Development of Novel Covalent Inhibitors and Other Scaffolds Through Multicomponent
Reactions
Sutanto, Fandi
DOI:10.33612/diss.133643092
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Publication date: 2020
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Sutanto, F. (2020). Development of Novel Covalent Inhibitors and Other Scaffolds Through Multicomponent Reactions. University of Groningen. https://doi.org/10.33612/diss.133643092
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CHAPTER 4
Multicomponent Reaction Based
Synthesis Of
1-Tetrazolyl-Imidazo[1,5-ɑ]Pyridines
This chapter is published
Santosh Kurhade, Elmar Diekstra, Fandi Sutanto, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, and Alexander Dömling
N N N N N N R2 R3 N H O H2N Ph Ph Ph N C R2 TMS-N3 R1 R1
ABSTRACT
A series of unprecedented tetrazole linked imidazo[1,5-α]pyridines are synthesized from simple and readily available building blocks. The reaction sequence involves an Azido-Ugi-deprotection reaction, followed by acetic anhydride mediated N-acylation-cyclization process to afford the
target heterocycle. Furthermore, the scope of the methodology was extended to diverse R3
-substitutions by employing commercial anhydrides, acid chlorides and acids as an acyl component. The scope for the post-modification reactions is explored and the usefulness of the synthesis is exemplified by an improved 3-step synthesis of a guanylate cyclase stimulator.
4
INTRODUCTION
The design and synthesis of new bis-heterocyclic systems are highly appreciated in modern drug discovery to achieve specific drug-receptor interactions[1]. Tetrazole linked imidazo[1,5-α]pyridine
is such an unprecedented class of bis-heterocycles. Individually, the imidazo[1,5-α]pyridine heterocycle is the core of naturally occurring antimicrobial and anti-neoplastic agent cribrostatin 6[2] as well as many bioactive molecules, for example 5-hydroxytryptamine
4 receptor (5-HT4R)
antagonists[3] and partial agonists,[4] CB2 agonists,[5] HIV protease inhibitors,[6] thromboxane A 2
synthesis inhibitors[7] and guanylate cyclase stimulators[8]. It has also found applications in material
chemistry[9]; and 1,5-disubstituted tetrazoles (1,5-DS-T’s) are bioisosteres of the cis-amide bond
of peptides,[10] which are present in various drugs,[11] such as cilostazol, antibiotics cefonicid and
latamoxef[12]. However, a combination of the two well-known imidazo[α]pyridine and
1,5-DS-T into a bis-heterocyclic system has not been explored much in medicinal chemistry due to limitations in synthetic feasibility (Figure 1). To the best of our knowledge only Schirok et al. have reported a 7-step synthesis of guanylate cyclase stimulator 3-(2-fluorobenzyl)-1-(1H-tetrazol-5-yl)imidazo[1,5-α]pyridine 9, starting from ethyl 2-(pyridin-2-yl) acetate with 1.8% overall yield (Scheme 2).[8] Therefore, developing more practical and efficient synthetic approaches for tetrazole
linked imidazo[1,5-α] pyridines is highly desirable. Our synthetic strategy for such bis-heterocyclic system involves the Ugi-azide four component reaction (Azido-Ugi 4CR)-deprotection to obtain the corresponding pyridin-2-yl(1H-tetrazol-5-yl) methanamine intermediate.[13] The intermediate
amine is then converted to tetrazolyl-imidazo[1,5-α]pyridine, via N-acylation-cyclization process (Figure 1).[14]
Thus, we describe the Ugi-azide four component reaction (Azido-Ugi 4CR) mediated synthesis of diverse analogues of 1-tetrazolyl-imidazo[1,5-α]pyridines.
Figure 1. Conceiving the idea.
RESULTS AND DISCUSSION
Here, we present the synthesis of 1-Tetrazolyl-Imidazo[1,5-α]Pyridines from Azido-Ugi reaction with tritylamine. Example 6a (Table 1, entry 1a) was selected as a model for screening and optimizing the reaction conditions. Equimolar amounts of aldehyde (1, R1 = H), trityl amine 2,
after 18 h. Trityl group-removal under acidic condition (4 N HCl/dioxane) gave the (1-benzyl-1H-tetrazol-5-yl)(pyridin-2-yl) methanamine hydrochloride. Then we tested the cyclization reaction under different reaction conditions, using Ac2O to form 6a. We screened several conditions and varying the reaction parameters such as temperature, base, Ac2O concentration. To our surprise no base was required; only Ac2O [0.5 M] and warming (75 °C). A reaction time of 1 h was found to be optimal, 6a being isolated in quantitative yield. With this optimized conditions in hand, we decided to switch to one pot protocol avoiding the isolation of the Azido-Ugi intermediate. Here the generally observed precipitation of trityl Ugi-azides was of great help. The Azido-Ugi product 5 was quickly isolated by filtration to remove the solvent methanol and subjected to cyclization without any further purification with 4 N HCl/dioxane (3.0 equiv), Ac2O [0.5 M] at 75 °C for 1 h, affording 6a in 85% overall yield. The reaction proceeds via in-situ trityl deprotection, followed by Ac2O mediated N-acylation-cyclization to form 6a. Using the optimized conditions, we next synthesized a series of novel 1-tetrazolyl-3-methylimidazo[1,5-α]pyridines 6b-6m, in a one-pot 2-step manner (Table 1, entries 1b-m). The scope of the substrate was evaluated using diverse isocyanides (3) and picolinaldehydes (1). Overall good to excellent yields were obtained. The highest yield of 90% was observed for product 6h. (Table 1, entry 1b). Additionally, a lower yield was observed for the product 6g (65%, entry 1g) and 6i (60%, entry 1d).
Table 1. Substrate Scope of the 1-Tetrazolyl-3-Methylimidazo[1,5-α]pyridine Synthesis.
Entrya Aldehyde 1 R1 Isocyanide 3 R2 Product 6 Yield(%)b
1a H 6a 85 HN N N N N N R2 N N N N N N R2 H3C N H O H2N Ph Ph Ph N C R2
+
1 2 3 4 6 TMS-N3 PhPh Ph R1 R1 R1 MeOH 16-24 h, rt Ac2O 4 N HCl/dioxane 75 oC, 1 h 54
1e H O 6e 87 1f H O 6f 80 1g H HN 6g 65c 1h H N O O 3 6h 90 1id H O H N Cl 6i 60 1j H MeO 6j 75 1k H 6k 77 1l 6-Me 6l 78 1m 5-Br 6m 74a Reaction scale 1.0 mmol. b Isolated yield. c Indole N-acylated product was isolated in 15 % yield. d Azido-Ugi product (5) was
isolated in 62% yield along with tetrazole regioisomeric product 20% yield.
Several structures have been confirmed by X-ray single crystal analyses [Figure 2 and Supporting Information (SI)]. The following interesting motifs could be observed in solid state: the scaffold in general is flat and therefore always stocking interactions with neighboring molecules are observed. In 6b the tetrazole, whereas in 6l the imidazopyridine moieties stack antiparallel, respectively. In
Figure 2. X-ray structures of selected products.
Encouraged by the initial results, we investigated more diverse synthesis by changing the R3 -substitutions on tetrazolyl-imidazo[1,5-α]pyridine core 8 according to our 2-steps procedure. Accordingly, step-1 involved the trityl deprotection of the Azido-Ugi 4CR product 5 under acidic condition (4 N HCl/dioxane, 10 min) gave the corresponding intermediate pyridin-2-yl (1H-tetrazol-5-yl) methanamine (intermediate a) as a HCl salt[13]. In step-2, intermediate a was N-acylated using
7 as commercial anhydrides or acid chlorides in DCM and NEt3 (2.2 equiv)as abase or, in case of acids, classical peptide coupling condition EDC, HOBt, NEt3 in DCM was used[15]. Then the in-situ
formed corresponding N-acyl intermediate (without purification) was subjected to cyclization (1.0 equiv 4 N HCl/dioxane, Ac2O [0.5 M], 120 °C, 1-2h) after removing DCM (Table 2, entries 2a-q). Anhydrides including cyclic glutaric anhydride (entries 2a-c) worked well under the optimized condition and produced 8a-c in 70-85% overall yield. A diverse set of acid chlorides (entries 2d-i), as the acyl component worked well and the corresponding products were formed in generally very good yield. We observed a drop in overall yields in the case of acids (40-79%, entries 2k-o) compared to anhydrides and acid chlorides, which may reflect worse coupling yields. In the case of N-Boc-protected amino acids, the corresponding N-acyl products 8m-o (entries 2m-p) were isolated in 40-60% yields. De-borylation was observed in case of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 8b was isolated with 70% yield. Thus, Boc and pinacol-borane groups were found to be labile under the optimized condition. In case of cyanoacetic acid trace
4
Table 2. R3-Substitutions on Tetrazolyl-imidazo[1,5-ɑ]Pyridine.
Entrya R2 7 R3 Product 8 Yield(%)b
2a O tBu O tBu O 8a 85 2b O Ph O Ph O 8b 78 2c O O O O HO 3 8c 70 2d O Cl O MeO 3 O MeO 3 8d 87 2e O Cl S 2 S 2 8e 85 2f O Cl 8f 80 2g O Cl F F 8g 82 2h O Cl Cl Cl 8h 70 2i N O O 3 O Cl 8i 85 2jc O Cl F F 8j 80
6
H2N N N N N N R2 N N N N N N R2 R3 intermediate a 8 Ac2O 4 N HCl/dioxane 120 oC, 1-2 h 4 N HCl/ dioxane 7 5 rt, 10 min HCl Azido-Ugi product2k N O O 3 S OH O S 8k 67 2l OH O O O 8l 79 2m O O OH O N Boc N O 8m 60 2n MeO OH O BocHN NHAc 8n 40 2o O O OH O BocHN NHAc 8o 45 2p O OH B O O 8b 70 2q O OH NC NC 8q trace
a Reaction scale 1.0 mmol. b Isolated yield. c The reaction scale was 5.0 mmol, reaction mixture was heated at 75 °C for 8 h.
A mechanism is proposed in Scheme 1. The Azido-Ugi reaction mechanism has been documented[13].
4
Scheme 1. Proposed Mechanism
Then, the Azido-Ugi product 5 undergoes N-acylation, forms intermediate 5-I via acid mediated trityl group deprotection. Further 5-I undergoes O-acylation-elimination process, provides nitrilium intermediate 5-II. Attacking the ring nitrogen lone pair of electrons from 5-II leads to the cyclic intermediate 5-III, which upon aromatization leads to the formation of the target product
6 (Scheme 1).
As an application of the methodology, we could improve upon the synthetic route of the guanylate cyclase stimulator 9 in three simple steps with 76% overall yield, via acid mediated tert-octyl group deprotectio[13] of 8j in the final step (Scheme 2). After demonstrating the successful synthesis of
diverse substituted tetrazolyl-imidazo[1,5-α]pyridines, we wanted to further demonstrate the
scope of the method by synthesizing unsubstituted (R3=H) examples and explore their
Scheme 2. Improved Route to the Guanylate Cyclase Stimulator (9)
Examples 8r and 8s were prepared from intermediate 6r and 6s in 74% and 78% yields, respectively,
via one pot N-formylation followed by POCl3 mediated dehydration-cyclization process (Scheme 3)[16].While attempting the de-benzylation of 8r under hydrogenation condition, we observed
selective pyridyl ring saturation product and 10 was isolated in 98% yield. The interesting low molecular weight free tetrazole 11 building block was obtained in 88% yield by deprotection of the tert-butyl group of 8s under acidic condition (Scheme 3)[17].
4
Scheme 3. Post Modification Scope
In continuation of exploring the post modification scope, the phthalimide group in 8i was deprotected to form the free amine 12 (90% yield), which was subjected to 3-different types of reactions (i) sulfonamide (ii) urea and (iii) thiourea formation[18].All 3-types of reactions worked
well and furnished the desired products 13a-c in very good yields of 75-85% (Scheme 3).
CONCLUSIONS
Taken together, we have developed a novel, simple and efficient two step method for the synthesis of tetrazolyl-imidazo[1,5-α]pyridines, a bis-heterocyclic system via the well-known Azido-Ugi 4CR reaction and an unprecedented acetic anhydride mediated post cyclization reaction. Work is ongoing to investigate the further synthetic applications and biological properties of the new compound class.
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Chem. 2008, 73, 7441.
3. King F.D., Gaster L.M., Joiner G.F. Imidazopyridines and indolizines as 5-HT4 antagonists. PCT Pat. Appl. WO 1993/008187 A1, 29 Apr. 1993.
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S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2005, 15, 2129. 7. Ford, F. F.; Browne, L. J.; Campbell, T.; Gemenden, C.; Goldstein, R.; Gude, C.; Wasley, J. W. F. J. Med.
Chem. 1985, 28, 164.
8. Schirok, H,; Mittendorf, J.; Stasch, J-P.; Wunder, F.; Stoll, F.; Schlemmer, K-H. Pyrazolopyridine, Indazole, Imidazopyridine, Imidazopyrimidine, Pyrazolopyrazine and Pyrazolopyridine derivatives as stimulator of guanylate cyclase for cardiovascular disorders. PCT Pat. Appl. WO 2008/031513 A1, 20 March 2008.
9. a) Shibahara, F.; Dohke, Y.; Murai, T. J. Org. Chem. 2012, 77, 5381; b) Yamaguchi, E.; Shibahara, F.; Murai, T. J. Org. Chem. 2011, 76, 6146 and references cited therein.
10. a) Zabrocki, J.; Smith, G. D.; Dunbar, J. B., Jr.; Iijima, H.; Marshall, G. R. J. Am. Chem. Soc. 1988, 110, 5875−5880; b) Rentería-Gómez, A.; Islas-Jacome, A.; Díaz-Cervantes, E.; Villaseñ or-Granados, T.; Robles, J.; Gamez-Montaño, R. Bioorg. Med. Chem. Lett. 2016, 26, 2333−2338.
11. Drugs containing tetrazole moiety (review): Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem.
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Kalinowska-4
18. a) For sulfonamide formation: K. Bahrami, M. M. Khodaei, M. Soheilizad, J. Org. Chem., 2009, 74, 9287-9291; b) For urea and thiourea formation: Chayah, M.; Camacho, M. E.; Carrion, M. D.; Gallo, M. A.; Romero, M.; Duarte, J. Med. Chem. Commun. 2016, 7, 667-678.
EXPERIMENTAL SECTION
Experimental procedures
Procedure A: synthesis of 1-tetrazolyl-3-methylimidazo[1,5-α] pyridines (6):
In a 4 mL screwcap glass vial picolinaldehyde (1, 1.0 mmol), tritylamine (2, 1.0 mmol) were stirred at room temperature in MeOH (0.5M) for 1 h. Isocyanide (3, 1.0 mmol) and trimethylsilyl azide (4, 1.0 mmol) were added and further stirred for 18-24 h. The intermediate product (5) as a solid, was collected by quick filtration and washed with diethyl ether (1 mL). Then the solid was transferred to the same screwcap glass vial, to it acetic anhydride (0.5M), 4N HCl/dioxane (3.0 eq.) were added. Then, the vial was closed and the reaction mixture was heated at 75 °C on a heating metal block for 1 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product (6)
Procedure B: synthesis of R3-substituted 1-tetrazolyl-3-imidazo[1,5-α]pyridines (8):
The differences from procedure A are as follows: The solid intermediate product (5) was dissolved in DCM (1 mL). To it 4N HCl/dioxane (3.0 eq.) was added and stirred for 10 min. The solvent was removed, diethyl ether (3 mL) was added and the amine-HCl salt (intermediate a) was collected as a solid by filtration and subjected to following 3-different kinds of reactions without further purification.
(i) Using anhydrides as an acyl component: In a 4 mL screwcap glass vial containing a suspension
of above intermediate amine-HCl salt (intermediate a) in DCM (2 mL) at room temperature were added NEt3 (2.2 eq.) and anhydride (1.2 eq.) After being stirred for 2-4 h, the solvent was removed and the acetic anhydride (0.5M), 4N HCl/dioxane (1.0 equiv.) were added. Then, the vial was closed and the reaction mixture was heated at 120 °C on a heating metal block for 1-2 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product (8a-8c).
4
(iii) Using acids as a acyl component: In a 4 mL screwcap glass vial containing a suspension
of above intermediate amine-HCl salt (intermediate a) in DCM (2 mL) at room temperature were added NEt3 (3 equiv.), HOBt (1.0 equiv.), acid (1.2 equiv.) and EDC.HCl (2.0 equiv.) After being stirred for 12-14 h, the solvent was removed and the acetic anhydride (0.5M), 4N HCl/dioxane (1.0 eq.) were added. Then, the vial was closed and the reaction mixture was heated at 120 °C on a heating metal block for 1-2 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product (8k-8q).
Characterization data
1-(1-benzyl-1H-tetrazol-5-yl)-3-methylimidazo [1,5-α]pyridine 6a:
The product was obtained using procedure A, yield 85%, 0.247 g, as off white solid, mp: 186-187 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.41 (dd, J = 9.20, 1.45 Hz, 1H), 7.80 (dd, J = 7.11, 1.30 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.33 – 7.21 (m, 3H), 7.04 (dd, J = 9.23, 6.44 Hz, 1H), 6.83 – 6.77 (m, 1H), 6.29 (s, 2H), 2.73 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 149.1, 136.2, 135.5, 131.9, 128.7, 128.2, 122.4, 121.2, 120.1, 114.6, 114.2, 51.5, 12.8; HRMS calcd for C16H14N6 [M+H]+: 291.1352, found [M+H]+:291.1351.
3-Methyl-1-(1-phenethyl-1H-tetrazol-5-yl) imidazo[1,5-α]pyridine 6b:
The product was obtained using procedure A, yield 88%, 0.268 g, as pale yellow solid, mp: 165-166 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.39 (dt, J = 9.16, 1.24 Hz, 1H), 7.82 (dt, J = 7.13, 1.12 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.23 – 7.16 (m, 1H), 7.05 (ddd, J = 9.23, 6.51, 0.95 Hz, 1H), 6.82 (ddd, J = 7.41, 6.53, 1.20 Hz, 1H), 5.26 – 5.17 (m, 2H), 3.32 – 3.22 (m, 2H); 13C NMR (126 MHz, Chloroform-d) δ 149.2, 137.5, 136.3, 131.8, 129.0, 128.6, 126.9, 122.2, 121.3, 120.1, 114.7, 114.2, 49.8, 36.3, 12.8; HRMS calcd for C17H16N6 [M+H]+: 305.1509, found [M+H]+: 305.1507. 1-(1-(tert-butyl)-1H-tetrazol-5-yl)-3-methylimidazo [1,5-α]pyridine 6c:
The product was obtained using procedure A, yield 82%, 0.210 g, as brown solid, mp: 183-184 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.27 (dt, J = 9.3, 1.2 Hz, 1H), 7.79 (dd, J = 7.1, 1.2 Hz, 1H), 6.98 (ddd, J = 9.3, 6.4, 1.0 Hz, 1H), 6.77 (td, J = 6.9, 1.2 Hz, 1H), 2.72 (s, 3H), 1.90 (s, 9H); 13C NMR (126 MHz, Chloroform-d) δ 149.7, 135.5, 132.2, 121.7, 121.1, 120.0, 115.2, 113.9, 62.2, 29.4, 12.7; HRMS calcd for C13H16N6 [M+H]+: 257.1509, found [M+H]+: 257.1509. 6a N N N N N N N N N N N N 6b N N N N N N 6c
1-(1-cyclohexyl-1H-tetrazol-5-yl)-3-methylimidazo[1,5-α]pyridine 6d:
The product was obtained using procedure A, yield 75%, 0212 g, as white solid, mp: 163-164 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J = 9.18 Hz, 1H), 7.80 (d, J = 7.08 Hz, 1H), 7.01 (dd, J = 9.21, 6.46 Hz, 1H), 6.82 – 6.73 (m, 1H), 5.65 (tt, J = 11.64, 3.92 Hz, 1H), 2.72 (s, 3H), 2.26 – 2.13 (m, 2H), 2.04 (qd, J = 12.43, 3.70 Hz, 2H), 1.94 (dt, J = 13.81, 3.50 Hz, 2H), 1.85 – 1.71 (m, 1H), 1.53 (qt, J = 13.24, 3.64 Hz, 2H), 1.35 (qt, J = 13.03, 3.71 Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 148.6, 136.1, 131.7, 121.9, 121.2, 120.0, 114.0, 58.3, 32.8, 25.5, 25.3, 12.8 ppm; HRMS calcd for C15H18N6 [M+H]+: 283.1665, found [M+H]+: 283.1665.
1-(1-(4-(benzyloxy)benzyl)-1H-tetrazol-5-yl)-3-methylimidazo[1,5-α]pyridine 6e:
The product was obtained using procedure A, yield 87%, 0.345 g, as white solid, mp: 160-161 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.47 – 8.36 (m, 1H), 7.86 – 7.75 (m, 1H), 7.49 – 7.41 (m, 2H), 7.41 – 7.33 (m, 4H), 7.30 (td, J = 5.94, 2.01 Hz, 1H), 7.03 (ddd, J = 8.91, 6.29, 2.05 Hz, 1H), 6.93 – 6.84 (m, 2H), 6.79 (td, J = 6.74, 1.79 Hz, 1H), 6.21 (s, 2H), 5.00 (s, 2H), 2.74 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 158.8, 149.0, 136.9, 136.1, 131.9, 130.2, 128.7, 128.1, 128.0, 127.5, 122.3, 121.2, 120.2, 115.0, 114.8, 114.2, 70.0, 51.0, 12.8; HRMS calcd for C23H20N6O [M+H]+: 397.1771, found [M+H]+: 397.1768. 1-(1-(furan-2-ylmethyl)-1H-tetrazol-5-yl)-3-methylimidazo[1,5-α]pyridine 6f:
The product was obtained using procedure A, yield 80%, 0.224 g, as brown solid, mp: 170-171 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.40
(dt, J = 9.33, 1.20 Hz, 1H), 7.82 (dt, J = 7.11, 1.13 Hz, 1H), 7.34 (dd, J = 1.86, 0.86 Hz, 1H), 7.04 (ddd, J = 9.24, 6.47, 0.96 Hz, 1H), 6.81 (ddd, J = 7.37, 6.53, 1.19 Hz, 1H), 6.46 (dd, J = 3.23, 0.81 Hz, 1H), 6.30 (s, 2H), 6.28 (dd, J = 3.31, 1.89 Hz, 1H), 2.74 (s, 3H) ; 13C NMR (126 MHz, Chloroform-d) δ 149.1, 148.4, 143.2, 136.3, 132.0, 122.4, 121.3, 120.1, 114.6, 114.2, 110.6, 110.1, 44.8, 12.8; HRMS calcd for C14H12N6O [M+H]+: 281.1145, found [M+H]+: 281.1144. 1-(1-(2-(1H-indol-3-yl)ethyl)-1H-tetrazol-5-yl)-3-methylimidazo [1,5-α]pyridine 6g:
The product was obtained using procedure A, yield 65% , 0.223 g, as off white solid, mp: 210-211 °C. 1H NMR for major
N N N N N N 6d N N N N N N O 6e N N N N N N O 6f N N N N
4
2-(3-(5-(3-methylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl)isoindoline-1,3-dione 6h:
The product was obtained using procedure A, yield 90%, 0.348 g, as pale yellow solid, mp: 172-173 °C. 1H NMR (500
MHz, Chloroform-d) δ 8.39 (d, J = 9.2 Hz, 1H), 7.91 – 7.77 (m, 2H), 7.78 – 7.65 (m, 3H), 7.03 (t, J = 7.7 Hz, 1H), 6.78 (t, J = 6.8 Hz, 1H), 5.08 (t, J = 7.7 Hz, 2H), 3.86 (t, J = 6.8 Hz, 2H), 2.55 – 2.31 (m, 5H); 13C NMR (126 MHz, Chloroform-d + Methanol-d 4) δ 168.3, 149.1, 136.5, 134.1, 131.8, 131.7, 123.1, 123.0, 122.6, 121.3, 119.3, 114.1, 113.8, 46.1, 35.0, 28.4, 11.9; HRMS calcd for C20H17N7O2 [M+H]+: 388.1516, found [M+H]+: 388.1516. N-(4-chlorobenzyl)-2-(5-(3-methylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)acetamide 6i:
The product was obtained using procedure A, yield 65%, 0.248 g, as pale yellow solid, mp: 170-171 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.97 (t, J = 5.91 Hz, 1H), 8.32 (d, J = 7.19 Hz, 1H), 8.03 – 8.00 (m, 1H), 7.33 – 7.20 (m, 4H), 7.19 – 7.13 (m, 1H), 6.95 (td, J = 6.86, 1.21 Hz, 1H), 5.78 (s, 2H), 4.84 (d, J = 5.68 Hz, 2H), 2.68 (s, 3H); 13C NMR (126 MHz, DMSO-d 6) δ 161.4, 153.7, 137.0, 135.6, 133.2, 131.3, 130.5, 127.9, 127.6, 126.5, 124.7, 123.5, 118.5, 114.7, 49.3, 32.1, 11.6; HRMS calcd for C18H16ClN7O [M+H]+: 382.1177, found
[M+H]+: 382.1177.
1-(1-(4-methoxyphenyl)-1H-tetrazol-5-yl)-3-methylimidazo[1,5-α]pyridine 6j:
The product was obtained using procedure A, yield 75%, 0.230 g, as off white solid, mp: 195-196 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.31 (d, J = 9.27 Hz, 1H), 7.77 (d, J = 6.97 Hz, 1H), 7.56 – 7.48 (m, 2H), 7.04 (dd, J = 9.22, 6.41 Hz, 1H), 7.01 – 6.97 (m, 2H), 6.79 (t, J = 6.73 Hz, 1H), 3.89 (d, J = 0.91 Hz, 3H), 2.56 (s, 3H); 13C NMR (126 MHz, Chloroform-d)
δ 160.4, 149.5, 136.4, 132.3, 128.4, 128.0, 127.4, 122.5, 121.4, 119.8, 114.1, 55.7, 12.8; HRMS calcd for C16H14N6O [M+H]+: 307.1301, found [M+H]+: 307.1301.
1-(1-mesityl-1H-tetrazol-5-yl)-3-methylimidazo[1,5-α]pyridine 6k:
The product was obtained using procedure A, yield 77%, 0.245 g, as brown solid, mp: 194-195 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.43
(d, J = 9.14 Hz, 1H), 7.73 (d, J = 7.02 Hz, 1H), 7.05 (dd, J = 9.25, 6.40 Hz, 1H), 6.99 (s, 2H), 6.77 (dd, J = 6.81, 1.17 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 1.90 (s, 6H); 13C NMR (126 MHz, Chloroform-d) δ 150.5, 139.7, 136.6, 135.5, 132.1, 132.0, 128.9, 122.3, 121.4, 119.9, 114.3, 113.9, 21.3, 17.7, 12.8; HRMS calcd for C18H18N6 [M+H]+: 319.1665, found [M+H]+: 319.1664. N N N N N N N O O 6h N N N N N N N H O Cl 6i N N N N N N O 6j N N N N N N 6k
1-(1-benzyl-1H-tetrazol-5-yl)-3,5-dimethylimidazo[1,5-α]pyridine 6l:
The product was obtained using procedure A, yield 78%, 0.238 g, as off white solid, mp: 142-143 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.31 (d, J = 9.2 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.33 – 7.21 (m, 3H), 6.86 (dd,
J = 9.2, 6.5 Hz, 1H), 6.41 (dt, J = 6.5, 1.2 Hz, 1H), 6.27 (s, 2H), 3.05 (s,
3H), 2.86 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 149.0, 137.6, 135.6,
134.4, 133.6, 128.7, 128.6, 128.2, 123.1, 118.3, 115.0, 114.3, 51.5, 20.9, 18.4; HRMS calcd for C17H16N6 [M+H]+: 305.1509, found [M+H]+: 305.1507.
1-(1-benzyl-1H-tetrazol-5-yl)-6-bromo-3-methylimidazo[1,5-α]pyridine 6m:
The product was obtained using procedure A, yield 74%, 0.272 g, as brown solid, mp: 154-155 °C.1H NMR (500 MHz, Chloroform-d)
δ 8.34 (dd, J = 9.6, 1.0 Hz, 1H), 7.96 (t, J = 1.3 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.33 – 7.26 (m, 3H), 7.08 (dd, J = 9.6, 1.5 Hz, 1H), 6.26 (s, 2H), 2.72 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 148.7, 136.3,
135.3, 130.0, 129.3, 128.7, 128.5, 128.3, 127.8, 125.7, 121.3, 120.7, 115.9, 109.7, 51.6, 12.8; HRMS calcd for C16H13BrN6 [M+H]+: 369.0457, found [M+H]+: 369.0458.
1-(1-benzyl-1H-tetrazol-5-yl)-3-(tert-butyl)imidazo[1,5-α]pyridine 8a:
The product was obtained using procedure B, yield 85%, 0.282 g, as off white solid, mp: 194-195 °C. 1H NMR (500 MHz, Chloroform-d) δ 1H
NMR (500 MHz, Chloroform-d) δ 8.48 (dt, J = 9.1, 1.3 Hz, 1H), 8.17 (dd, J = 7.3, 1.1 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.32 – 7.22 (m, 3H), 7.02 (ddd, J = 9.2, 6.4, 0.9 Hz, 1H), 6.74 (ddd, J = 7.5, 6.4, 1.3 Hz, 1H), 6.30 (s, 2H), 1.60 (s, 9H); 13C NMR (126 MHz, Chloroform-d) δ 149.2, 146.4, 135.7, 133.2, 128.7, 128.5, 128.2, 123.5, 122.0, 120.8, 114.2, 113.7, 51.7, 33.9, 28.4; HRMS calcd for C29H20N6 [M+H]+: 333.1822, found [M+H]+: 333.1821. 1-(1-benzyl-1H-tetrazol-5-yl)-3-phenylimidazo[1,5-α]pyridine 8b:
The product was obtained using procedure B, yield 78%, 0.275 g, as off white solid, mp: 143-144 °C.1H NMR (500 MHz, Chloroform-d) δ 8.54 (dt, J = 9.2, 1.2 Hz, 1H), 8.36 (dt, J = 7.2, 1.1 Hz, 1H), 7.84 – 7.79 (m, 2H), 7.63 – 7.57 (m, 2H), 7.56 – 7.51 (m, 1H), 7.51 – 7.46 (m, 2H), 7.34 – 7.23 (m, 3H), 7.10 (ddd, J = 9.1, 6.5, 0.9 Hz, 1H), 6.80 (ddd, J = 7.5, 6.6, 1.3 Hz, 1H), 6.33 (s, N N N N N N 6l N N N N N N Br 6m N N N N N N 8a N N N N N N 8b
4
4-(1-(1-benzyl-1H-tetrazol-5-yl)imidazo[1,5-α]pyridin-3-yl)butanoic acid 8c:
The product was obtained using procedure B, yield 70%, 0.253 g, as brown solid, mp: 154-155 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.35
(dt, J = 9.3, 1.2 Hz, 1H), 7.91 (dt, J = 7.2, 1.2 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.31 – 7.15 (m, 3H), 7.03 (ddd, J = 9.2, 6.5, 0.9 Hz, 1H), 6.77 (td, J = 6.8, 1.2 Hz, 1H), 6.24 (s, 2H), 3.07 (t, J = 7.5 Hz, 2H), 2.48 (t, J = 7.0 Hz, 2H), 2.21 (p, J = 7.2 Hz, 2H); 13C NMR (126 MHz, Chloroform-d + Methanol-d 4) δ 175.6, 149.2, 139.3, 135.2, 132.1, 128.6, 128.2, 128.2, 122.9, 121.4, 119.7, 114.2, 51.6, 32.9, 25.5, 21.6; HRMS calcd for C19H18N6O2 [M+H]+: 363.1564, found [M+H]+: 363.1563. Methyl 4-(1-(1-benzyl-1H-tetrazol-5-yl)imidazo[1,5-α]pyridin-3-yl)butanoate 8d:
The product was obtained using procedure B, yield 87%, 0.327 g, as off white solid, mp: 121-122 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.43
(dt, J = 9.3, 1.2 Hz, 1H), 7.92 (dt, J = 7.1, 1.2 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.35 – 7.22 (m, 3H), 7.05 (ddd, J = 9.2, 6.5, 0.9 Hz, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H), 6.28 (s, 2H), 3.69 (s, 3H), 3.09 (t, J = 7.4 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 2.26 (p, J = 7.2 Hz, 2H); 13C NMR (126 MHz, Chloroform-d) δ 173.6,
149.1, 138.9, 135.5, 132.0, 128.6, 128.3, 128.2, 121.3, 120.1, 114.7, 114.2, 51.8, 51.6, 32.9, 25.6, 21.6; HRMS calcd for C20H20N6O2 [M+H]+: 377.1720, found
[M+H]+: 377.1720.
1-(1-benzyl-1H-tetrazol-5-yl)-3-(2-(methylthio)ethyl)imidazo[1,5-α]pyridine 8e:
The product was obtained using procedure B, yield 85%, 0.298 g, as off white solid, mp: 144-145 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.43 (dt, J = 9.1, 1.2 Hz, 1H), 7.89 (dt, J = 7.2, 1.2 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.34 – 7.20 (m, 3H), 7.04 (ddd, J = 9.2, 6.5, 0.9 Hz, 1H), 6.86 – 6.76 (m, 1H), 6.27 (s, 2H), 3.31 (t, J = 7.4 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 2.13 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 149.1, 138.2, 135.5, 132.0, 128.7, 128.2, 122.7, 121.1, 120.2, 115.0, 114.3, 51.6, 31.4, 26.9, 16.0; HRMS calcd for C18H18N6S [M+H]+: 351.1386, found [M+H]+: 351.1384. 1-(1-benzyl-1H-tetrazol-5-yl)-3-(cyclohexylmethyl)imidazo[1,5-α]pyridine 8f:
The product was obtained using procedure B, yield 80%, 0.298 g, as off white solid, mp: 148-149 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.42 (dt, J = 9.2, 1.3 Hz, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.52 – 7.42 (m, 2H), 7.34 – 7.20 (m, 3H), 7.06 – 6.98 (m, 1H), 6.82 – 6.72 (m, 1H), 6.29 (s, 2H), 2.92 (d, J = 7.1 Hz, 2H), 1.95 (ttt, J = 10.6, 6.9, 3.1 Hz, 1H), 1.84 – 1.63 (m, 5H), 1.34 – 1.16 (m, 3H), 1.10 (qd, J = 13.5, 12.6, 3.7 Hz, 2H); 13C NMR (126 MHz, Chloroform-d) δ 149.2, 139.3, 135.5, 131.8, 128.6, 128.5, 128.2, N N N N N N O HO 8c N N N N N N O O 8d N N N N N N S 8e N N N N N N 8f
1-(1-benzyl-1H-tetrazol-5-yl)-3-(4-fluorobenzyl)imidazo[1,5-α]pyridine 8g:
The product was obtained using procedure B, yield 82%, 0.315 g, as off white solid, mp: 197-198 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.44 (dt, J = 9.2, 1.2 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.29 – 7.23 (m, 3H), 7.19 – 7.12 (m, 2H), 7.08 – 6.96 (m, 3H), 6.76 – 6.69 (m, 1H), 6.25 (s, 2H), 4.43 (s, 2H); 13C NMR (126 MHz, Chloroform-d) δ 162.0 (d, J = 245.9 Hz), 149.1, 138.0, 135.4, 132.3, 131.2, 130.1 (d, J = 6.8 Hz), 128.7, 128.5, 128.2, 122.8 (d, J = 10.7 Hz), 121.3, 121.1, 120.3 (d, J = 6.9 Hz), 115.9 (dd, J = 21.4, 8.3 Hz), 115.1, 114.5 (d, J = 16.7 Hz), 51.6, 32.6; HRMS calcd for C22H17FN6 [M+H]+: 385.1571, found [M+H]+: 385.1571. 1-(1-benzyl-1H-tetrazol-5-yl)-3-(4-chlorophenyl)imidazo[1,5-α]pyridine 8h:
The product was obtained using procedure B, yield 70%, 0.270 g, as off white solid, mp: 206-207 °C. 1H NMR (500 MHz, Chloroform-d)
δ 8.55 (dd, J = 9.1, 1.2 Hz, 1H), 8.30 (dd, J = 7.1, 1.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.61 – 7.54 (m, 2H), 7.48 – 7.41 (m, 2H), 7.34 – 7.24 (m, 3H), 7.12 (dd, J = 9.2, 6.5 Hz, 1H), 6.87 – 6.80 (m, 1H), 6.30 (s, 2H); 13C NMR
(126 MHz, Chloroform-d) δ 149.0, 138.0, 135.6, 135.5, 133.1, 133.1, 129.7, 129.6, 129.4, 128.8, 128.6, 128.4, 128.4, 127.9, 123.5, 121.9, 120.8, 117.0, 115.4, 115.2, 51.9; HRMS calcd for C21H15ClN6 [M+H]+: 387.1119, found
[M+H]+: 387.1119.
2-(3-(5-(3-cyclopropylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl)isoindoline-1,3-dione 8i:
The product was obtained using procedure B, yield 85%, 0.351 g, as off white solid, mp: 188-189 °C. 1H NMR (500 MHz, Chloroform-d)
δ 8.39 (dt, J = 9.2, 1.3 Hz, 1H), 8.06 (dt, J = 7.2, 1.1 Hz, 1H), 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.04 (ddd, J = 9.3, 6.4, 1.0 Hz, 1H), 6.80 (ddd, J = 7.4, 6.5, 1.2 Hz, 1H), 5.12 – 5.03 (m, 2H), 3.86 (t, J = 6.9 Hz, 2H), 2.46 – 2.35 (m, 2H), 2.00 (tt, J = 7.1, 5.8 Hz, 1H), 1.05 – 1.00 (m, 4H); 13C NMR (126 MHz, Chloroform-d) δ 168.2, 149.3, 141.4, 134.1, 132.1, 132.1, 123.4, 122.6, 121.3, 120.2, 114.2, 114.0, 46.6, 35.5, 29.0, 6.8, 6.7, 6.6; HRMS calcd for C22H19N7O2 [M+H]+: 414.1673, found [M+H]+: 414.16714; [M+Na]+: 436.14908. N N N N N N F 8g N N N N N N Cl 8h N N N N N N N O O 8i
4
J = 3.9 Hz), 129.1 (d, J = 8.0 Hz), 124.6, 123.0 (d, J = 15.6 Hz), 122.2 (d, J = 8.3 Hz), 121.1 (d, J = 15.5 Hz),
120.4 (d, J = 5.2 Hz), 116.0, 115.7 (d, J = 22.1 Hz), 114.3 (d, J = 12.6 Hz), 31.7, 30.8, 30.4 (q, J = 7.5 Hz), 26.3 (d, J = 3.8 Hz); HRMS calcd for C23H27FN6 [M+H]+: 407.2354, found [M+H]+: 407.2353.
2-(3-(5-(3-(thiophen-2-yl)imidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl)isoindoline-1,3-dione 8k:
The product was obtained using procedure B, yield 67%, 0.305 g, as off white solid, The product was obtained using procedure B, 85%, amount g, as off white solid, mp: 205-206 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.54 (dt, J = 9.2, 1.3 Hz, 1H), 8.42 (td, J = 7.2, 1.1 Hz, 1H), 7.80 – 7.72 (m, 2H), 7.71 – 7.63 (m, 2H), 7.52 (dd, J = 3.7, 1.1 Hz, 1H), 7.37 (dd, J = 5.0, 1.0 Hz, 1H), 7.20 – 7.10 (m, 2H), 6.91 (td, J = 6.8, 1.2 Hz, 1H), 5.21 – 5.10 (m, 2H), 3.90 (t, J = 6.8 Hz, 2H), 2.54 – 2.43 (m, 2H); 13C NMR (126 MHz, Chloroform-d) δ 168.3, 148.9, 134.0, 132.8, 132.1, 131.4, 127.9, 127.0, 125.5, 125.5, 123.3, 122.3, 120.6, 116.8, 115.6, 115.5, 115.5, 46.8, 35.5, 29.0; HRMS calcd for C23H17N7O2S [M+H]+: 456.1237, found
[M+H]+: 456.1236.
(E)-1-(1-cyclohexyl-1H-tetrazol-5-yl)-3-(2-(furan-2-yl)vinyl)imidazo[1,5-α]pyridine 8l:
The product was obtained using procedure B, yield 79%, 0.284 g, as off white solid, mp: 187-188 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.49 (d, J =
9.1 Hz, 1H), 8.14 (d, J = 7.1 Hz, 1H), 7.56 – 7.37 (m, 2H), 7.17 (d, J = 15.4 Hz, 1H), 7.08 (dd, J = 9.2, 6.5 Hz, 1H), 6.94 – 6.82 (m, 1H), 6.59 – 6.43 (m, 2H), 5.68 (tt, J = 11.7, 3.8 Hz, 1H), 2.36 – 2.21 (m, 2H), 2.17 – 1.95 (m, 4H), 1.82 (d, J = 13.4 Hz, 1H), 1.56 (qt, J = 13.4, 3.5 Hz, 2H), 1.40 (ddt, J = 16.6, 12.9, 6.4 Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 152.5, 148.4, 143.2, 143.1, 137.3, 132.5, 122.9, 121.2, 120.6, 119.5, 117.6, 115.0, 112.3, 111.1, 109.6, 58.9, 32.7, 25.7, 25.3; HRMS calcd for C20H20N6O2 [M+H]+: 361.1771, found [M+H]+: 361.1771.
1-(4-(1-(1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-tetrazol-5-yl)imidazo[1,5-α]pyridin-3-yl) piperidin-1-yl)ethanone 8m:
The product was obtained using procedure B, yield 60%, 0.267 g, as off white solid, mp: 106-107 °C. 1H NMR (500 MHz, Chloroform-d)
δ 8.45 (dt, J = 9.2, 1.3 Hz, 1H), 7.93 (d, J = 7.1 Hz, 1H), 7.06 (dd, J = 9.2, 6.4 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 7.9, 1.7 Hz, 1H), 6.81 (dd, J = 6.7, 1.2 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.15 (d, J = 1.9 Hz, 2H), 5.90 (s, 2H), 4.65 (ddd, J = 13.6, 5.3, 3.6 Hz, 1H), 4.08 – 3.97 (m, 1H), 3.35 (tdt, J = 10.5, 7.6, 3.5 Hz, 2H), 2.99 (ddd, J = 13.9, 11.3, 3.1 Hz, 1H), 2.18 (s, 3H), 2.14 (q, J = 3.4 Hz, 1H), 2.12 – 2.03 (m, 2H), 2.02 – 1.91 (m, N N N N N N N O O S 8k N N N N N N O 8l N N N N N N O O N O 8m
N-(1-(1-(1-(4-methoxyphenyl)-1H-tetrazol-5-yl)imidazo[1,5-α]pyridin-3-yl)-2-phenylethyl) acetamide 8n:
The product was obtained using procedure B, yield 40%, 0.181 g, as off white solid, mp: 109-110 °C. 1H NMR (500 MHz, Chloroform-d) δ
8.29 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.14 (d, J = 6.4 Hz, 3H), 7.06 – 6.96 (m, 3H), 6.87 – 6.79 (m, 2H), 6.65 (t, J = 6.8 Hz, 1H), 6.09 (d, J = 8.5 Hz, 1H), 5.64 (q, J = 7.6 Hz, 1H), 3.86 (s, 3H), 3.21 – 3.13 (m, 2H), 1.91 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 169.4, 160.7, 149.5, 138.5, 136.5, 132.7, 129.5, 128.6, 128.5, 128.2, 127.0, 123.5, 121.9, 119.7, 114.4, 113.8, 55.8, 46.7, 40.0, 23.1; HRMS calcd for C25H23N7O2 [M+H]+: 454,1986, found [M+H]+: 454.19858. N-(1-(1-(1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-tetrazol-5-yl)imidazo[1,5-α]pyridin-3-yl)-2-phenylethyl)acetamide 8o:
The product was obtained using procedure B, yield 45%, 0.216 g, as brown solid, mp: 253-254 °C. 1H NMR (500 MHz, DMSO-d
6) δ 8.66 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 7.1 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.27 – 7.23 (m, 3H), 7.23 – 7.17 (m, 2H), 7.14 (dd, J = 8.5, 5.9 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.98 – 6.93 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 14.6 Hz, 1H), 6.16 (d, J = 14.7 Hz, 1H), 5.97 (d, J = 6.6 Hz, 2H), 5.76 (q, J = 8.1 Hz, 1H), 3.48 (dd, J = 13.6, 6.8 Hz, 1H), 3.38 (dd, J = 13.6, 8.5 Hz, 1H), 1.77 (s, 3H); 13C NMR (126 MHz, DMSO-d 6) δ 169.3, 148.5, 147.4, 147.1, 140.5, 137.6, 131.3, 129.4, 129.1, 128.0, 126.3, 124.2, 123.2, 121.9, 118.3, 114.2, 113.3, 108.6, 108.3, 101.1, 45.7, 38.3, 22.2; HRMS calcd for C26H23N7O3 [M+H]+: 482.19351, found [M+H]+: 482.19333.
Procedure C: Synthesis of 8r and 8s:
In a 4 mL glass screw cap vial compound 6 (0.2 g), NEt3 (2.2 equiv.) and ethyl formate (2.0 mL) heated at 60 °C for 4 h. The solvent was removed and the crude product was dissolved in DCM (1.5 mL) were added NEt3 (2.2 equiv.) and POCl3 (1.0 equiv.) at 0 °C and slowly warmed to room temperature and further stirred for overnight. Reaction mixture was quenched by addition of aqueous saturated NaHCO3 (2.0 mL) and extracted with DCM, washed with brine and finally dried
over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was
purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product (8)
N N N N N N N H O O 8n N N N N N N O O NH O 8o
4
1-(1-(tert-butyl)-1H-tetrazol-5-yl)imidazo[1,5-α]pyridine 8s:
The product was obtained using procedure C, yield 75%, white solid, mp: 157-158 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (dq, J = 9.3, 1.1 Hz, 1H), 8.22
(s, 1H), 8.05 (dt, J = 7.0, 1.1 Hz, 1H), 7.02 (ddd, J = 9.3, 6.5, 1.0 Hz, 1H), 6.77 (td, J = 6.7, 1.1 Hz, 1H), 1.90 (s, 9H); 13C NMR (126 MHz, Chloroform-d) δ 149.6, 132.1,
127.9, 123.0, 122.7, 119.9, 116.8, 114.4, 62.3, 29.4; HRMS calcd for C12H14N6 [M+H]+:
243.1353, found [M+H]+: 243.1353.
Procedure D: Synthesis of Guanylate Cyclase Stimulator:
3-(2-fluorobenzyl)-1-(1H-tetrazol-5-yl)imidazo[1,5-α]
pyridine 9:
In a 4 mL glass screw cap vial, 8j (0.1 g, 0.25 mmol) and 4N HCl/dioxane (4.0 equiv. 0.25 mL) heated at 100 °C for 2 h on a heating metal block. Product 9 was collected by filtration.
Yield 95%, 0.69 g, off white solid, mp: 215-216 °C. 1H NMR (500 MHz,
DMSO-d6) δ 11.16 (br s, 1H), 8.41 (d, J = 7.1 Hz, 1H), 8.19 (dd, J = 9.2, 1.4 Hz, 1H), 7.39 – 7.26 (m, 1H), 7.26 – 7.16 (m, 3H), 7.13 (td, J = 7.5, 1.2 Hz, 1H), 6.98 – 6.92 (m, 1H), 4.58 (s, 2H); 13C NMR (126 MHz, DMSO-d 6) δ 160.4 (d, J = 244.7 Hz), 138.0, 130.7 (d, J = 4.1 Hz), 130.0, 129.0 (d, J = 8.1 Hz), 124.7 (d, J = 3.4 Hz), 123.4 (d, J = 15.5 Hz), 123.3, 122.9, 118.2, 115.4 (d, J = 21.3 Hz), 114.4, 114.0, 25.6 (d, J = 3.2 Hz); HRMS calcd for C15H11FN6 [M+H]+: 295.1102, found
[M+H]+: 295.1102.
Procedure for synthesis of 10:
To a stirred solution of 8r (0.1g, 0.36 mmol) in MeOH (1.0 mL) was added 10% Pd/C (20 mg) and hydrogenation reaction was carried out using balloon hydrogen for overnight. The reaction mixture was filtered through the celite pad, washed with excess ethyl acetate. The solvent was removed under reduced pressure afforded pure 10 without any purification.
1-(1-benzyl-1H-tetrazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-α]pyridine 10:
Yield 98%, 0.1 g, off white solid, mp: 85-86 °C. 1H NMR (500 MHz,
Chloroform-d) δ 7.46 (s, 1H), 7.40 – 7.34 (m, 2H), 7.29 – 7.18 (m, 3H), 6.15 (s, 2H), 4.01 (t, J = 6.0 Hz, 2H), 3.16 (t, J = 6.5 Hz, 2H), 1.95 (dtt, J = 9.6, 6.0, 3.4 Hz, 2H), 1.87 (dtt, J = 9.4, 6.3, 3.2 Hz, 2H). 13C NMR (126 MHz, Chloroform-d)
δ 149.3, 136.0, 135.9, 135.5, 132.8, 128.7, 128.5, 128.2, 122.1, 51.4, 43.8, 22.7, 22.5, 20.3. LC-MS calcd for C15H16N6 [M+H]+: 281.33 found [M+H]+: 281.25. N N N N N N 8s N N N N N HN F 9 10 N N N N N N
Procedure for synthesis of 11: Prepared according to
procedure D.
1-(1H-tetrazol-5-yl)imidazo[1,5-α]pyridine 11:
Yield 88%, 0.67 g, off white solid, mp: 230-231 °C. 1H NMR (500 MHz, DMSO-d 6) δ 13.34 (s, 1H), 8.72 (s, 1H), 8.56 (td, J = 7.0, 1.2 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 9.2, 6.4 Hz, 1H), 6.94 (td, J = 6.8, 1.2 Hz, 1H); 13C NMR (126 MHz, DMSO-d 6) δ 150.9, 130.1, 129.5, 124.5, 124.0, 117.8, 114.9, 114.0; HRMS calcd for C8H6N6 [M+H]+:187.0727, found [M+H]+: 187.0728.
Procedure for synthesis of 12:
To a stirred solution of 8i (0.6 g, 1.45 mmol ) in EtOH (10 mL) was added 64-65% N2H4.H2O (0.56 mL, 7.26 mmol) and heated at 60 °C for 2.5 h. The solid by-product was removed by filtration and the filtrate was collected, EtOH was removed under reduced pressure afforded crude 12. The crude product 12 was dissolved in DCM (25 mL) and given water (10 mL) and brine (10 mL) wash to remove excess hydrazine. Finally, DCM layer was separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure afforded pure 12 without any purification.
3-(5-(3-cyclopropylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propan-1-amine 12:
Yield 90%, 0.37 g, pale yellow solid, mp: 123-124 °C. 1H NMR (500 MHz,
Chloroform-d) δ 8.40 (dt, J = 9.3, 1.3 Hz, 1H), 8.11 (d, J = 7.1 Hz, 1H), 7.05 (dd, J = 9.2, 6.4 Hz, 1H), 6.86 – 6.78 (m, 1H), 5.08 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H), 2.19 – 2.03 (m, 3H), 1.19 – 1.12 (m, 2H), 1.12 – 1.06 (m, 2H); 13C
NMR (126 MHz, Chloroform-d) δ 149.4, 141.3, 132.1, 122.6, 121.3, 120.1, 114.3, 114.1, 46.0, 38.7, 33.6, 6.7; HRMS calcd for C14H17N7 [M+H]+: 284.16182, found
[M+H]+: 284.16165. 11 N N N N N HN 12 N N N N N N H2N
4
Procedure for synthesis of 13a:
To a stirred solution of 12 (0.1 g, 0.35 mmol ) in pyridine (0.5 mL) was added methane sulfonyl chloride (0.027 mL, 0.35 mmol) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product 13a.
N-(3-(5-(3-cyclopropylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl) methanesulfonamide 13a:
Yield 85%, 0.108 g, white solid, mp: 210-211 °C. 1H NMR (500 MHz,
Chloroform-d) δ 8.41 (dt, J = 9.2, 1.2 Hz, 1H), 8.17 (dt, J = 7.1, 1.1 Hz, 1H), 7.12 (ddd, J = 9.2, 6.5, 0.9 Hz, 1H), 6.88 (td, J = 6.8, 1.2 Hz, 1H), 6.33 (t, J = 6.5 Hz, 1H), 5.11 – 5.02 (m, 2H), 3.07 (q, J = 6.3 Hz, 2H), 2.86 (s, 3H), 2.35 (dq, J = 7.4, 6.0 Hz, 2H), 2.12 (tt, J = 8.3, 5.0 Hz, 1H), 1.29 – 1.20 (m, 2H), 1.12 – 1.07 (m, 2H); 13C NMR (126 MHz, DMSO-d 6) δ 148.8, 142.0, 131.1, 123.5, 122.8, 118.4, 113.9, 112.9, 54.9, 45.9, 29.7, 7.1, 6.2; HRMS calcd for C15H19N7O2S [M+H]+: 362.13937, found [M+H]+: 362.13934.
Procedure for synthesis of 13b:
To a stirred solution of 12 (0.1 g, 0.35 mmol ) in DCM (1.0 mL) was added NEt3 (0.073 mL, 0.52 mmol) and phenyl isocyanate (0.046 mL, 0.42 mmol) and stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product 13b.
1-(3-(5-(3-cyclopropylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl)-3-phenylurea 13b:
Yield 75%, 0.107 g, off white solid, mp: decomposed above
250 °C. 1H NMR (500 MHz, DMSO-d 6) δ 8.57 (d, J = 7.1 Hz, 1H), 8.45 (s, 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.24 – 7.14 (m, 3H), 6.98 (t, J = 6.8 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.23 (t, J = 5.8 Hz, 1H), 4.95 (t, J = 7.1 Hz, 2H), 3.15 (q, J = 6.5 Hz, 2H), 2.47 – 2.39 (m, 1H), 2.06 (p, J = 6.8 Hz, 2H), 1.14 – 0.98 (m, 4H); 13C NMR (126 MHz, DMSO-d 6) δ 155.2, 148.8, 141.9, 140.4, 131.1, 128.5, 123.4, 122.7, 120.9,
118.5, 117.6, 113.9, 113.0, 46.1, 36.4, 30.1, 7.1, 6.2; HRMS calcd for C21H22N8O2 [M+H]+: 403.1989, found
[M+H]+: 403.1988. N N N N N N N S O H3C O H 13a N N N N N N H N O H N 13b
Procedure for synthesis of 13c:
To a stirred solution of 12 (0.1 g, 0.35 mmol ) in DCM (1.0 mL) was added NEt3 (0.073 mL, 0.52 mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.077 mL, 0.42 mmol) and stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (Hexanes: Ethyl acetate 0 to 100%) to afford product 13c.
1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(5-(3-cyclopropylimidazo[1,5-α]pyridin-1-yl)-1H-tetrazol-1-yl)propyl)thiourea 13c:
Yield 77%, 0.15 g, off white solid, mp: 199-200 °C. 1H NMR
(500 MHz, DMSO-d6) δ 10.19 – 9.95 (m, 1H), 8.58 (d, J = 7.1 Hz, 1H), 8.39 – 8.10 (m, 4H), 7.73 (s, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 4.99 (t, J = 7.2 Hz, 2H), 3.72 – 3.48 (m, 2H), 2.31 – 2.12 (m, 2H), 1.24 – 0.95 (m, 4H); 13C NMR (126 MHz, DMSO-d 6) δ 181.1, 149.3, 142.4, 142.3, 131.6, 124.8, 124.0, 123.2, 122.6, 122.4, 118.9, 116.5, 114.4, 113.5, 46.6, 41.5, 29.1, 7.6, 6.0; HRMS calcd for C23H20F6N8O2 [M+H]+: 555.15086, found [M+H]+:
555.15088.
CRYSTAL STRUCTURE DETERMINATION
X-ray diffraction data for single crystals of compounds 5 (entry 1c), 6b, 6l, 6m, 8d, 8e and 8f were collected using SuperNova (Rigaku - Oxford Diffraction) four circle diffractometer with a mirror monochromator and a microfocus CuKα radiation source (λ = 1.5418 Å). Additionally, the diffractometer was equipped with a CryoJet HT cryostat system (Oxford Instruments) allowing low temperature experiments, performed at 130(2) K. The obtained data sets were processed with CrysAlisPro software [S1]. The phase problem was solved with direct methods using SIR2004 [S2]. Parameters of obtained models were refined by full-matrix least-squares on F2 using SHELXL-2014/6
[S3]. Calculations were performed using WinGX integrated system (ver. 2014.1) [S4]. Figure was prepared with Mercury 3.7 software [S5].
All non-hydrogen atoms were refined anisotropically. All hydrogen atoms attached to carbon atoms were positioned with the idealised geometry and refined using the riding model with the isotropic displacement parameter U [H] = 1.2 U [C] or U [H] = 1.2 U [C] (the last for methylene group only).
N N N N N N H N S H N F3C F3C 13c
4
conformer interact only with molecules exhibiting the same conformation. In the case of structure 6l a pseudosymmetry effect is observed. Two molecules of the asymmetric unit are related via (pseudo) inversion centre in the estimated position (0.25; 0.5; 0.25). The fitness of molecules transformed via mentioned pseudosymmetry element is 82%, with the average deviation 0.395. Atoms with no symmetry related counterparts are carbon atoms of the six-membered ring of the imidazo[1,5-α]pyridine moiety (namely: C18, C19, C20, C21 (molecule 1, shown in Figure 1) and corresponding atoms: C48, C49, C50 and C51 (molecule 2 - not shown in the figure)).
In the case of structure 8e, a positional disorder of the S17 atom is observed, with refined site occupancies being 92% and 8% for both alternative conformers. In the proximity of the more abundant conformer an additional electron density is observed in the Fourier difference map (0.88 e·Å-3), indicating more complicated disorder model. The positional disorder is also observed
in molecules of 5 (entry 1c). The pyridyl ring can be oriented in two different positions with equal site occupancies. These alternate positions are caused by C-H...π close contacts with the neighbouring aromatic rings, in which the mentioned pyridyl ring serves as π electron donor and adjust the orientation for optimal interaction geometry. The disorder is additionally caused by relatively close distance between two pyridyl rings of the neighbouring molecules related via inversion centre, which could lead to clashes if only one conformation was possible.
6l 6m
5 (entry 1c)
Figure S1. Molecular geometry observed in crystal structures of compounds 6b (one
of two molecules of the asymmetric unit), 8e, 8f, 8d, 6l (one of two molecules
of the asymmetric unit), 6m and 5 (entry 1c) showing the atom labelling scheme.
In structure 8e and 5 (entry 1c) a positional disorder is observed. In case of 8e sulphur atom is in two alternative positions (here only the most abundant
conformer with site occupancy 92%), and for 5 (entry 1c) the pyridyl ring is in
two alternative positions, with equal site occupancies (approx. 50%). Displacement ellipsoids of non-hydrogen atoms are drawn at the 30% probability level. H atoms are presented as small spheres with an arbitrary radius.
4
Crystal data and structure refinement results for compounds
6b , 8e , 8f , 8d , 6l , 6m and 5 (entry 1c) 6b 8e 8f 8d 6l 6m 5( en tr y 1c ) ic al m oi et y f or mu la 2x (C17 H16 N6 ) C18 H18 N6 S C22 H24 N6 C20 H20 N6 O2 C17 H16 N6 C16 H13 B r N6 C30 H30 N6 la we igh t [ g/ m ol ] 60 8. 71 35 0. 44 37 2. 47 376 .4 2 30 4. 36 36 9. 23 474 .6 0 Cr ys ta l s ys te m O rt horhom bi c M on ocl ini c M on ocl ini c M on ocl ini c Tr icl ini c O rt horhom bi c M on ocl ini c Sp ac e gr oup Pb c21 P2 1/ c C2 /c Pa P Pb ca P2 1/ c c ell d im ens io ns a = 1 8. 50 65 (2 ) Å b = 2 2. 5777 (3 ) Å c = 7 .5 34 2( 1) Å a = 1 1.7 87 9( 2) Å b = 9 .9 65 2( 1) Å c = 1 5. 20 13 (3 ) Å b= 10 9. 27 9( 2) ° a = 2 6. 99 45 (6 ) Å b = 6 .93 65 (1 ) Å c = 2 0. 89 20 (4 ) Å b= 96 .8 52( 2) ° a = 7 .41 79 (2 ) Å b = 1 3. 07 54 (3 ) Å c = 1 0. 04 62 (3 ) Å b= 111 .14 7( 3) ° a = 9 .6 21 6( 6) Å b = 1 2. 70 87 (6 ) Å c = 1 3. 44 37 (8 ) Å α=7 0. 39 4( 5) ° b= 77. 74 0( 5) ° γ= 80 .19 1( 5) ° a = 1 7.8 89 1( 3) Å b = 7 .0 83 7( 1) Å c = 2 3. 72 11 (4 ) Å a = 1 0.1 67 1( 1) Å b = 1 3. 66 55 (2 ) Å c = 1 8. 92 95 (3 ) Å b=1 03 .5 07 (2 )° Vo lu m e [ Å3] 31 48 .0 5( 7) 16 85 .5 4( 5) 38 84 .0 3( 13 ) 90 8. 78 (5 ) 15 04 .4 5( 16 ) 30 05 .9 6( 8) 25 57. 29 (6 ) Z 8 ( Z’ =2 ) 4 8 2 4 8 4 ca lc [Mg /m 3] 1. 28 4 1. 38 1 1. 274 1. 37 6 1. 34 4 1.6 32 1. 23 3 μ [ m m -1 ] 0. 655 1. 813 0. 624 0. 761 0. 685 3. 802 0. 587 F( 000 ) 12 80 73 6 15 84 39 6 640 14 88 10 08 ys ta l s ize [ m m 3] 0. 5 x 0. 3 x 0. 1 0. 5 x 0. 4 x 0. 2 0. 5 x 0. 2 x 0. 1 0. 4 x 0. 2 x 0. 1 0. 5 x 0. 4 x 0. 2 0. 5 x 0. 3 x 0. 1 0. 6 x 0. 5 x 0. 5 Θ ra nge 3. 09 ° t o 7 1.4 9° 3. 97 ° t o 7 1.5 8° 3. 30 ° t o 7 1. 28 ° 4. 72 ° t o 7 6. 80 ° 3. 54° t o 7 1. 39 ° 3. 73 ° t o 7 1.4 4° 4. 03 ° t o 7 1.5 1° In de x r ange s -2 2 ≤ h ≤ 2 2, -2 7 ≤ k ≤ 2 2, -9 ≤ l ≤ 8 -1 4 ≤ h ≤ 1 4, -1 2 ≤ k ≤ 1 0, -1 6 ≤ l ≤ 1 8 -3 2 ≤ h ≤ 3 2, -8 ≤ k ≤ 4 , -2 5 ≤ l ≤ 2 4 -9 ≤ h ≤ 9 , -1 6 ≤ k ≤ 1 6, -1 1 ≤ l ≤ 1 2 -1 1 ≤ h ≤ 7 , -1 5 ≤ k ≤ 1 5, -1 6 ≤ l ≤ 1 6 -2 0 ≤ h ≤ 2 1, -8 ≤ k ≤ 8 , -2 4 ≤ l ≤ 2 9 -1 2 ≤ h ≤ 1 2, -1 6 ≤ k ≤ 1 6, -2 3 ≤ l ≤ 2 1 Re fl. c ol le ct ed 19 98 3 10 38 0 10 48 8 14 48 6 902 9 17 74 4 17 63 9 en den t r efl ec tio ns 513 2 [R (in t) = 0. 03 91 ] 32 41 [R (in t) = 0 .0 36 9] 36 64 [R (in t) = 0. 04 40 ] 367 2 [R (int ) = 0 .05 08 ] 56 71 [R (in t) = 0. 02 84 ] 29 23 [R (in t) = 0. 06 86 ] 49 24 [R (in t) = 0. 04 05 ] pl et en es s [ % ] t o Θ 99 .9 ( Θ 6 7.7 °) 10 0 ( Θ 6 7.7 °) 97. 9 ( Θ 6 7.7 °) 99 .8 ( Θ 6 7.7 °) 98 .9 ( Θ 6 7.7 °) 10 0. 0 ( Θ 6 7.7 °) 10 0. 0 ( Θ 6 7.7 °) pt ion c or re ct ion M ul ti-sc an M ul ti-sc an M ul ti-sc an M ul ti-sc an M ul ti-sc an M ul ti-sc an M ul ti-sc an in . a nd Tm ax . 0. 56 4 a nd 1 .0 00 0. 41 9 a nd 1 .0 00 0. 89 0 a nd 1 .0 00 0. 28 6 a nd 1 .0 00 0. 52 4 a nd 1 .0 00 0. 49 6 a nd 1 .0 00 0. 65 1 a nd 1 .0 00 st ra in ts/ pa ra me te rs 51 32 / 1 / 4 18 32 41 / 0 / 2 38 36 64 / 0 / 2 54 36 72 / 2 / 2 54 56 71 / 0 / 4 20 29 23 / 0 / 2 10 49 24 / 0 / 3 82 G oo F o n F 2 1.0 59 1.0 71 1.0 47 1.15 4 1.0 77 1.0 49 1.0 25 in dic es [I >2s ig m a( I)] R1 = 0. 03 43 , w R2 = 0. 08 80 R1 = 0. 04 96 , w R2 = 0. 13 62 R1 = 0. 04 41 , w R2 = 0. 12 00 R1 = 0. 06 71 , w R2 = 0. 18 32 R1 = 0. 04 91 , w R2 = 0. 13 86 R1 = 0. 03 49 , w R2 = 0. 09 35 R1 = 0. 04 20 , w R2 = 0. 10 81 nd ic es ( al l d at a) R1 = 0. 03 83 , w R2 = 0. 09 19 R1 = 0. 05 22 , w R2 = 0. 13 90 R1 = 0. 05 25 , w R2 = 0. 12 96 R1 = 0. 06 73 , w R2 = 0. 18 33 R1 = 0. 05 27 , w R2 = 0. 14 15 R1 = 0. 03 73 , w R2 = 0. 09 68 R1 = 0. 04 77 , w R2 = 0. 11 49 ax , Δρ m in [ e· Å-3] 0. 24 a nd -0.1 9 0. 88 a nd -0. 36 0. 24 a nd -0. 22 0. 34 a nd -0. 29 0. 36 a nd -0. 25 0. 73 a nd -0. 51 0. 26 a nd -0. 21
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[S2] Maria C. Burla, Rocco Caliandro, Mercedes Camalli, Benedetta Carrozzini, Giovanni L. Cascarano, Liberato De Caro, Carmelo Giacovazzo, Giampiero Polidori and Riccardo Spagna J. Appl.Cryst.
2005, 38, Issue 2, pages 381–388.
[S3] Sheldrick, G. M. Acta Cryst. 2008, A64, 112-122. [S4] Farrugia, L., J. Appl. Cryst. 1999, 32, 837-838.
[S5] Macrae C. F., Edgington P.R., McCabe P., Pidcock E., Shields G.P., Taylor R., Towler M., & van de Streek J., J. Appl. Cryst. 2006, 39, 453-457.
