An Expedient Approach to Pyrazolo[3,4-b]pyridine-3-carboxamides via Palladium-Catalyzed Aminocarbonylation

Abstract

Pyrazolo[3,4-b]pyridine is a privileged scaffold found in many small drug molecules that possess a wide range of pharmacological properties. Efforts to further develop and exploit synthetic methodologies that permit the functionalization of this heterocyclic moiety warrant investigation. To this end, a series of novel 1,3-disubstituted pyrazolo[3,4-b]pyridine-3-carboxamide derivatives have been prepared by introducing the 3-carboxamide moiety using palladium-catalyzed aminocarbonylation methodology and employing CO gas generated ex situ using a two-chamber reactor (COware^®). The functional group tolerance of this optimized aminocarbonylation protocol is highlighted through the synthesis of a range of diversely substituted C-3 carbox­amide pyrazolo[3,4-b]pyridines in excellent yields of up to 99%.

Key words

pyrazolo[3,4-b]pyridine - 7-azaindazole - palladium - aminocarbonylation - carboxamide

From a pharmaceutical perspective, the development of synthetic strategies affording pyrazolo[3,4-b]pyridine derivatives is of significant interest. The pyrazolo[3,4-b]pyridine heterocyclic motif is a privileged scaffold, present in a large number of biologically active small molecules. For example, 1,3-disubstituted pyrazolo[3,4-b]pyridines, 1 [riociguat, Adempas^® (Bayer)] and 2 [vericiguat, Verquvo^® (Merck)] both possess vasodilatory properties (Figure [1]).[1] Moreover, pyrazolo[3,4-b]pyridine derivatives, including 3–6 and 7, have been shown to possess anticancer[2] [3] [4] [5] and antiviral activity,[6] respectively. Several examples of central nervous system (CNS) active agents also contain a pyrazolo[3,4-b]pyridine heterocyclic core and have been investigated for their potential use in the treatment of neurological disorders, such as multiple sclerosis (8),[7] Parkinson’s disease (9),[8] and Alzheimer’s disease (10).[9] Furthermore, recent literature has highlighted that certain 1,3-disubstituted pyrazolo[3,4-b]pyridines, such as 11, possess high affinity and efficacy at both the cannabinoid receptor subtypes 1 and 2.[10]

Figure 1 Examples of biologically active pyrazolo[3,4-b]pyridine derivatives 1–11 [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

As part of ongoing work in our laboratory, we became interested in accessing a series of N-1-substituted pyrazolo[3,4-b]pyridine-3-carboxamide derivatives 12 (Scheme [1]). Pyrazolo[3,4-b]pyridine 13 represents a pivotal intermediate in the synthesis of carboxamide 12. However, several previous reports[10] [11] [12] [13] [14] outlining the preparation of N-1-substituted pyrazolo[3,4-b]pyridine 12 often require multistep routes (Scheme [1], Routes A–D). Palladium-catalyzed alkoxycarbonylation has previously been employed to great effect to furnish C-3 carboxylate esters of indazole[15] and pyrazolo[3,4-b]pyridine.[16] Blake and co-workers have prepared pyrazolo[3,4-b]pyridine-3-carboxamide derivatives under Pd-catalyzed aminocarbonylative conditions, using a balloon of CO, albeit in poor yield.[17] Similarly, Kannaboina et al. have demonstrated the Pd-catalyzed aminocarbonylation of a limited number (n = 3) of 3-iodo-1H-pyrazolo[3,4-b]pyridines in fair yield (57–70%) using CO generated in situ­.[18] Thus, considering these suboptimal yields and tedious purification steps associated with routes A–D, we aimed to explore and develop an efficient aminocarbonylation strategy that would permit rapid and direct access to a wide range of functionally diverse pyrazolo[3,4-b]pyridine-3-carboxamide derivatives 12 from aryl iodide 14 in high yield.

Scheme 1 Synthetic methods for the preparation of N-1-substituted pyrazolo[3,4-b]pyridine-3-carboxamides 12

While carbon monoxide (CO) gas has been utilized for decades as part of many useful synthetic industrial processes,[19] the handling and manipulation of this toxic and flammable gas presents significant safety concerns. Prior to recent advances made by the Skrydstrup group,[20] [21] transition-metal-catalyzed aminocarbonylative transformations were carried out using pressurized autoclave reactors[22] or performed at atmospheric pressure using a balloon of CO gas. Several aminocarbonylation procedures utilize CO generated in situ using liquid or solid CO surrogates, such as chloroform,[18,23] dimethylformamide,[24] and metal carbonyl derivatives.[25] [26] [27] Although the latter approach obviates the use of CO gas, the CO surrogate and/or by-products thereof may potentially hinder the desired aminocarbonylation reaction.[20] Alternatively, ex situ CO generation has been successfully applied in dual-chamber reaction vessels.[28] [29] [30] [31] [32] Verseyer­ et al. have generated CO ex situ, from formic acid, mesyl chloride, and triethylamine, facilitating aminocarbonylative transformations to great effect.[33] Comprehensive reviews[19] ^, [34] [35] [36] indicate that a wide array of palladium catalysts and ligands may be used to facilitate palladium-catalyzed aminocarbonylations. To this end, the initial investigation of our desired pyrazolo[3,4-b]pyridine-3-carboxamide 12 panel sought to examine the effect of varying the palladium catalyst precursor and ligand, whilst using a two-chamber reaction vessel (COware^®)[20] and ex situ generated CO,[33] on the conversion of aryl iodide 15 [37] to exemplar pyrazolo[3,4-b]pyridine 16 (Table [1]).

Table 1 Effect of Pd Catalyst Precursor and Phosphine Ligand on the Yield of 16 ^a,b,c

Entry	Catalyst precursor	Ligand (mol%)	Yield of 16 (%)d
1	PdCl2	L1 (5)	72
2	Pd(dba)2	L1 (5)	84
3	Pd(OAc)2	L1 (5)	95
4	Pd(OAc)2	L2 (5)	46
5	Pd(OAc)2	L3 (5)	26
6	Pd(OAc)2	L4 (5)	16
7	Pd(OAc)2	L5 (10)	87
8	Pd(OAc)2	L6 (10)	62
9	Pd(OAc)2	L7 (10)	68
10	Pd(OAc)2	L8 (10)	64
11	Pd(OAc)2	–	22
12	–	L1 (5)	0

^a Reaction scale: 0.14 mmol (with respect to aryl iodide 15).

^b Reaction concentration: 0.5 M (with respect to aryl iodide 15).

^c CO was generated ex situ.[33]

^d Isolated yield following wet flash column chromatography.

The reaction of aryl iodide 15 with our chosen amine nucleophile, benzylamine, proceeded smoothly to furnish the desired C-3 carboxamide 16 in good to excellent yield when employing several palladium catalyst precursors (5 mol%), including PdCl₂ (72%), Pd(dba)₂ (84%), and Pd(OAc)₂ (95%) (Table [1], entries 1–3), in the presence of Xantphos (L1) (5 mol%). Taking Pd(OAc)₂ as the optimal catalyst precursor, we then screened a range of mono- and bidentate phosphane ligands to determine the impact of ligand variation on the yield of carboxamide 16 (Table [1], entries 4–10). When compared with Xantphos (L1, bite angle 107°) (95% yield 16; Table [1], entry 3), DPEphos (L2, bite angle 103°), dppf (L3, bite angle 96°), and dppp (L4, bite angle 91°) all gave 16 in significantly lower yields (16–46%, Table [1], entries 4–6).[38] Notably, employing DPEphos (L2) as ligand showed a greater than two-fold decrease in the yield of amide 16 (Table [1], entry 4), despite having similar electronic properties to Xantphos (L1). These latter results (Table [1], entries 1–10) suggest that optimal conversion of aryl iodide 15 to C-3 carboxamide 16 is achieved when a wide bite angle phosphane ligand, such as Xantphos (L1), is employed. Notably, while screening several bidentate phosphane ligands for the Pd-catalyzed carbonylation of aryl bromides, Buchwald and co-workers found that Xantphos (L1) gave superior results when compared with similar bidentate phosphane ligands that possess a similar bite angle, such as DPEphos and dppf.[39] This latter finding has been attributed to the flexibility of the backbone of L1 (flexibility range 97–133°)[40] which may provide a dynamic coordination environment and facilitate distinct steps in the catalytic cycle.[39]

To probe the effect of monodentate phosphane ligands L5–L8 on the formation of 16, a series of electron-rich ligands possessing varying degrees of steric bulk, including PPh₃ (L5; Tolman cone angle Θ = 145°), PCy₃ (L6; Θ = 170°),[41] MePhos (L7; Θ = 190°), and SPhos (L8; Θ = 205°),[42] were investigated (Table [1], entries 7–10). While PPh₃ furnished amide 16 in very good yield (87%, Table [1], entry 7), the use of bulkier monodentate phosphane ligands with a larger Tolman cone angle (≥170°) only gave 16 in moderate yields (62–68%, Table [1], entries 8–10). Although bulkier ligands can facilitate the reductive elimination step of the catalytic cycle, CO coordination and/or acyl insertion into the aryl carbon-palladium bond may be hindered by sterically demanding ligands.[43] [44] [45]

Following the identification of L1 as the optimal ligand for the carbonylation of 15 to give amide 16, control experiments to examine the necessity of the bidentate phosphane ligand revealed that, in the absence of Xantphos, the yield of 16 is significantly reduced (22% vs 95%, Table [1], entries 11 and 3, respectively). As expected, in the absence of Pd(OAc)₂, the formation of carboxamide 16 was not observed (Table [1], entry 12). These latter control experiments highlight the crucial role that both Pd(OAc)₂ and Xantphos play in the aminocarbonylation of aryl iodide 15 to afford 16. Attempts to substitute sodium carbonate with other bases, such as potassium carbonate or triethylamine did not significantly impact the yield of 16 (Table [2], entries 1 and 2 vs Table [1], entry 3). However, replacing toluene with polar aprotic solvents, such as dimethylformamide (DMF) and dimethyl sulfoxide, (DMSO) caused a notable decline in the yield of carboxamide 16 from 95% (Table [1], entry 3) to 58% and 38%, respectively (Table [2], entries 3 and 4).

Table 2 Effect of Base and Solvent on the Yield of 16 ^a,b,c

Entry	Base	Solvent	Yield of 16 (%)d
1	K2CO3	toluene	90
2	NEt3	toluene	86
3	Na2CO3	DMF	58
4	Na2CO3	DMSO	38

^a Reaction scale: 0.14 mmol (with respect to aryl iodide 15).

^b Reaction concentration: 0.5 M (with respect to aryl iodide 15).

^c CO was generated ex situ.[33]

^d Isolated yield following wet flash column chromatography.

Numerous reports[23] [33] [46] [47] outlining the aminocarbonylation of aryl (psuedo)halides typically describe the use of between 1 to 3 equivalents of CO surrogate. To determine if the transformation of 15 to carboxamide 16 could be achieved with less than 10 equivalents of CO, our attention turned to reducing the number of equivalents of our chosen CO surrogate (formic acid, mesyl chloride, and triethylamine)[33] with respect to aryl iodide 15 (Table [3]), while keeping all other variables constant including the COware^® apparatus volume (20 mL). Notably, lowering the CO surrogate­ from 10 equivalents (Table [1], entry 3) to 5 equivalents (Table [3], entry 1), with respect to aryl iodide 15, did not cause a significant decline in the yield of carboxamide 16 (95% vs 89%, respectively). However, a significant decrease in the yield of 16 was observed (50%, Table [3], entry 2), when employing only 2.5 equivalents of the CO surrogate. Interestingly, scaling the reaction up to 1 mmol 15 (Table [3], entry 3) from 0.14 mmol (Table [1], entry 3), while keeping the amount of CO surrogate constant (1.4 mmol) and COware^® apparatus volume (20 mL) constant, permitted access to amide 16 in a comparably high yield (94%). The latter result indicates that 16 can be obtained in excellent yield under specific conditions using only 1.4 equivalents of CO surrogate, rather than a ten-fold excess.

Table 3 Effect of Variation of CO Equivalents on the Yield of 16 ^a,b

Entry	CO (equiv.)	Yield of 16 (%)c
1	5	89d
2	2.5	50d
3	1.4	94e

^a Reaction concentration: 0.5 M (with respect to aryl iodide 15).

^b CO was generated ex situ.[33]

^c Isolated yield following wet flash column chromatography.

^d Reaction scale: 0.14 mmol (with respect to aryl iodide 15).

^e Reaction scale: 1 mmol (with respect to aryl iodide 15).

Efforts to examine the effect of catalyst loading on the yield of 16 (Table [4], entries 1–3) from 5 mol% Pd(OAc)₂ and L1 (Table [1], entry 3) revealed that the carboxamide could still be obtained in excellent yield (98%) using a 10-fold lower precatalyst and ligand load of 0.5 mol% Pd(OAc)₂ and L1, respectively (Table [4], entry 3). Furthermore, attempts to reduce the reaction time for the transformation of 15 to 16 (Table [4], entries 4–6) showed that the conversion of aryl iodide 15 proceeded to give the desired C-3 carboxamide 16 in near quantitative yield (99%, Table [4], entry 6) in only 15 minutes. To our knowledge, such comparable rapid aminocarbonylative transformations have only previously been reported under microwave-heating reaction conditions.[48] [49] Using the latter 15-minute protocol, the p-methoxy congener of 17 was similarly obtained in excellent yield (93%, Table [4], entry 7).

Table 4 Optimization of Catalyst Loading and Reaction Time for Carboxamides­ 16–19 ^a,b,c

Entry	R	Pd(OAc)2 (mol%)	L1 (mol%)	Time (h)	Product	Yield (%)d
1	Bn	2.5	2.5	18	16	96
2	Bn	1	1	18	16	98
3	Bn	0.5	0.5	18	16	98
4	Bn	0.5	0.5	1	16	99
5	Bn	0.5	0.5	0.5	16	97
6	Bn	0.5	0.5	0.25	16	99
7		0.5	0.5	0.25	17	93
8		0.5	0.5	0.25	18	12
9		0.5	0.5	0.25	19	23

^a Reaction scale: 0.14 mmol (with respect to aryl iodide 15).

^b Reaction concentration: 0.5 M (with respect to aryl iodide 15).

^c CO was generated ex situ. [33]

^d Isolated yield following wet flash column chromatography.

However, further extension of these conditions to other intended amine nucleophile substrates (Table [4], entries 8 and 9) proved to be relatively unsuccessful, affording carboxamide derivatives 18 and 19 in poor yield (12% and 23%, respectively), and suggested that the 15-minute reaction time may only be applicable to a limited range of desirable targets.

Aiming to identify an adequately general set of reaction conditions that would provide access to a diverse range of pyrazolo[3,4-b]pyridine-3-carboxamide derivatives in excellent yield, α-keto amine nucleophile 20 (employed in Table [4], entry 8) was chosen for further investigation (Table [5]). Initial attempts to improve the yield of carboxamide 18, through increasing the reaction time from 15 minutes (Table [4], entry 8) to 1 hour (Table [5], entry 1) were met with disappointment (19%, yield 18). Furthermore, increasing the Pd catalyst loading from 0.5 mol% to 1 mol% furnished 18 in similarly poor yield after 1 hour (24%, Table [5], entry 2) and 51% yield after 6 hours (Table [5], entry 3). Importantly, employing our initial reaction conditions, using 5 mol% catalyst loading and a prolonged reaction time (18 h) (see Table [1], entry 3), furnished the desired pyrazolo[3,4-b]pyridine 18 in excellent yield (93%, Table [5], entry 4). This result also suggests the Table [1], entry 3 protocol to be potentially generative towards the efficient synthesis of a disparate range of pyrazolo[3,4-b]pyridine-3-carboxamides.

Table 5 Effect of Catalyst Loading and Reaction Time on the Yield of 18 ^a,b,c

Entry	Pd(OAc)2 (mol%)	L1 (mol%)	Time (h)	Yield (%)c
1	0.5	0.5	1	19
2	1	1	1	24
3	1	1	6	51
4	5	5	18	93

^a Reaction scale: 0.14 mmol (with respect to aryl iodide 15).

^b Reaction concentration: 0.5 M (with respect to aryl iodide 15).

^c CO was generated ex situ.[33]

^d Isolated yield following wet flash column chromatography.

To investigate further the generality of our initial aminocarbonylation protocol (Table [1], entry 3), we applied the methodology to the synthesis of a diverse range of pyrazolo[3,4-b]pyridine-3-carboxamides 21 employing a wide array of primary amine substrates (Scheme [2]). Varying the electronic properties of benzylamine, our prototypical amine nucleophile, had little effect on the isolated yield of respective C-3 carboxamides 17 (p-OMe) and 22–25. For example, the inclusion of electron-withdrawing substituents (p-NO₂ and p-CF₃) both gave carboxamides 22 and 23 in 84% yield. Notably, no evidence of palladium-catalyzed reduction of the nitro functionality of pyrazolo[3,4-b]pyridine 22 was observed under these investigated conditions. Similarly, the presence of electron-donating groups, including p-OMe and p-Me, gave the corresponding amides 17 and 24 in excellent yields of 93% and 89%, respectively.

Scheme 2 Synthesis of N-1-substituted pyrazolo[3,4-b]pyridine-3-carboxamides 17–19, 22–37, and 39–44. Reagents and conditions: aryl iodide 15 (0.28 mmol), amine (0.42 mmol), Pd(OAc)₂ (5 mol%), Xantphos (5 mol%), Na₂CO₃ (3 equiv.), toluene (0.56 mL), CO surrogate (5 equiv.), 100 °C, 18 h.

The protocol tolerates the presence of a p-Br substituent (90%, yield 25). While aryl iodides are more reactive than aryl bromides under typical aminocarbonylation conditions,[50] the latter result highlights both the chemoselectivity and utility of this transformation, offering a potential synthetic handle for subsequent functionalization of pyrazolo[3,4-b]pyridine 25. Further incorporation of sterically hindered amine nucleophiles, including cumylamine and 1-adamantylamine, proceeded smoothly under the optimized conditions to give the desired amides 26 and 27 in excellent yield (98% and 95%, respectively). Similarly, inclusion of the bridged bicycloalkane, norbornylamine, furnished the corresponding product 28 in 98% yield.

The aminocarbonylation protocol demonstrated a high degree of tolerance for various functional groups, exemplified by sulfone (96% yield), sulfonamide (92%), and alkenyl (98%) derivatives, 29, 30, and 31, respectively. However, terminal alkyne 32 was obtained in a comparatively lower yield (62% 32 vs >90% 29–31). Evidence for the formation of several oligomeric by-products, likely arising from the uncontrolled aminocarbonylation of the reactive terminal alkynyl CH of 32,[51] [52] [53] was observed using high-resolution mass spectrometry (HRMS) (see Supporting Information). Efforts to further probe the chemoselectivity of the catalyst system, using ethanolamine and the related gem-dimethyl congener as nucleophiles, revealed that, in both cases, carbonylation occurs via the N atom, rather than the O atom, to afford carboxamides 33 (94% yield) and 34 (97% yield), respectively, rather than their analogous carboxylate ester derivatives. Bisamide 35 and methyl esters (S)-36 and (R)-36 could be prepared in high yield (89%, 97%, and 90%, respectively), without any observable evidence of lactam or ester hydrolysis. Importantly, using chiral chromatography (see Supporting Information), it was possible to demonstrate that racemization of α-amino ester derivative enantiomers (S)-36 and (R)-36 does not occur under these aminocarbonylation conditions when their corresponding enantiopure phenylalanine methyl esters were used as the amine substrates [>99% ee, (S)-36 and (R)-36, respectively].

Employing a conformationally rigid cyclic α-amino amide nucleophile gave the corresponding primary amide derivative 37 in significantly poor yield (28%), alongside the formation of by-product 38 (59% yield, Figure [2]). The structural elucidation of 38 was accomplished using a combination of nuclear magnetic resonance (NMR) spectroscopy, including ¹H-¹⁵N heteronuclear multiple bond correlation (HMBC), and HRMS. While aryl imide bond formation has previously been documented using Pd catalysis, in the presence of CO[54] it is reasonable that pyrazolo[3,4-b]pyridine dimer 38 may have similarly arisen from the carbonylative cross-coupling of amide 37 and aryl iodide 15.

Figure 2 Dimeric by-product 38

Utilizing heterocyclic amine nucleophiles afforded pyrazinyl 19, thiophenyl 39, tetrahydropyranyl 40, and piperidinyl 41 derivatives in yields exceeding 95%, highlighting the significant tolerance of this aminocarbonylation protocol for diverse heterocyclic-containing amine nucleophiles. Also of note is the 95% yield of pyrazinyl carboxamide 19 relative to its much lower yield of 23% when a significantly shorter reaction time of 15 minutes and lower loadings of Pd(OAc)₂ precatalyst and Xanthphos (L1) ligand were employed (see Table [4], entry 9). Furthermore, no evidence for the formation of side products arising from the unwanted Buchwald–Hartwig cross coupling of aryl iodide 15 and amine nucleophiles were observed over the course of these reactions. When using aniline as an example of an aromatic amine nucleophile, its pyrazolo[3,4-b]pyridine derivative 42 was obtained in excellent yield (99%). To demonstrate the tolerance of this catalyst system for sterically hindered anilines, o-methylaniline was employed to give the corresponding amide 43 in 95% yield. However, the use of 2,5-bis(trifluoromethyl)aniline failed to give the corresponding carboxamide 44.

Following the identification of a reliable general method for the aminocarbonylation of aryl iodide 15 to give a wide range of secondary amides 17–19, 22–37, and 39–44 (see Scheme [2]), we proceeded to extend this aminocarbonylation protocol to the preparation of pyrazolo[3,4-b]pyridine tertiary carboxamide derivatives of the general structure 45 (Scheme [3]).

Scheme 3 Extension of general aminocarbonylation protocol to the synthesis of N-1-substituted pyrazolo[3,4-b]pyridine tertiary amide derivatives­ 46–51. Reagents and conditions: aryl iodide 15 (0.28 mmol), amine (0.42 mmol), Pd(OAc)₂ (5 mol%), Xantphos (5 mol%), Na₂CO₃ (3 equiv.), toluene (0.56 mL), CO surrogate (5 equiv.), 100 °C, 18 h.

Employing dimethylamine HCl afforded the corresponding tertiary amide 46 in very good yield (82%). However, using the more sterically hindered secondary amine nucleo­phile, N-methylaniline, furnished the corresponding tertiary amide 47 in only fair yield (57%), when compared with aniline carboxamides 42 and 43 (99% and 95%, respectively). Unfortunately, employing diphenylamine or dicyclohexylamine HCl both failed to give the desired amides 48 and 49, respectively. Notwithstanding the latter steric limitations exemplified through the attempted synthesis of 48 and 49, other pharmaceutically relevant amines, such as 2-oxa-6-azaspiro[3.3]heptane and tetrahydroisoquinoline, could be utilized to afford the corresponding tertiary amides 50 and 51 in satisfactory yield (75% and 98%, respectively).

In summary, an expedient protocol for the synthesis of pyrazolo[3,4-b]-3-carboxamide derivatives, from commercially available 3-iodo-1H-pyrazolo[3,4-b]pyridine, has been developed. This method tolerates a wide range of primary amine nucleophiles, affording structurally diverse secondary and tertiary carboxamides in excellent yield (up to 99%). No evidence for the formation of the corresponding dicarbonylation or α-ketoamide products arising from aryl iodide 15 was observed.[55] Practically, these aminocarbonylative transformations do not require the handling of gaseous CO or pressurized autoclave reactors, as CO is generated ex situ from bench stable liquid reagents (formic acid, mesyl chloride, and triethylamine) in a conveniently sealed two-chamber reaction vessel (COware^®). Given the current interest in the pharmacological potential of pyrazolo[3,4-b]pyridine derivatives, this methodology would suitably facilitate the rapid synthesis of diverse structural analogues for biological assessment.

All reagents were obtained from commercial sources and were used without further purification, unless otherwise stated. Toluene was dried over 3 Å molecular sieves (which were dried prior to use, by heating to 175 °C for 48 h). Room temperature (rt) ranged between 16.5–24 °C with an average value of 20 °C. TLC was carried out on pre-coated Merck silica gel GF254 plates, using UV254 nm light detection. Wet flash column chromatography was performed using Merck Kieselgel­ 60 (particle size 0.040–0.063 mm, density 0.8 g/cm³).

¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were recorded on a Bruker Avance 300 MHz NMR spectrometer. ¹H (400 MHz) and ¹³C (100 MHz) NMR spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. ¹H (600 MHz) and ¹³C (150 MHz) NMR spectra were obtained using a Bruker Avance III 600 MHz NMR spectrometer equipped with a dual CH cryoprobe. All spectra were recorded at 20 °C, using CDCl₃ (with TMS as internal standard, δ_H = 0.00) as sample solvent. Chemical shift values (δ_H and δ_C) are reported in ppm relative to TMS (CDCl₃) and coupling constants (J) are expressed in hertz (Hz), in the following format: chemical shift value (multiplicity, coupling constant, integration). ¹H NMR spectral data are described, using the standard abbreviations. ¹³C NMR spectral data were calibrated using the solvent signal for CDCl₃ (δ_C = 77.0, t).

Melting points were obtained using a Unimelt Thomas–Hoover capillary melting point apparatus and are uncorrected. IR spectra were obtained using a PerkinElmer FTIR UATR2 spectrophotometer. Optical rotations were obtained using an Autopol^® V Plus automatic polarimeter (Rudolph Research Analytical). High-resolution mass spectrometry (HRMS) experiments were performed on a Waters Micromass LCT Premier time-of-flight (TOF) mass spectrometer or a Waters Vion IMS QTOF mass spectrometer using electrospray ionization (ESI). The eluent system employed for MS analysis consisted of MeCN/H₂O (1:1) and contained 0.1% v/v formic acid. HRMS experiments were performed using leucine enkephalin as an internal calibrant.

1-(4-Fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine (15)

To a 100 mL round-bottomed flask was added 3-iodo-1H-pyrazolo[3,4-b]pyridine (1.8 g, 7.35 mmol) and DMF (7.5 mL). The resulting solution was treated with Cs₂CO₃ (2.633 g, 8.08 mmol) and allowed to stir at rt for a further 30 min. 4-Fluorobenzyl bromide (1 mL, 8.08 mmol) was added, and the resulting mixture was allowed to stir at rt for a further 16 h. The reaction mixture was diluted with sat. aq Na₂S₂O₃ (100 mL) and further stirred at rt for 1 h. The suspension was filtered under vacuum and the resulting solids were subsequently washed with H₂O (3 × 20 mL). Recrystallization from EtOH furnished title compound 15; yield: 1.950 g (75%); fine colorless needles; mp 132–133 °C (EtOH); R_f = 0.67 (EtOAc/hexane 3:7).

IR (ATR): 3058, 3040, 3010, 2953, 1599, 1567, 1507, 1452, 1264, 1211, 1157, 1121, 970, 779, 765, 479 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.58 (dd, J = 4.5, 1.2 Hz, 1 H), 7.80 (dd, J = 8.1, 1.2 Hz, 1 H), 7.39–7.35 (m, 2 H), 7.18 (dd, J = 8.1, 4.5 Hz, 1 H), 7.01–6.95 (m, 2 H), 5.67 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.3 Hz), 150.3, 150.1, 132.4 (d, J _C,F = 3.2 Hz), 130.6, 129.9 (d, J _C,F = 8.2 Hz), 120.5, 117.7, 115.5 (d, J _C,F = 21.6 Hz), 90.2, 50.4.

¹⁹F NMR (376 MHz, CDCl₃): δ = –114.3.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₃H₁₀FIN₃: 353.9898; found: 353.9904.

Pyrazolo[3,4-b]pyridine-3-carboxamides 16–19, 22–43, 46, 47, 50, and 51; General Procedure

To Chamber A of an oven-dried 20 mL two-chamber reactor (SyTracks^®) was added Pd(OAc)₂ (3.14 mg, 14 μmol) in anhyd toluene (0.2 mL), Xantphos (8.1 mg, 14 μmol) in anhyd toluene (0.3 mL), anhyd toluene (0.06 mL), Na₂CO₃ (90 mg, 0.42 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.28 mmol), and appropriate amine (0.42 mmol). To Chamber B of the two-chamber reactor was added formic acid (0.05 mL, 1.4 mmol) and MsCl (0.11 mL, 1.4 mmol). The vessel was then flushed with N₂ for 10 min (N₂ flow inlet through Chamber A and flow outlet through Chamber B). Chamber B was treated with NEt₃ (0.39 mL, 2.8 mmol) and the resulting Chamber B mixture allowed to stir at rt for a further 10 min. Both Chambers A and B were immersed in an oil bath set to 100 °C and allowed to stir rapidly (800 rpm) for 18 h. The vessel was then cooled to rt and reactor caps removed. The contents of Chamber A were transferred to a 50 mL round-bottomed flask using EtOAc (5 × 2 mL), mixed with Celite (ca. 200 mg), and concentrated in vacuo. The resulting crude mixture was subjected to gradient wet flash column chromatography using varying mixtures of EtOAc and hexane (unless specified otherwise) to yield the desired carboxamide.

N-Benzyl-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (16)

Yield: 96 mg (95%); pale yellow crystalline solid; mp 105 °C; R_f = 0.20 (EtOAc/hexane 1:3).

IR (ATR): 3291, 3030, 2940, 1638, 1542, 1510, 1391, 1222, 1165, 1138, 781, 737, 695, 525, 521, 423 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (dd, J = 8.1, 1.6 Hz, 1 H), 8.60 (dd, J = 4.5, 1.6 Hz, 1 H), 7.40–7.26 (m, 9 H), 5.66 (s, 2 H), 4.68 (d, J = 6.0 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.7 Hz), 161.7, 149.6, 138.2, 136.9, 132.2, 132.0 (d, J _C,F = 3.2 Hz), 129.7 (d, J _C,F = 8.2 Hz), 128.7, 127.9, 127.5, 118.9, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 50.4, 43.0.

¹⁹F NMR (376 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₁₈FN₄O: 361.1459; found: 361.1465.

1-(4-Fluorobenzyl)-N-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (17)

Yield: 102 mg (93%); colorless oil; R_f = 0.56 (EtOAc/hexane 1:1).

IR (ATR): 3415, 3320, 3068, 3006, 2934, 2836, 1659, 1534, 1510, 1245, 1223, 1172, 1033, 812, 782, 774, 520 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.70 (dd, J = 8.1, 1.6 Hz, 1 H), 8.59 (dd, J = 4.5, 1.6 Hz, 1 H), 7.33–7.25 (m, 6 H), 7.00–6.93 (m, 2 H), 6.91–6.86 (m, 2 H), 5.65 (s, 2 H), 4.61 (d, J = 6.0 Hz, 2 H), 3.80 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.6 Hz), 161.6, 159.0, 151.0, 149.6, 137.0, 132.1, 132.0 (d, J _C,F = 3.2 Hz), 130.2, 129.7 (d, J _C,F = 8.2 Hz), 129.2, 118.8, 115.5 (d, J _C,F = 21.6 Hz), 114.8, 114.1, 55.2, 50.3, 42.5.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₀FN₄O₂: 391.1565; found: 391.1557.

N-(3,3-Dimethyl-2-oxobutyl)-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (18)

Yield: 96 mg (93%); colorless oil; R_f = 0.17 (EtOAc/hexane 3:7).

IR (ATR): 3398, 3312, 3064, 2970, 2936, 2872, 1717, 1661, 1531, 1510, 1493, 1222, 1158, 781, 755, 608, 562, 520, 483 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.63 (dd, J = 8.0, 1.6 Hz, 1 H), 8.59 (dd, J = 4.5, 1.6 Hz, 1 H), 7.75 (t, J = 4.5 Hz, 1 H), 7.40–7.35 (m, 2 H), 7.26 (dd, J = 8.1, 4.5 Hz, 1 H), 7.03–6.95 (m, 2 H), 5.70 (s, 2 H), 4.51 (d, J = 4.7 Hz, 2 H), 1.26 (s, 9 H).

¹³C NMR (75 MHz, CDCl₃): δ = 210.3, 162.5 (d, J _C,F = 246.7 Hz), 161.9, 151.0, 149.6, 136.6, 132.0 (d, J _C,F = 3.2 Hz), 131.9, 130.0 (d, J _C,F = 8.2 Hz), 118.9, 115.6 (d, J _C,F =21.5 Hz), 114.8, 50.5, 44.3, 43.2, 24.6.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.2.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₂FN₄O₂: 369.1721; found: 369.1723.

1-(4-Fluorobenzyl)-N-(pyrazin-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (19)

Yield: 96 mg (95%); yellow crystalline solid; mp 159 °C; R_f = 0.27 (EtOAc­/hexane 3:1).

IR (ATR): 3539, 3411, 3314, 3061, 2936, 1660, 1536, 1510, 1493, 1392, 1272, 1222, 1158, 1018, 811, 773, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.71 (d, J = 1.1 Hz, 1 H), 8.66 (dd, J = 8.1, 1.6 Hz, 1 H), 8.59 (dd, J = 4.5, 1.6 Hz, 1 H), 8.54 (dd, J = 2.4, 1.5 Hz, 1 H), 8.50 (d, J = 2.5 Hz, 1 H), 7.92 (t, J = 5.4 Hz, 1 H), 7.36–7.31 (m, 2 H), 7.27 (dd, J = 8.1, 4.5 Hz, 1 H), 7.01–6.94 (m, 2 H), 5.69 (s, 2 H), 4.85 (d, J = 5.9 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.7 Hz), 162.0, 152.8, 151.0, 149.6, 144.0, 143.9, 143.5, 136.6, 131.94 (d, J _C,F = 2.8 Hz), 131.92, 129.7 (d, J _C,F = 8.2 Hz), 118.9, 115.5 (d, J _C,F = 21.7 Hz), 114.8, 50.4, 42.1.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₉H₁₆FN₆O: 363.1364; found: 363.1358.

1-(4-Fluorobenzyl)-N-(4-nitrobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (22)

Yield: 95 mg (84%); pale yellow solid; mp 160 °C; R_f = 0.27 (EtOAc/ hexane 2:3).

IR (ATR): 3411, 3312, 3073, 2937, 1662, 1510, 1499, 1343, 1222, 731 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.66 (dd, J = 8.1, 1.5 Hz, 1 H), 8.62 (dd, J = 4.5, 1.5 Hz, 1 H), 8.18 (d, J = 8.7 Hz, 2 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.35–7.27 (m, 4 H), 7.01–6.95 (m, 2 H), 5.68 (s, 2 H), 4.76 (d, J = 6.3 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.5 (d, J _C,F = 246.9 Hz), 162.1, 151.1, 149.9, 147.3, 145.9, 136.5, 132.00, 131.95 (d, J _C,F = 3.5 Hz), 129.8 (d, J _C,F = 8.2 Hz), 128.3, 123.9, 119.2, 115.7 (d, J _C,F = 21.6 Hz), 114.8, 50.5, 42.4.

¹⁹F NMR (282 MHz, CDCl₃): δ = –113.9.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₁₇FN₅O₃: 406.1310; found: 406.1308.

1-(4-Fluorobenzyl)-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (23)

Yield: 101 mg (84%); beige crystalline solid; mp 138 °C; R_f = 0.23 (EtOAc­/hexane 3:7).

IR (ATR): 3422, 3317, 3064, 2940, 1660, 1533, 1510, 1323, 1270, 1224, 1159, 1120, 1110, 1066, 837, 810, 782, 773 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (dd, J = 8.1, 1.6 Hz, 1 H), 8.60 (dd, J = 4.5, 1.6 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.50–7.44 (m, 3 H), 7.35–7.25 (m, 3 H), 7.01–6.93 (m, 2 H), 5.67 (s, 2 H), 4.72 (d, J = 6.2 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.5 (d, J _C,F = 246.8 Hz), 162.0, 151.1, 149.8, 142.4 (app d, J _C,F = 0.9 Hz), 136.7, 132.1, 132.0 (d, J _C,F = 3.3 Hz), 129.81 (d, J _C,F = 8.2 Hz), 129.78 (q, J _C,F = 32.4 Hz), 128.0, 125.7 (q, J _C,F = 3.8 Hz), 124.1 (q, J _C,F = 272.0 Hz), 119.1, 115.6 (q, J _C,F = 21.6 Hz), 114.9, 50.5, 42.5.

¹⁹F NMR (282 MHz, CDCl₃): δ = –62.5, –114.0.

HRMS-ESI: m/z [M + H]+ calcd for C₂₂H₁₇F₄N₄O: 429.1333; found: 429.1326.

1-(4-Fluorobenzyl)-N-(4-methylbenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (24)

Yield: 93 mg (89%); pale yellow crystalline solid; mp 136 °C; R_f = 0.60 (EtOAc/hexane 1:1).

IR (ATR): 3419, 3316, 3064, 3023, 2924, 2859, 1658, 1531, 1509, 1498, 1390, 1269, 1222, 1158, 811, 781, 774, 483 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.69 (dd, J = 8.1, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.33–7.24 (m, 6 H), 7.15 (d, J = 7.9 Hz, 2 H), 7.00–6.92 (m, 2 H), 5.64 (s, 2 H), 4.63 (d, J = 6.1 Hz, 2 H), 2.33 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.6 Hz), 161.7, 151.0, 149.6, 137.2, 137.0, 135.1, 132.2, 132.0 (d, J _C,F = 3.2 Hz), 129.7 (d, J _C,F = 8.2 Hz), 129.4, 127.9, 118.9, 115.5 (d, J _C,F = 21.7 Hz), 114.9, 50.4, 42.8, 21.0.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₀FN₄O: 375.1616; found: 375.1607.

N-(4-Bromobenzyl)-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (25)

Yield: 111 mg (90%); colorless crystalline solid; mp 143–144 °C; R_f = 0.60 (EtOAc/hexane 1:1).

IR (ATR): 3413, 3316, 3064, 2936, 1548, 1531, 1509, 1488, 1269, 1222, 1158, 1011, 810, 775, 520, 483 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.67 (dd, J = 8.1, 1.6 Hz, 1 H), 8.59 (dd, J = 4.5, 1.6 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.38 (t, J = 5.6 Hz, 1 H), 7.34–7.23 (m, 5 H), 7.00–6.92 (m, 2 H), 5.65 (s, 2 H), 4.61 (d, J = 6.2 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.6 Hz), 161.8, 151.0, 149.7, 137.3, 136.7, 132.05, 131.96 (d, J _C,F = 3.2 Hz), 131.7, 129.7 (d, J _C,F = 8.2 Hz), 129.4, 121.4, 119.0, 115.6 (d, J _C,F = 21.6 Hz), 114.8, 50.4, 42.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₁₇ ⁷⁹BrFN₄O: 439.0564; found: 439.0549.

1-(4-Fluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (26)

Yield: 107 mg (98%); colorless oil; R_f = 0.17 (EtOAc/hexane 1:4).

IR (ATR): 3409, 3334, 3060, 2977, 2935, 1669, 1522, 1510, 1269, 1222, 1158, 849, 781, 762, 698, 563, 547, 520, 484 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (dd, J = 8.1, 1.6 Hz, 1 H), 8.56 (dd, J = 4.5, 1.6 Hz, 1 H), 7.51–7.48 (m, 2 H), 7.37–7.33 (m, 5 H), 7.26–7.19 (m, 2 H), 7.03–6.98 (m, 2 H), 5.70 (s, 2 H), 1.85 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.6 Hz), 160.9, 151.0, 149.5, 146.8, 137.6, 132.4, 132.1 (d, J _C,F = 3.2 Hz), 129.7 (d, J _C,F = 8.2 Hz), 128.4, 126.7, 124.7, 118.7, 115.6 (d, J _C,F = 21.6 Hz), 114.8, 55.9, 50.4, 29.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₃H₂₁FN₄ONa: 411.1591; found: 411.1574.

N-[(3s,5s,7s)-Adamantan-1-yl]-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (27)

Yield: 108 mg (95%); colorless oil; R_f = 0.50 (EtOAc/hexane 3:7).

IR (ATR): 3402, 3312, 2907, 2850, 1665, 1529, 1510, 1494, 1277, 1223, 861, 778, 731, 519, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.67 (dd, J = 8.1, 1.6 Hz, 1 H), 8.57 (dd, J = 4.5, 1.7 Hz, 1 H), 7.35–7.28 (m, 2 H), 7.24 (dd, J = 8.1, 4.5 Hz, 1 H), 7.03–6.95 (m, 2 H), 6.77 (br s, 1 H), 5.67 (s, 2 H), 2.18–2.14 (m, 9 H), 1.78–1.69 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.5 Hz), 161.2, 151.0, 149.4, 137.9, 132.3, 132.2 (d, J _C,F = 3.2 Hz), 129.6 (d, J _C,F = 8.3 Hz), 118.7, 115.5 (d, J _C,F = 21.6 Hz), 114.8, 52.0, 50.3, 41.7, 36.3, 29.4.

¹⁹F NMR (376 MHz, CDCl₃): δ = –114.2.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₄H₂₆FN₄O: 405.2085; found: 405.2082.

N-[(1R,2R,4S)-Bicyclo[2.2.1]heptan-2-yl]-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (28)

Yield: 100 mg (98%); amber oil; [α]_D ²⁵ +4.50 (c 0.10, CHCl₃); R_f = 0.33 (EtOAc/hexane 3:7).

IR (ATR): 3423, 3317, 3068, 2952, 2871, 1652, 1526, 1510, 1493, 1275, 1222, 1157, 781, 730, 520, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.67 (dd, J = 8.1, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.7 Hz, 1 H), 7.35–7.28 (m, 2 H), 7.25 (dd, J = 8.2, 4.6 Hz, 1 H), 7.02–6.94 (m, 2 H), 6.85 (d, J = 7.2 Hz, 1 H), 5.68 (s, 2 H), 3.95 (app dt, J = 7.5, 3.5 Hz, 1 H), 2.38–2.34 (m, 2 H), 1.93–1.86 (m, 1 H), 1.63–1.05 (m, 7 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.6 Hz), 161.1, 151.1, 149.6, 137.3, 132.3, 132.2 (d, J _C,F = 3.3 Hz), 129.7 (d, J _C,F = 8.2 Hz), 118.8, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 52.6, 50.4, 42.5, 40.3, 35.76, 35.71, 28.2, 26.5.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.2.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₂₂FN₄O: 365.1772; found: 365.1769.

1-(4-Fluorobenzyl)-N-[2-(methylsulfonyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (29)

Yield: 50 mg (96%); colorless oil; R_f = 0.23 (EtOAc/hexane 3:1).

IR (ATR): 3287, 3030, 3004, 2953, 2927, 1656, 1542, 1511, 1291, 1273, 1220, 1128, 956, 766, 625, 522, 500, 484, 418 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.61 (dd, J = 3.7, 1.6 Hz, 1 H), 8.59 (s, 1 H), 7.64 (t, J =6.1 Hz, 1 H), 7.39–7.32 (m, 2 H), 7.29–7.25 (m, 1 H), 7.02–6.94 (m, 2 H), 5.67 (s, 2 H), 4.00 (dd, J = 6.1, 6.1 Hz, 2 H), 3.40 (t, J = 6.1 Hz, 2 H), 2.99 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.9 Hz), 162.2, 150.9, 149.7, 136.2, 131.8 (d, J _C,F = 3.3 Hz), 131.7, 129.9 (d, J _C,F = 8.2 Hz), 119.0, 115.5 (d, J _C,F = 21.6 Hz), 114.7, 54.0, 50.5, 41.7, 33.0.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₇H₁₈FN₄O₃S: 377.1078; found: 377.1074.

1-(4-Fluorobenzyl)-N-{2-[(4-methylphenyl)sulfonamido]ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (30)

Yield: 120 mg (92%); beige solid; mp 142 °C; R_f = 0.48 (EtOAc).

IR (ATR): 3265, 3063, 2935, 2876, 1652, 1538, 1510, 1156, 1092, 907, 727, 661, 549 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.54 (dd, J = 4.5, 1.2 Hz, 1 H), 8.52 (dd, J = 8.1, 1.6 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.43 (t, J = 6.1 Hz, 1 H), 7.36–7.30 (m, 2 H), 7.20 (dd, J = 8.1, 4.5 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.99–6.91 (m, 2 H), 5.87 (t, J = 5.9 Hz, 1 H), 5.60 (s, 2 H), 3.58 (dt, J = 5.9, 5.8 Hz, 2 H), 3.22 (dt, J = 5.9, 5.8 Hz, 2 H), 2.27 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.5, 162.4 (d, J _C,F = 246.6 Hz), 150.6, 149.4, 143.2, 136.7, 136.3, 131.83 (d, J _C,F = 3.2 Hz), 131.79, 129.9 (d, J _C,F = 8.5 Hz), 129.5, 126.9, 118.9, 115.5 (d, J _C,F = 21.7 Hz), 114.6, 50.3, 43.2, 39.0, 21.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₃H₂₃FN₅O₃S: 468.1500; found: 468.1497.

1-(4-Fluorobenzyl)-N-(2-methylallyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (31)

Yield: 89 mg (98%); dark red oil; R_f = 0.30 (EtOAc/hexane 3:7).

IR (ATR): 3526, 3424, 3321, 3073, 2974, 2923, 1652, 1532, 1509, 1270, 1221, 1158, 810, 772, 483, 419 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.68 (dd, J = 8.1, 1.7 Hz, 1 H), 8.59 (dd, J = 4.5, 1.6 Hz, 1 H), 7.37–7.30 (m, 2 H), 7.26 (dd, J = 8.1, 4.5 Hz, 1 H), 7.17 (t, J = 5.6 Hz, 1 H), 7.02–6.94 (m, 2 H), 5.68 (s, 2 H), 4.96–4.89 (m, 2 H), 4.04 (d, J = 6.3 Hz, 2 H), 1.81 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.7 Hz), 161.7, 151.0, 149.6, 141.9, 136.9, 132.1, 132.0 (d, J _C,F = 3.2 Hz), 129.7 (d, J _C,F = 8.2 Hz), 118.8, 115.5 (d, J _C,F = 21.6 Hz), 114.8, 111.2, 50.3, 44.5, 20.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –14.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₈H₁₈FN₄O: 325.1459; found: 325.1465.

1-(4-Fluorobenzyl)-N-(2-methylbut-3-yn-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (32)

Yield: 58 mg (62%); colorless oil; R_f = 0.42 (EtOAc/hexane 3:7).

IR (ATR): 3411, 3301, 3253, 3060, 2983, 2936, 1669, 1523, 1510, 1493, 1382, 1269, 1221, 1158, 858, 776, 730, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.70 (dd, J = 8.1, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.34–7.29 (m , 2 H), 7.26 (dd, J = 8.1, 4.5 Hz, 1 H), 7.10 (br s, 1 H), 7.63–6.95 (s, 2 H), 2.42 (s, 1 H), 1.80 (s, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.5 (d, J _C,F = 246.6 Hz), 161.0, 151.1, 149.7, 137.2, 132.3, 132.1 (d, J _C,F = 3.3 Hz), 129.7 (d, J _C,F = 8.2 Hz), 118.9, 115.6 (d, J _C,F = 21.6 Hz), 114.8, 87.0, 69.4, 50.4, 47.4, 29.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₉H₁₈FN₄O: 337.1459; found: 337.1449.

1-(4-Fluorobenzyl)-N-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (33)

Yield: 83 mg (94%); colorless solid; mp 108 °C; R_f = 0.27 (EtOAc/ hexane­ 1:3).

IR (ATR): 3415, 3321, 3071, 2937, 2877, 1650, 1539, 1509, 1494, 1392, 1272, 1221, 1171, 1159, 1061, 774, 520, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.60 (dd, J = 8.1, 1.6 Hz, 1 H), 8.56 (dd, J = 4.5, 1.6 Hz, 1 H), 7.50 (t, J = 5.3 Hz, 1 H), 7.32–7.27 (m, 2 H), 7.22 (dd, J = 8.1, 4.5 Hz, 1 H), 6.99–6.92 (m, 2 H), 5.63 (s, 2 H), 3.86–3.83 (m, 2 H), 3.67–3.61 (m, 2 H), 2.95 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.7, 162.3 (d, J _C,F = 246.7 Hz), 150.8, 149.6, 136.7, 132.0, 131.9 (d, J _C,F = 3.0 Hz), 129.7 (d, J _C,F = 8.5 Hz), 118.9, 115.5 (d, J _C,F = 21.8 Hz), 114.7, 62.0, 50.3, 42.0.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₆H₁₆FN₄O₂: 315.1252; found: 315.1198.

1-(4-Fluorobenzyl)-N-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (34)

Yield: 93 mg (97%); amber oil; R_f = 0.20 (EtOAc/hexane 1:1).

IR (ATR): 3412, 3068, 2973, 2932, 1740, 1651, 1539, 1510, 1392, 1274, 1222, 1158, 1139, 919, 812, 774, 610, 521, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.64 (dd, J = 8.1, 1.7 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.46 (t, J = 6.1 Hz, 1 H), 7.36–7.22 (m, 2 H), 7.24 (dd, J = 8.1, 4.5 Hz, 1 H), 7.01–6.93 (m, 2 H), 5.67 (s, 2 H), 3.50 (d, J = 6.3 Hz, 2 H), 2.81 (s, 1 H), 1.31 (s, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.8, 162.5 (d, J _C,F = 246.7 Hz), 151.0, 149.6, 136.8, 132.1, 132.0 (d, J _C,F = 3.3 Hz), 129.8 (d, J _C,F = 8.3 Hz), 118.9, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 71.1, 50.4, 50.0, 27.4.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1

HRMS-ESI: m/z [M + Na]⁺ calcd for C₁₈H₁₉FN₄O₂Na: 365.1384; found: 365.1386.

1-(4-Fluorobenzyl)-N-(2-oxoazepan-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (35)

Yield: 95 mg (89%); beige crystalline solid; mp 218–219 °C; R_f = 0.63 (EtOAc/hexane 3:1).

IR (ATR): 3381, 3291, 3073, 2933, 2854, 1650, 1510, 1222, 910, 783, 727, 576 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.63 (dd, J = 8.1, 1.5 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 8.30 (d, J = 6.2 Hz, 1 H), 7.41–7.35 (m, 2 H), 7.25 (dd, J = 8.1, 4.6 Hz, 1 H), 7.02–6.94 (m, 2 H), 6.56 (t, J = 6.1 Hz, 1 H), 5.71 (ABq, ΔδAB = 0.05, J _A,B =14.9 Hz, 2 H), 4.78 (ddd, J = 11.0, 6.3, 1.5 Hz, 1 H), 3.42–3.25 (m, 2 H), 2.28–2.24 (m, 1 H), 2.11–2.04 (m, 1 H), 1.99–1.85 (m, 2 H), 1.72–1.58 (m, 1 H), 1.53–1.39 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 175.3, 162.4 (d, J _C,F = 246.5 Hz), 161.1, 150.9, 149.4, 136.7, 132.0 (d, J _C,F = 3.3 Hz), 131.8, 129.9 (d, J _C,F = 8.2 Hz), 118.8, 115.5 (d, J _C,F = 21.6 Hz), 114.9, 52.0, 50.4, 42.1, 31.7, 29.0, 28.0.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.3.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₁FN₅O₂: 382.1674; found: 382.1666.

Methyl [1-(4-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]-l-phenylalaninate [(S)-36]

Yield: 117 mg (97%); pale yellow oil; [α]_D ²⁵ +46.5 (c 0.10, CHCl₃); R_f = 0.13 (EtOAc/hexane 1:3).

IR (ATR): 3415, 3325, 3068, 3034, 2952, 1740, 1663, 1526, 1510, 1278, 1219, 1169, 781, 730, 700, 520, 483 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.61 (dd, J = 8.0, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.38–7.33 (m, 2 H), 7.30–7.16 (m, 6 H), 7.03–6.95 (m, 2 H), 5.66 (ABq, ΔδAB = 0.06, J _A,B = 14.9 Hz, 2 H), 5.09 (dt, J = 8.1, 6.1 Hz, 1 H), 3.74 (ABX, J _A,B = 13.9 Hz, J _B,X = 6.2 Hz, J _A,X = 6.0 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.9, 162.5 (d, J _C,F = 246.6 Hz), 161.4, 151.0, 149.6, 136.3, 135.9, 132.0 (d, J _C,F = 3.7 Hz), 131.9, 130.0 (d, J _C,F = 8.2 Hz), 129.3, 128.6, 127.1, 119.0, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 52.9, 52.4, 50.5, 38.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₄H₂₂FN₄O₃: 433.1670; found: 433.1664.

Methyl [1-(4-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]-d-phenylalaninate [(R)-36]

Yield: 109 mg (90%); colorless oil; [α]_D ²⁵ –31.0 (c 0.10, CHCl₃); R_f = 0.13 (EtOAc/hexane 1:3).

IR (ATR): 3411, 3330, 3064, 3029, 2952, 1740, 1663, 1527, 1511, 1493, 1279, 1219, 1169, 1158, 782, 731, 701, 484 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.62 (dd, J = 8.0, 1.4 Hz, 1 H), 8.58 (dd, J = 4.5, 1.4 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.37–7.34 (m, 2 H), 7.29–7.23 (m, 4 H), 7.19–7.17 (m, 2 H), 7.01–6.98 (m, 2 H), 5.67 (ABq, ΔδAB = 0.06, J _A,B = 15.0 Hz, 2 H), 5.10 (dt, J = 7.9, 6.2 Hz, 1 H), 3.75 (s, 3 H, ABX, J _A,B = 13.9 Hz, J _B,X = 6.2 Hz, J _A,X = 6.1 Hz, 2 H).

¹³C NMR (150 MHz, CDCl₃): δ = 171.9, 162.5 (d, J _C,F = 246.5 Hz), 161.3, 150.9, 149.5, 136.2, 135.9, 131.97, 131.96, 130.0 (d, J _C,F = 8.1 Hz), 129.3, 128.6, 127.1, 119.0, 115.6 (d, J _C,F = 21.8 Hz), 114.9, 52.9, 52.4, 50.5, 38.2.

¹⁹F NMR (565 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₄H₂₂FN₄O₃: 433.1670; found: 433.1664.

N-(1-Carbamoylcyclopentyl)-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (37)

Yield: 30 mg (28%); colorless solid; mp 209–210 °C; R_f = 0.43 (EtOAc/ hexane 1:1).

IR (ATR): 3364, 2966, 2880, 1752, 1652, 1509, 1470, 1220, 1124, 773, 556, 521, 485 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.66 (dd, J = 8.0, 1.0 Hz, 1 H), 8.46 (dd, J = 4.5, 1.2 Hz, 1 H), 8.51 (br s, 1 H), 7.37–7.35 (m, 2 H), 7.29 (dd, J = 8.0, 4.6 Hz, 1 H), 7.00–6.98 (m, 2 H), 5.70 (s, 2 H), 2.11–1.93 (m, 8 H).

¹³C NMR (150 MHz, CDCl₃): δ = 186.4, 162.5 (d, J _C,F = 246.6 Hz), 151.8, 151.1, 150.0, 133.5, 132.1, 131.9 (d, J _C,F = 3.2 Hz), 130.0 (d, J _C,F = 8.3 Hz), 118.8, 115.6 (d, J _C,F = 21.6 Hz), 114.1, 78.7, 50.5, 37.7, 26.1.

¹⁹F NMR (282 MHz, CDCl₃): δ = –113.9.

HRMS-ESI: m/z [M – H₂O]⁺ calcd for C₂₀H₁₈FN₅O: 364.1568; found: 364.1567.

1-(4-Fluorobenzyl)-N-(1-{[1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]carbamoyl}cyclopentyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (38)

Yield: 52 mg (59%); colorless solid; mp 214–215 °C; R_f = 0.23 (EtOAc/ hexane 1:1).

IR (ATR): 3360, 2964, 2883, 1752, 1652, 1509, 1470, 1220, 1124, 773, 556, 521, 485, 422 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 10.95 (s, 1 H), 8.64–8.61 (m, 2 H), 8.59–8.56 (m, 2 H), 7.42 (s, 1 H), 7.41–7.39 (m, 2 H), 7.28–7.26 (m, 1 H), 7.24 (dd, J = 8.1, 4.5 Hz, 1 H), 7.06–7.03 (m, 2 H), 6.97 (app t, J = 8.6 Hz, 2 H), 6.62 (app t, J = 8.6 Hz, 2 H), 5.71 (s, 2 H), 5.44 (s, 2 H), 2.67–2.62 (m, 2 H), 2.26–2.22 (m, 2 H), 1.96–1.85 (m, 4 H).

¹³C NMR (151 MHz, CDCl₃): δ = 171.5, 162.5 (d, J _C,F = 246.8 Hz), 162.4, 162.3 (d, J _C,F =246.7 Hz), 159.2, 151.0, 149.99, 149.97, 136.3, 136.1, 131.96, 131.91, 131.8 (d, J _C,F = 3.1 Hz), 131.4 (d, J = 3.2 Hz), 130.0 (d, J _C,F =7.9 Hz), 129.6 (d, J _C,F = 8.4 Hz), 119.6, 119.2, 115.7 (d, J _C,F = 22.0 Hz), 115.3 (d, J _C,F = 21.6 Hz), 114.7, 68.4, 50.64, 50.58, 36.9, 24.2.

¹⁹F NMR (282 MHz, CDCl₃): δ = –113.66, –113.79.

HRMS-ESI: m/z [M + H]⁺ calcd for C₃₄H₂₉F₂N₈O₃: 635.2325; found: 635.2318.

1-(4-Fluorobenzyl)-N-(thiophen-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (39)

Yield: 97 mg (95%); colorless crystalline solid; mp 129 °C; R_f = 0.27 (EtOAc/hexane 3:7).

IR (ATR): 3410, 3318, 3071, 2932, 1659, 1526, 1510, 1391, 1221, 1158, 810, 781, 701, 520, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.68 (dd, J = 8.1, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.44 (t, J = 5.6 Hz, 1 H), 7.33–7.20 (m, 4 H), 7.04 (dd, J = 3.4, 1.0 Hz, 1 H), 6.99–6.91 (m, 3 H), 5.64 (s, 2 H), 4.83 (d, J = 6.0 Hz, 2 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.3 (d, J _C,F = 246.5 Hz), 161.4, 150.9 149.5, 140.7, 136.7, 132.1, 131.9 (d, J _C,F = 3.2 Hz), 129.7 (d, J _C,F = 8.1 Hz), 126.8, 126.1, 125.2, 118.9, 115.5 (d, J _C,F = 21.9 Hz), 114.8, 50.3, 37.6.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₉H₁₆FN₄OS: 367.1023; found: 367.1019.

1-(4-Fluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (40)

Yield: 97 mg (98%); beige solid; mp 186–189 °C; R_f = 0.20 (EtOAc/hexane 1:1).

IR (ATR): 3526, 3411, 3314, 3073, 2954, 2848, 1652, 1530, 1510, 1494, 1384, 1222, 1139, 1088, 811, 776, 781, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.66 (dd, J = 8.1, 1.6 Hz, 1 H), 8.59 (dd, J = 4.5, 1.7 Hz, 1 H), 7.37–7.30 (m, 2 H), 7.27 (dd, J = 8.1, 4.5 Hz, 1 H), 7.03–6.95 (m, 2 H), 6.91 (d, J = 8.0 Hz, 1 H), 5.69 (s, 2 H), 4.24 (tdt, J = 11.8, 8.1, 4.1 Hz, 1 H), 4.02 (ddd, J = 12.0, 3.9, 2.8 Hz, 2 H), 3.55 (ddd, J = 11.7, 11.7, 2.1 Hz, 2 H), 2.05–2.00 (m, 2 H), 1.66 (dddd, J = 12.8, 11.4, 11.4, 4.5 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.5 (d, J _C,F = 246.8 Hz), 161.2, 151.1, 149.7, 137.0, 132.14, 132.10 (d, J _C,F = 3.3 Hz), 129.7 (d, J _C,F = 8.2 Hz), 118.9, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 66.8, 50.4, 45.5, 33.2.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.1

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₉H₂₀FN₄O₂: 355.1565; found: 355.1558.

1-(4-Fluorobenzyl)-N-(piperidin-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (41)

Yield: 95 mg (89%); colorless oil; R_f = 0.30 (1% v/v NEt₃ in MeOH/CH₂Cl₂ 1:39).

IR (ATR): 3410, 3300, 2933, 2856, 1651, 1538, 1510, 1271, 1222, 1159, 915, 810, 781, 730, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.51 (dd, J = 4.5, 1.6 Hz, 1 H), 8.48 (dd, J = 8.1, 1.6 Hz, 1 H), 7.89 (t, J = 5.5 Hz, 1 H), 7.39–7.32 (m, 2 H), 7.18 (dd, J = 8.1, 4.5 Hz, 1 H), 6.99–6.91 (m, 2 H), 5.59–5.56 (m, 3 H), 3.89–3.79 (m, 2 H), 3.50–3.43 (m, 2 H), 2.93–2.83 (m, 1 H), 1.98–1.70 (m, 5 H), 1.56–1.48 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 163.1, 162.3 (d, J _C,F = 246.7 Hz), 150.6, 149.5, 136.0, 131.7 (d, J _C,F = 3.2 Hz), 131.4, 130.0 (d, J _C,F = 8.3 Hz), 118.9, 115.5 (d, J _C,F = 21.6 Hz), 114.4, 57.0, 50.3, 45.2, 42.3, 26.9, 22.6, 22.3.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₁₆FN₄O: 368.1881; found: 368.1877.

1-(4-Fluorobenzyl)-N-phenyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (42)

Yield: 96 mg (99%); brown oil; R_f = 0.42 (EtOAc/hexane 3:7).

IR (ATR): 3389, 3312, 3193, 3060, 3021, 2940, 1674, 1595, 1531, 1510, 1461, 1312, 1223, 1157, 1121, 781, 753, 691 cm^–1.

1H NMR (300 MHz, CDCl₃): δ = 8.82 (s, 1 H), 8.70 (dd, J = 8.1, 1.6 Hz, 1 H), 8.61 (dd, J = 4.5, 1.6 Hz, 1 H), 7.72 (dd, J = 8.6, 1.0 Hz, 2 H), 7.40–7.31 (m, 4 H), 7.27 (dd, J = 8.1, 4.5 Hz, 1 H), 7.13 (ddd, J = 7.4, 1.1, 1.1 Hz, 1 H), 7.03–6.95 (m, 2 H), 5.71 (s, 2 H).

13C NMR (75 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.9 Hz), 159.6, 151.2, 149.8, 137.5, 137.0, 132.1, 131.9 (d, J _C,F = 3.3 Hz), 129.8 (d, J _C,F = 8.2 Hz), 129.0, 124.3, 119.8, 119.1, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 50.5.

19F NMR (282 MHz, CDCl₃): δ = –113.9.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₁₆FN₄O: 347.1303; found: 347.1303.

1-(4-Fluorobenzyl)-N-(o-tolyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (43)

Yield: 96 mg (95%); colorless crystalline solid; mp 130 °C; R_f = 0.30 (EtOAc/hexane 1:4).

IR (ATR): 3407, 3064, 3021, 2979, 2936, 2867, 1681, 1589, 1530, 1510, 1462, 1222, 1157, 1126, 842, 775, 754, 606 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.76 (br s, 1 H), 8.71 (dd, J = 8.1, 1.6 Hz, 1 H), 8.62 (dd, J = 4.5, 1.6 Hz, 1 H), 8.13 (dd, J = 8.0, 0.8 Hz, 1 H), 7.42–7.35 (m, 2 H), 7.31–7.21 (m, 3 H), 7.09 (dt, J = 7.4, 1.2 Hz, 1 H), 7.04–6.97 (m, 2 H), 5.73 (s, 2 H), 2.38 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.5 (d, J _C,F = 246.9 Hz), 159.6, 151.2, 149.8, 137.2, 135.5, 132.1, 131.9 (d, J _C,F = 3.3 Hz), 130.5, 129.9 (d, J _C,F = 8.2 Hz), 128.2, 126.8, 124.8, 122.0, 119.1, 115.6 (d, J _C,F = 21.6 Hz), 114.9, 50.5, 17.6.

¹⁹F NMR (282 MHz, CDCl₃): δ = –113.9.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₁₈FN₄O: 361.1459; found: 361.1456.

1-(4-Fluorobenzyl)-N,N-dimethyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (46)

Yield: 69 mg (82%); beige crystalline solid; mp 92 °C; R_f = 0.27 (EtOAc/ hexane 1:1).

IR (ATR): 3061, 3023, 2936, 1622, 1509, 1276, 1221, 1154, 1107, 1011, 895, 793, 780, 680, 521, 484 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.58 (dd, J = 4.5, 1.4 Hz, 1 H), 8.54 (dd, J = 8.1, 1.4 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.23 (dd, J = 8.1, 4.5 Hz, 1 H), 7.00–6.96 (m, 2 H), 5.70 (s, 2 H), 3.47 (s, 3 H), 3.18 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 163.0, 162.3 (d, J _C,F = 246.4 Hz), 150.2, 149.3, 138.1, 132.3, 131.2 (d, J _C,F = 3.1 Hz), 129.7 (d, J _C,F = 7.9 Hz), 118.4, 116.6, 115.5 (d, J _C,F = 21.8 Hz), 50.2, 38.9, 36.2.

¹⁹F NMR (565 MHz, CDCl₃): δ = –114.3.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₆H₁₆FN₄O: 299.1303; found: 299.1300.

1-(4-Fluorobenzyl)-N-methyl-N-phenyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (47)

Yield: 58 mg (57%); beige crystalline solid; mp 127 °C; R_f = 0.07 (EtOAc­/hexane 1:4).

IR (ATR): 3068, 3026, 2936, 1634, 1595, 1509, 1495, 1475, 1338, 1277, 1221, 1112, 979, 864, 774, 697, 484 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.51 (dd, J = 4.5, 1.6 Hz, 1 H), 8.46 (dd, J = 8.1, 1.5 Hz, 1 H), 7.30–7.15 (m, 6 H), 7.03–6.99 (m, 2 H), 6.91–6.85 (m, 2 H), 5.40 (s, 2 H), 3.56 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 163.2, 162.3 (d, J _C,F = 246.1 Hz), 150.0, 149.2, 145.0, 137.6, 132.0 (d, J _C,F = 3.2 Hz), 131.6, 129.9 (d, J _C,F = 8.2 Hz), 129.0, 127.1, 126.8, 118.4, 116.1, 115.2 (d, J _C,F = 21.5 Hz), 50.1, 38.6.

¹⁹F NMR (282 MHz, CDCl₃): δ = –114.6.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₁₈FN₄O: 361.1459; found: 361.1457.

[1-(4-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl](2-oxa-6-aza­spiro[3.3]heptan-6-yl)methanone (50)

Yield: 74 mg (75%); colorless oil; R_f = 0.30 (EtOAc).

IR (ATR): 2944, 2869, 1630, 1509, 1485, 1342, 1221, 976, 857, 786, 731 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.64 (dd, J = 8.0, 1.6 Hz, 1 H), 8.58 (dd, J = 4.5, 1.6 Hz, 1 H), 7.39–7.32 (m, 2 H), 7.24 (dd, J = 8.0, 4.5 Hz, 1 H), 7.04–6.96 (m, 2 H), 5.69 (s, 2 H), 4.85 (s, 4 H), 4.80 (s, 2 H), 4.37 (s, 2 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.3 (d, J _C,F = 246.6 Hz), 161.8, 150.2, 149.4, 137.0, 132.2, 132.0 (d, J _C,F = 3.2 Hz), 129.8 (d, J _C,F = 8.0 Hz), 118.8, 115.7, 115.5 (d, J _C,F = 21.2 Hz), 80.8, 63.1, 57.7, 50.3, 38.9.

¹⁹F NMR (565 MHz, CDCl₃): δ = –114.0.

HRMS-ESI: m/z [M + H]⁺ calcd for C₁₉H₁₈FN₄O₂: 353.1408; found: 353.1410.

(3,4-Dihydroisoquinolin-2(1H)-yl)[1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]methanone (51)

Yield: 106 mg (98%); pale yellow oil; R_f = 0.50 (EtOAc/hexane 1:1).

IR (ATR): 3068, 3030, 2936, 2850, 1620, 1509, 1482, 1443, 1379, 1279, 1222, 1158, 1136, 792, 780, 747, 732 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.58 (dd, J = 4.5, 1.5 Hz, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 7.40–7.35 (m, 2 H), 7.25–7.18 (m, 5 H), 7.02–6.97 (m, 2 H), 5.72 (m, 2 H), 5.29 (s, 1 H), 4.95 (s, 1 H), 4.30 (t, J = 5.6 Hz, 1 H), 4.04 (t, J = 5.6 Hz, 1 H), 3.00 (app t, J = 5.9 Hz, 2 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.4 (d, J _C,F = 246.5 Hz), 162.2, 161.9, 150.2, 149.4, 138.0, 137.8, 134.7, 134.5, 133.5, 133.1, 132.25, 132.18, 129.9, 129.8, 128.8, 128.5, 126.67, 126.64, 126.5, 126.4, 126.3, 125.9, 118.5, 116.6, 115.5 (d, J _C,F = 21.7 Hz), 50.3, 48.8, 45.2, 44.7, 40.9, 29.7, 28.3.

Note: Peaks in ¹³C NMR spectrum split as a ca. 1:1 mixture of rota­mers. Both rotamers are described. Several rotamer peaks missing due to signal overlap.

¹⁹F NMR (565 MHz, CDCl₃): δ = –114.1.

HRMS-ESI: m/z [M + H]⁺ calcd for C₂₃H₂₀FN₄O: 387.1616; found: 387.1604.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors wish to thank Dr. Nuala M. Maguire for assistance with chiral HPLC.

• References

• 1 Zheng W, Wang Z, Jiang X, Zhao Q, Shen J. J. Med. Chem. 2020; 63: 15153
• 2 Smith LM, Ladziata V, Delucca I, Pinto DJ. P, Orwat MJ, Dilger AK, Pabbisetty KB, Yang W, Shaw SA, Glunz PW, Panda M. WO 2017123860A1, 2017
• 3 Shi J, Xu G, Zhu W, Ye H, Yang S, Luo Y, Han J, Yang J, Li R, Wei Y, Chen L. Bioorg. Med. Chem. Lett. 2010; 20: 4273
• 4 Lin R, Connolly PJ, Lu Y, Chiu G, Li S, Yu Y, Huang S, Li X, Emanuel SL, Middleton SA, Gruninger RH, Adams M, Fuentes-Pesquera AR, Greenberger LM. Bioorg. Med. Chem. Lett. 2007; 17: 4297
• 5 Andoh N, Sanpei O, Toga T, Morris DL, Aston R, Tanaka K, Hino T. World Patent WO2015037747A1, 2016
• 6 Xing Y, Zuo J, Krogstad P, Jung ME. J. Med. Chem. 2018; 61: 1688
• 7 Collier PN, Twin HC, Knegtel RM. A, Boyall D, Brenchley G, Davis CJ, Keily S, Mak C, Miller A, Pierard F, Settimo L, Bolton CM, Chiu P, Curnock A, Doyle E, Tanner AJ, Jimenez J. ACS Med. Chem. Lett. 2019; 10: 1134
• 8 Panarese JD, Engers DW, Wu Y, Bronson JJ, Macor JE, Chun A, Rodriguez AL, Felts AS, Engers JL, Loch MT, Emmitte KA, Castelhano AL, Kates MJ, Nader MA, Jones CK, Blobaum AL, Conn PJ, Niswender CM, Hopkins CR, Lindsley CW. ACS Med. Chem. Lett. 2019; 10: 255
• 9 Umar T, Shalini S, Raza MK, Gusain S, Kumar J, Seth P, Tiwari M, Hoda N. Eur. J. Med. Chem. 2019; 175: 2
• 10 Moir M, Lane S, Lai F, Connor M, Hibbs DE, Kassiou M. Eur. J. Med. Chem. 2019; 180: 291
• 11 Aronov A, Lauffer DJ, Li P, Tomlinson RC. WO2003078423A1, 2005
• 12 Lynch BM, Khan MA, Teo HC, Pedrotti F. Can. J. Chem. 1988; 66: 420
• 13 Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K, Radtke M, Schirok H, Schlemmer K, Stahl E, Straub A, Wunder F, Stasch J. ChemMedChem 2009; 4: 853
• 14a Buchler IP, Hayes MJ, Hegde SG, Hockerman SL, Jones DE, Kortum SW, Rico JG, Tenbrink RE, Wu KK. WO2009106980, 2009
• 14b Buchler IP, Hayes MJ, Hegde SG, Hockerman SL, Jones DE, Kortum SW, Rico JG, Tenbrink RE, Wu KK. WO2009106982, 2009
• 15 Buchstaller H, Wilkinson K, Burek K, Nisar Y. Synthesis 2011; 3089
• 16 Blaquiere N, Burch J, Castanedo G, Feng JA, Hu B, Staben S, Wu G, Yuen P. WO 2015025025A1, 2015
• 17 Blake JF, Boyd SA, Cohen F, De Messe J, Fong KC, Gaudino JJ, Kaplan T, Marlow AL, Seo J, Thomas AA, Tian H, Young WB. WO 2007103308, 2007
• 18 Kannaboina P, Raina G, Kumar KA, Das P. Chem. Commun. 2017; 53: 9446
• 19 Brennführer A, Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 4114
• 20 Friis SD, Lindhardt AT, Skrydstrup T. Acc. Chem. Res. 2016; 49: 594
• 21 Neumann KT, Lindhardt AT, Bang-Andersen B, Skrydstrup T. Org. Lett. 2015; 17: 2094
• 22 Bhilare S, Shah J, Gaikwad V, Gupta G, Sanghvi YS, Bhanage BM, Kapdi AR. Synthesis 2019; 51: 4239
• 23 Gockel SN, Hull KL. Org. Lett. 2015; 17: 3236
• 24 Wan Y, Alterman M, Larhed M, Hallberg A. J. Org. Chem. 2002; 67: 6232
• 25 Kaiser NK, Hallberg A, Larhed M. J. Comb. Chem. 2002; 4: 109
• 26 Mamone M, Aziz J, Le Bescont J, Piguel S. Synthesis 2018; 50: 1521
• 27 Babjak M, Caletková O, Ďurišová D, Gracza T. Synlett 2014; 25: 2579
• 28 Friis SD, Taaning RH, Lindhardt AT, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 18114
• 29 Hermange P, Lindhardt AT, Taaning RH, Bjerglund K, Lupp D, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 6061
• 30 Flinker M, Lopez S, Nielsen DU, Daasbjerg K, Jensen F, Skrydstrup T. Synlett 2017; 28: 2439
• 31 Yin Z, Wu X. Org. Process Res. Dev. 2017; 21: 1869
• 32 Markovič M, Lopatka P, Koóš P, Gracza T. Org. Lett. 2015; 17: 5618
• 33 Veryser C, Van Mileghem S, Egle B, Gilles P, De Borggraeve WM. React. Chem. Eng. 2016; 1: 142
• 34 Peng J, Geng H, Wu X. Chem 2019; 5: 526
• 35 Barnard CF. J. Organometallics 2008; 27: 5402
• 36 Fang W, Zhu H, Deng Q, Liu S, Liu X, Shen Y, Tu T. Synthesis 2014; 46: 1689
• 37 Jian X, Yang F, Jiang C, You W, Zhao P. Bioorg. Med. Chem. Lett. 2020; 30: 127025
• 38 Dierkes P, Van Leeuwen PW. N. M. J. Chem. Soc., Dalton Trans. 1999; 1519
• 39 Martinelli JR, Watson DA, Freckmann DM. M, Barder TE, Buchwald SL. J. Org. Chem. 2008; 73: 7102
• 40 Van der Veen LA, Keeven PH, Schoemaker GC, Reek JN. H, Kamer PC. J, Van Leeuwen PW. N. M, Lutz M, Spek AL. Organometallics 2000; 19: 872
• 41 Jover J, Cirera J. Dalton Trans. 2019; 15036
• 42 Doherty S, Knight JG, Ward NA. B, Bittner DM, Wills C, McFarlane W, Clegg W, Harrington RW. Organometallics 2013; 32: 1773
• 43 Roy S, Roy S, Gribble GW. Tetrahedron 2012; 68: 9867
• 44 Beller M, Wu X. A Discussion Between Carbonylation, Noncarbonylation and Decarbonylation. Transition Metal Catalyzed Carbonylation Reactions: Carbonylative Activation of C-X Bonds. Springer-Verlag; Berlin: 2013: 215-221
• 45 Langueux-Tremblay P, Fabrikant A, Arndtsen BA. ACS Catal. 2018; 8: 5350
• 46 Nielsen DU, Taaning RH, Lindhardt AT, Gøgsig TM, Skrydstrup T. Org. Lett. 2011; 13: 4454
• 47 Ismael A, Gevorgyan A, Skrydstrup T, Bayer A. Org. Process Res. Dev. 2020; 24: 2665
• 48 Wannberg J, Larhed M. J. Org. Chem. 2003; 68: 5750
• 49 Åkerbladh L, Schembri LS, Larhed M, Odell LR. J. Org. Chem. 2017; 82: 12520
• 50 Boyarskii VP. Russ. J. Gen. Chem. 2008; 78: 1511
• 51 Gabriele B, Salerno G, Veltri L, Costa M. J. Organomet. Chem. 2001; 622: 84
• 52 Dong Y, Sun S, Yang F, Zhu Y, Zhu W, Qiao H, Wu Y, Wu Y. Org. Chem. Front. 2016; 3: 720
• 53 Hughes NL, Brown CL, Irwin AA, Cao Q, Muldoon MJ. ChemSusChem 2017; 10: 675
• 54 Ran L, Ren Z, Wang Y, Guan Z. Chem. Asian J. 2014; 9: 577
• 55 Das D, Bhanage BM. Adv. Synth. Catal. 2020; 362: 3022

Publikationsverlauf

Eingereicht: 02. Juni 2021

Angenommen nach Revision: 26. Juli 2021

Artikel online veröffentlicht:
26. August 2021