameix-Welti et al., Nat. Commun. 5:5104, 2014.

[0209] Antiviral assay-1 and cytotoxicity assays for Brechnal were determined in HEp-2 cells using the Cell Titer Glo(R) luminescent cell viability assay (Promega) after 72 hours of incubation with these compounds.

[0210] The antiviral activity of 1 and Brechnal was determined by PRA. Briefly, HEp-2 cells were seeded in a 24-well plate (3 × 10⁻¹⁶). 5Individual cells (per well) were exposed to different concentrations of 1 or 1 brequinal 1 hour prior to infection, and then infected with RSV A or B (50 PFU / well). After viral adsorption (2 hours at 37°C), the cultures were maintained in a medium containing 0.3% methylcellulose (Sigma) and the compound. 96 hours post-infection (hpi), the cells were fixed and stained with 20% ethanol and 1% crystal violet. Plaques were counted microscopically, and the average plaque count for each concentration was expressed as the ratio of the average plaque count of the control virus. The number of plaques was plotted against the compound concentration, and the EC (European Clinical Laboratory) was used. 50 This was determined to be the compound concentration that produces a 50% reduction in plaque count.

[0211] Alpha- and beta-coronaviruses. Cell lines of human lung fibroblasts MRC5 (ATCC CCL-171), human colorectal cancer HCT-8 (ATCC CCL-244), human lung adenocarcinoma Calu-3 (ATCC HTB-55), and African green monkey kidney VeroE6 (ATCC CRL-1586) were purchased from the American Type Culture Collection (ATCC) and maintained in Dulbecco's Modified Eagle Medium (DMEM; Euroclone) supplemented with 10% fetal bovine serum (FBS, Euroclone), 2 mM glutamine, 1 mM sodium pyruvate, 100 U / ml penicillin, and 100 μg / ml streptomycin sulfate (P / S, both from Euroclone).

[0212] hCoV-229E (ATCC VR-740) and hCoV-OC43 (ATCC VR-1558) were purchased from ATCC, grown, and titrated in MRC5 cells and HCT-8 cells, respectively. SARS-CoV-2 (2019-nCoV / Italy-INMI1) was obtained from EVAg, grown, and titrated in VeroE6 cells. SARS-CoV-2 / 01 / human / 2020 / SWE was isolated from nasopharyngeal samples on VeroE6 cells, cultured, and titrated as previously described

[18] .

[0213] Cytotoxicity assay Cells were seeded in 96-well plates and, after 24 hours, were exposed to gradually increasing concentrations of the compound or a vehicle (DMSO) as a control. After 72 hours of incubation, the number of viable cells was determined using either the Cell Titer Glo(R) luminescent cell viability assay (Promega) or the MTT method

[19] , following the manufacturer's instructions.

[0214] Antiviral assay To select a minilibrary of hDHODH inhibitors, a cell fossil formation atinomy assay (FFRA)

[20] was performed on HCT-8 cell monolayers treated with 0.1 μM of different compounds, or alternatively with the vehicle (DMSO), 1 hour prior to or at the time of infection with hCoV-OC43 (100 PFU / well). 72 hours post-infection (pi), the cell monolayers were fixed and subjected to indirect immunoperoxidase staining with mAbs (1:100 dilution) against hCoV-OC43 N protein (clone .542-D7; Millipore). Viral foci were microscopically counted, and the average count for each drug concentration was expressed as a percentage of the average plaque count of the control virus (DMSO). To determine the anti-hCoV-229E activity of MEDS433 or Brekinal, MRC5 cell monolayers were treated with different concentrations of the compound 1 hour before or at the time of infection with hCoV-229E (100 PFU / well). 72 hours after infection, cell viability was measured using the CellTiter Glo assay as a surrogate measure of viral cytopathic effect (CPE), as described previously

[21] . To measure the anti-SARS-CoV-2 activity of MEDS433 or Brekinal, viral yield reduction assays (VRAs) were performed using VeroE6 or Calu-3 cells. Briefly, cell monolayers were treated with vehicle or gradually increasing concentrations of the compound 1 hour before and at the time of infection with SARS-CoV-2 (50 or 100 PFU / well). 48 hours post-infection, SARS-CoV-2 in the cell supernatant was titrated by a plaque assay against VeroE6 cells. Compound concentration (EC) that causes a 50% or 90% reduction in plaque formation 50The efficacy was determined by comparing it to the control treatment (DMSO).

[0215] SARS-CoV-2 Cells, culture conditions, and virus-VeroE6 cells (ATCC CRL-1586) were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 1 mM sodium pyruvate, 100 U / ml penicillin, and 100 μg / ml streptomycin sulfate. The SARS-CoV-2 virus strain 2019-nCoV / Italy-INMI1 was obtained from the Istituto Nazionale Malattie Infettive "Lazzaro Spallanzani" and grown and titrated in VeroE6 cells.

[0216] Antiviral assay-1 and cytotoxicity assays of Brechnal were performed on VeroE6 cells by MTT after 72 hours of incubation with the compound.

[0217] The antiviral activity of 1 and Brekinal was determined by viral yield reduction assay (VRA). Briefly, VeroE6 cells were seeded in 24-well plates, treated with different concentrations of 1 or Brekinal 1 hour prior to infection after 24 hours, and then infected with SARS-CoV-2 (50 PFU / well). After viral adsorption (2 hours at 37°C), the cultures were maintained in a medium containing the compounds. 72 hours post-infection (hpi), the cell supernatant was collected, and its infectivity was titrated by plaque assay in the E6 cell monolayer. Plaques were counted microscopically at 72 hours post-infection, and the average plaque count for each concentration was expressed as a percentage of the average plaque count for the control virus. Plaque counts were plotted against compound concentration, and the EC (Emission Control Value) was also calculated. 50 This was determined to be the compound concentration that produces a 50% reduction in SARS-CoV-2 infection rates. The present invention includes the following embodiments: <Aspect 1> A pharmaceutical composition comprising a compound selected from the group consisting of compounds represented by the following formula, for use in inhibiting viral replication or in the therapeutic treatment of viral infection in a subject: - Compound of formula (I):

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[0218] References 1. Brown, K. K.; Spinelli, J. B.; Asara, J. M.; Toker, A., Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discovery 2017, 7 (4), 391-399. 2. Mathur, D.; Stratikopoulos, E.; Ozturk, S.; Steinbach, N.; Pegno, S.; Schoenfeld, S.; Yong, R.; Murty, V. V.; Asara, J. M.; Cantley, L. C.; Parsons, R., PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition. Cancer Discovery 2017, 7 (4), 380-390. 3. Koundinya, M.; Sudhalter, J.; Courjaud, A.; Lionne, B.; Touyer, G.; Bonnet, L.; Menguy, I.; Schreiber, I.; Perrault, C.; Vougier, S.; Benhamou, B.; Zhang, B.; He, T.; Gao, Q.; Gee, P.; Simard, D.; Castaldi, M. P.; Tomlinson, R.; Reiling, S.; Barrague, M.; Newcombe, R.; Cao, H.; Wang, Y.; Sun, F.; Murtie, J.; Munson, M.; Yang, E.; Harper, D.; Bouaboula, M.; Pollard, J.; Grepin, C.; Garcia-Echeverria, C.; Cheng, H.; Adrian, F.; Winter, C.; Licht, S.; Cornella-Taracido, I.; Arrebola, R.; Morris, A., Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. Cell Chemical Biology 2018, 25 (6), 705-717.e11. 4. Okesli, A.; Khosla, C.; Bassik, M. C., Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy. Current Opinion in Biotechnology 2017, 48, 127-134. 5. WO 2019234186 (Boschi D. et al), published on 12 December 2019. 6. Sainas, S.; Pippione, A. C.; Lupino, E.; Giorgis, M.; Circosta, P.; Gaidano, V.; Goyal, P.; Bonanni, D.; Rolando, B.; Cignetti, A.; Ducime, A.; Andersson, M.; Jarva, M.; Friemann, R.; Piccinini, M.; Ramondetti, C.; Buccinna, B.; Al-Karadaghi, S.; Boschi, D.; Saglio, G.; Lolli, M. L., Targeting myeloid differentiation using potent 2-hydroxypyrazolo[1,5- a]pyridine scaffold-based human dihydroorotate dehydrogenase inhibitors. J Med Chem 2018, 61 (14), 6034-6055. 7. Dorel, R.; Grugel, C. P.; Haydl, A. M., The Buchwald-Hartwig amination after 25 years. Angew Chem Int Ed Engl 2019, 58 (48), 17118-17129. 8. Takahashi, Y.; Hibi, S.; Hoshino, Y.; Kikuchi, K.; Shin, K.; Murata-Tai, K.; Fujisawa, M.; Ino, M.; Shibata, H.; Yonaga, M., Synthesis and structure-activity relationships of pyrazolo[1,5-a]pyridine derivatives: potent and orally active antagonists of corticotropin-releasing factor 1 receptor. J Med Chem 2012, 55 (11), 5255-69. 9. Williams-Noonan, B. J.; Yuriev, E.; Chalmers, D. K., Free energy methods in drug design: Prospects of “alchemical perturbation” in medicinal chemistry. J Med Chem 2018, 61 (3), 638-649. 10. Christian, S.; Merz, C.; Evans, L.; Gradl, S.; Seidel, H.; Friberg, A.; Eheim, A.; Lejeune, P.; Brzezinka, K.; Zimmermann, K.; Ferrara, S.; Meyer, H.; Lesche, R.; Stoeckigt, D.; Bauser, M.; Haegebarth, A.; Sykes, D. B.; Scadden, D. T.; Losman, J. A.; Janzer, A., The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia 2019, 33 (10), 2403-2415. 11. Gradl, S. N.; Mueller, T.; Ferrara, S.; Sheikh, S. E.; Janzer, A.; Zhou, H.-J.; Friberg, A.; Guenther, J.; Schaefer, M.; Stellfeld, T.; Eis, K.; Kroeber, M.; Nguyen, D.; Merz, C.; Niehues, M.; Stoeckigt, D.; Christian, S.; Zimmermann, K.; Lejeune, P.; Bruening, M.; Meyer, H.; Puetter, V.; Scadden, D. T.; Sykes, D. B.; Seidel, H.; Eheim, A.; Michels, M.; Haegebarth, A.; Bauser, M., Abstract 2: Discovery of BAY 2402234 by phenotypic screening: A human dihydroorotate dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies. Cancer Res. 2019, 79 (13 Supplement), 2. 12. Zhou, J.; Quah, J. Y.; Ng, Y.; Chooi, J. Y.; Toh, S. H.; Lin, B.; Tan, T. Z.; Hosoi, H.; Osato, M.; Seet, Q.; Ooi, A. G. L.; Lindmark, B.; McHale, M.; Chng, W. J., ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia. Haematologica 2019, 105 (9), 2286-2297. 13. Waring, M. J., Lipophilicity in drug discovery. Expert Opin Drug Discov 2010, 5 (3), 235-48. 14. Hao, X.; in, X.; Zhang, X.; Ma, B.; Qi, G.; Yu, T.; Han, Z.; Zhu, C., Identification of quinoxalin-2(1H)-one derivatives as a novel class of multifunctional aldose reductase inhibitors. Future Med. Chem. 2019, 11 (23), 2989-3004. 15. Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020, 30 (3), 269-271. 16. Sheahan, T. P.; Sims, A. C.; Zhou, S.; Graham, R. L.; Pruijssers, A. J.; Agostini, M. L.; Leist, S. R.; Schafer, A.; Dinnon, K. H., 3rd; Stevens, L. J.; Chappell, J. D.; Lu, X.; Hughes, T. M.; George, A. S.; Hill, C. S.; Montgomery, S. A.; Brown, A. J.; Bluemling, G. R.; Natchus, M. G.; Saindane, M.; Kolykhalov, A. A.; Painter, G.; Harcourt, J.; Tamin, A.; Thornburg, N. J.; Swanstrom, R.; Denison, M. R.; Baric, R. S., An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020, 12 (541). 17. Yoon, J.-J.; Toots, M.; Lee, S.; Lee, M.-E.; Ludeke, B.; Luczo, J. M.; Ganti, K.; Cox, R. M.; Sticher, Z. M.; Edpuganti, V.; Mitchell, D. 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Claims

1. A pharmaceutical composition comprising a compound selected from the group consisting of compounds represented by the following formula, for use in inhibiting viral replication or in the therapeutic treatment of viral infection in a subject: 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】

2. The pharmaceutical composition according to claim 1, wherein the virus is a DNA virus or an RNA virus.

3. The pharmaceutical composition according to claim 1, wherein the virus is selected from the group consisting of the Herpesviridae, Orthomyxoviridae, Paramyxoviridae, and Coronaviridae families.

4. The pharmaceutical composition according to claim 1, wherein the virus is selected from the group consisting of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), influenza A virus, influenza B virus, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome-associated coronavirus (MERS-CoV).

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising a carrier, excipient and / or diluent that is pharmaceutically acceptable.

6. The pharmaceutical composition according to claim 5, wherein the viral infection is caused by a DNA virus or an RNA virus.

7. The pharmaceutical composition according to claim 5, wherein the viral infection is caused by a virus selected from the group consisting of the Herpesviridae, Orthomyxoviridae, Paramyxoviridae, and Coronaviridae families.

8. Compounds selected from the following groups: 【Chemistry 10-1】 【Chemistry 10-2】

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