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DOI: 10.1055/s-0032-1317145
Palladium-Catalyzed Synthesis of Substituted Pyrido[2,3-d]pyridazines at Positions 5 and 8
Publication History
Received: 22 June 2012
Accepted after revision: 27 July 2012
Publication Date:
31 August 2012 (online)
Abstract
Several synthetic strategies were developed for the preparation of highly substituted pyrido[2,3-d]pyridazines. We particularly focused on the impact of the pyridine nitrogen atom on pyridazine ring reactivity toward aromatic substitutions, alkylations, or pallado-catalyzed cross-coupling reactions.
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Phthalazines have been extensively described in the medicinal chemistry literature as an interesting scaffold that allows regioselective functionalization at the 1- and 6-positions.[ 1 ] Moreover the nitrogen atoms at the 2- and 3-positions can establish hydrogen-bond acceptor/donor interactions with the active site of the target protein. However, although the pyridazine ring of the bicycle has been fully explored, only Pakulska et al. and Kaizerman et al. have recently reported the introduction of a nitrogen atom into the benzo ring, leading to pyridopyridazines, as analgesic agents and hedgehog/smoothened receptor antagonists, respectively.[2] [3] From a medicinal chemistry point of view, the introduction of azaheterocycles is interesting because it may modify the electron distribution inside the scaffold leading to a modification of the chemical and physical properties of the compounds (solubility, polar surface area, etc). The reactivity of the scaffold towards metabolic pathways will be also modified, along with its capacity to cross biological barriers. Moreover, a supplementary nitrogen atom may constitute a putative additional interaction within the binding site of the protein target.
The efficacy of a medicinal chemistry program often relies on building focused libraries in order to rapidly explore the chemical space around a specific scaffold. This requires practical synthetic methods that allow the introduction of chemical diversity at various positions of the scaffold. The aim of this work was to develop various synthetic pathways leading to regioselective functionalization of the pyrido[2,3-d]pyridazine scaffold.
5,8-Dichloropyrido[2,3-d]pyridazine (1) was prepared by sequential treatment of commercially available 2,3-pyridinedicarboxylic anhydride with hydrazine and POCl3, as described by Kaizerman et al.[ 3 ] Interestingly, in the same paper, it was reported that a regioselective heteroaromatic substitution at the 5-position by a piperazine derivative gave a low yield. Surprisingly, in our hands, the reaction of 1 with benzylamine led to both regioisomers 2a and 2b, respectively substituted at the 5- and 8-positions, with 90% conversion (Table [1]). Each amidine was isolated by chromatography on silica gel, and the position of the amino group was characterized by the presence or absence of a NOESY correlation between the NH group and the pyridine ring.
No diaminated product was detected. The isolated ratio (1.25:1) showed an almost equal electronic effect of the pyridine ring towards both the 5- and 8-positions. Iminochlorides 2a and 2b were hydrolyzed with sodium acetate in acetic acid to give the corresponding amides 3a and 3b in 75 and 69% yield, respectively.
a Reaction conditions: (a) BnNH2, Na2CO3, DMF, MW (30 min, 130 °C); (b) AcONa, AcOH, MW (5 min, 120 °C); (c) RX, K2CO3, DMF; (d) ROH, Na, 100 °C.
a Reaction conditions: Method A: [Pd(PPh3)4], Na2CO3, ArB(OH)2, DME, H2O, MW (120 °C, 30 min); Method B: Pd(OAc)2, Cs2CO3, binap, amine, dioxane, 110 °C, 14 h; Method C: [PdCl2(PPh3)2], CuI, TEA, alkyne, MeCN, MW (80 °C, 30 min).
Alternatively, reaction of iminochlorides 2 with alcoholates led to the corresponding iminoethers 4a–c in excellent yields. We next evaluated the reactivity of compounds 3a and 3b under alkylating conditions (RX, K2CO3, DMF). Only the pyridazinone nitrogen was alkylated (5a–f) in good yields, and neither NH-benzyl alkylation nor O-alkylation was detected. In both systems, alkylation of the pyridazinone nitrogen was obtained as expected, and was not disturbed by the presence of the pyridine ring.
We next focused our attention on the reactivity of iminochlorides 2a and 2b towards palladium-catalyzed cross-coupling reactions, which are very powerful tools for introducing chemical diversity. First, Suzuki–Miyaura reactions were performed with iminochlorides 2a and 2b, which were treated with various boronic acids in the presence of palladium tetrakis, leading to 6a–h (Table [2]). Both the 5- and 8-positions showed about the same reactivity. We next evaluated the reactivity of iminochlorides 2a and 2b towards the Sonogashira reaction (Table [2]). Using standard conditions ([PdCl2(PPh3)2], CuI), we were able to isolate the expected compounds with yields ranging from 44 to 90% (7a–d). Interestingly, the 5-position appeared to be more reactive than the 8-position (7a vs. 7b).
We have previously shown with compound 1 that when the first chlorine atom is substituted by an amino group, no second heteroaromatic substitution could be observed on the second chlorine atom, even at high temperature. This loss of reactivity prevents the formation of bisamidines. We tried to circumvent this difficulty by employing the Buchwald reaction (Table [2]). Using the catalytic system Pd(OAc)2/binap in dioxane at 110 °C, we were able to introduce a range of amines at the 8-position in yields of between 25 to 78% (8a–f). Surprisingly, no reaction was observed with compound 2b when a chlorine atom was present at the 5-position. Under Buchwald conditions, the pyridine ring appeared to differentially impact the reactivity of iminochlorides at the 5- or 8-positions, inhibiting the 5-position, which appeared to be the most reactive position towards both Suzuki–Miyaura and Sonogashira reactions. It should be noted that under thermal amination conditions by nucleophilic substitution, even at high temperature, the introduction of a second amine was never observed for either iminochlorides 2a or 2b.
Similar to phthalazines, 1,2,3,4-tetrahydroquinolines have been extensively described in the literature due to the presence of this bicycle in many natural or pharmaceutical products, along with other industrial applications.[ 4 ] Direct reduction of the corresponding quinoline is still the best option for the preparation of tetrahydroquinolines.
Interestingly, pyrido[2,3-d]pyridazine may be viewed as an easily accessible precursor of the corresponding 1,2,3,4-tetrahydropyrido[2,3-d]pyridazine. To validate this hypothesis, compound 7d was treated with Pd/C under hydrogen pressure (Scheme [1]). Reduction of 7d for 48 hours under 40 psi of hydrogen led to the expected 1,2,3,4-tetrahydropyrido[2,3-d]pyridazine 10 in excellent yield (92%). We were also able to selectively reduce the triple bond into the alkene 9 (40 psi for 12 h, 80% yield), or into alkane 11 [79% yield, starting from 7c by using higher hydrogen pressure (60 psi)]. Interestingly, regardless of the hydrogenolysis conditions, no deprotection of the N-benzyl moiety was observed.
Due to its capability to establish multiple hydrogen-bond acceptor/donor interactions in the ATP binding site present in all protein kinases, pyrido[2,3-d]pyridazines 3–9, 11 and 1,2,3,4-tetrahydropyrido[2,3-d]pyridazine 10 appear to be promising compounds as protein kinase inhibitors. Preliminary screening of this focus library over four kinases (GSK3αβ, CDK5/p25, CK1, and DYRK1A)[5] [6] [7] [8] led to the identification of compound 8b as a CK1 inhibitor (IC50 = 10 μM).
To conclude, we described in this work several synthetic pathways that allow the regioselective introduction of chemical diversity on the pyrido[2,3-d]pyridazine scaffold. We also showed that the presence of the pyridine group did not interfere with the reactivity of the pyridazine ring towards palladium-catalyzed cross-coupling reactions, except for the Buchwald reaction at the 5-position. In addition, we reported the capability of this easily functionalized pyrido[2,3-d]pyridazine scaffold to act as a precursor of the corresponding 1,2,3,4-tetrahydropyrido[2,3-d]pyridazine.
Chemicals and solvents were purchased puriss p.A. from commercial suppliers. Analytical thin-layer chromatography was performed using silica gel plates (Merck 60F254) and plates were visualized by exposure to ultraviolet light. Compounds were purified using Armen spot flash chromatography on silica gel Merck 60 (particle size 0.040–0.063 mm). Yields refer to isolated compounds, estimated to be >97% pure as determined 1H NMR spectroscopic or HPLC analyses. The melting points are uncorrected. 1H and 13C NMR spectra were recorded with a Bruker Avance spectrometer operating at 300 or 400 MHz, and 100 MHz, respectively. All chemical shift values and coupling constants (J) are quoted in ppm and in Hz, respectively. Low-resolution mass spectra were performed with an Agilent Technologie 6100 Series instrument by the Analytical Service. Elementary analyses were obtained with a Perkin–Elmer 2400 elemental analyzer. Microwave irradiation was performed with a Biotage Initiator EXP.
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N-Benzyl-8-chloropyrido[2,3-d]pyridazin-5-amine (2a) and N-Benzyl-5-chloropyrido[2,3-d]pyridazin-8-amine (2b)
To a solution of compound 1 (2 g, 10 mmol) in DMF (20 mL) were added sodium carbonate (2.12 g, 20 mmol) and benzyl amine (1.64 mL, 15 mmol). The mixture was heated in a microwave at 130 °C for 30 min. The mixture was then washed with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The isomer mixture was separated by flash chromatography (EtOAc–heptane).
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N-Benzyl-8-chloropyrido[2,3-d]pyridazin-5-amine (2a)
Yield: 110 mg (0.4 mmol, 40%); white solid; mp 126−128 °C.
1H NMR (400 MHz, CDCl3): δ = 9.09 (dd, J = 4.4, 1.6 Hz, 1 H), 8.40 (dd, J = 8.3, 1.6 Hz, 1 H), 7.61 (dd, J = 8.3, 4.4 Hz, 1 H), 7.25−7.04 (m, 5 H), 6.35 (t, J = 5.1 Hz, 1 H), 4.72 (d, J = 5.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 155.3, 154.2, 147.8, 140.9, 138.1, 131.0, 128.7, 128.2, 127.6, 126.8, 116.6, 46.3.
Anal. Calcd for C14H11ClN4: C, 62.11; H, 4.10; N, 20.70. Found: C, 62.34; H, 4.23; N, 21.12.
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N-Benzyl-5-chloropyrido[2,3-d]pyridazin-8-amine (2b)
Yield: 140 mg (0.5 mmol, 50%); white solid; mp 154−156 °C.
1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, J = 4.4, 1.6 Hz, 1 H), 8.26 (dd, J = 8.3, 1.6 Hz, 1 H), 7.67 (dd, J = 8.3, 4.4 Hz, 1 H), 7.37–7.34 (m, 2 H), 7.27−7.16 (m, 3 H), 6.80 (t, J = 6.0 Hz, 1 H), 4.79 (d, J = 6.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 154.4, 154.0, 143.7, 138.4, 135.8, 133.4, 128.8, 128.2, 127.6, 127.4, 121.9, 45.5.
Anal. Calcd for C14H11ClN4: C, 62.11; H, 4.10; N, 20.70. Found: C, 62.23; H, 4.12; N, 20.92.
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5-(Benzylamino)pyrido[2,3-d]pyridazin-8(7H)-one (3a) and 8-(Benzylamino)pyrido[2,3-d]pyridazin-5(6H)-one (3b)
To a solution of compounds 2a or 2b (100 mg, 0.370 mmol) in acetic acid (1.5 mL) was added sodium acetate trihydrate (75.4 mg, 0.554 mmol). The mixture was heated in a microwave for 5 min at 120 °C. Acetic acid was evaporated until dryness and the residue was purified by flash chromatography to afford compounds 3a or 3b.
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5-(Benzylamino)pyrido[2,3-d]pyridazin-8(7H)-one (3a)
Purified by flash chromatography (MeOH–CH2Cl2, 15%).
Yield: 60 mg (0.255 mmol, 69%); white solid; mp 258−260 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.77 (s, 1 H), 9.05 (dd, J = 8.3, 1.3 Hz, 1 H), 8.64 (dd, J = 8.3, 1.3 Hz, 1 H), 7.91 (dd, J = 8.3, 4.5 Hz, 1 H), 7.38−7.29 (m, 5 H), 7.22 (m, 1 H), 4.48 (d, J = 5.5 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 157.0, 153.2, 144.2, 144.0, 139.7, 131.9, 128.1, 127.2, 127.1, 126.5, 121.8, 44.5.
MS (ESI): m/z = 253.
Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.90; H, 4.90; N, 22.43.
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8-(Benzylamino)pyrido[2,3-d]pyridazin-5(6H)-one (3b)
Purified by flash chromatography (EtOAc–Heptane, 60%).
Yield: 70 mg (0.281 mmol, 75%); white solid; mp 178−180 °C.
1H NMR (400 MHz, CDCl3): δ = 10.6 (br s, 1 H), 8.97 (dd, J = 4.6, 1.3 Hz, 1 H), 8.72 (dd, J = 8.1, 1.3 Hz, 1 H), 7.70 (dd, J = 8.1, 4.6 Hz, 1 H), 7.44−7.28 (m, 5 H), 6.37 (t, J = 6.5 Hz, 1 H), 4.61 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 159.1, 153.9, 146.2, 141.2, 138.7, 135.6, 128.7, 127.8, 127.4, 126.2, 124.2, 45.4.
MS (ESI): m/z = 253.
Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.96; H, 4.85; N, 22.24.
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N-Benzyl-5-(benzyloxy)pyrido[2,3-d]pyridazin-8-amine (4a)
Sodium metal (40 mg) was added slowly to benzyl alcohol (2 mL) in THF (2 mL) and the mixture was stirred at r.t. until the sodium completely disappeared. Compound 2b (100 mg, 0.370 mmol) was added and the mixture was stirred at 100 °C for 5 h. The organic solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (EtOAc–heptane, 50%) to afford 4a.
Yield: 106 mg (0.311 mmol, 84%); white solid; mp 124–126 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.15 (dd, J = 4.4, 1.4 Hz, 1 H), 8.47 (dd, J = 8.3, 1.4 Hz, 1 H), 8.47 (dd, J = 8.3, 1.4 Hz, 1 H), 7.93 (dd, J = 8.3, 4.4 Hz, 1 H), 7.75 (t, J = 5.9 Hz, 1 H), 7.53 (d, J = 7.2 Hz, 2 H), 7.42–7.28 (m, 7 H), 7.21 (t, J = 6.9 Hz, 1 H), 5.50 (s, 2 H), 4.72 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 154.0, 153.5, 152.1, 140.3, 137.1, 136.5, 131.5, 128.4, 128.2, 128.0, 127.8, 127.3, 126.4, 115.7, 67.6, 43.9.
MS (ESI): m/z = 343.
Anal. Calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.90; H, 5.60; N, 16.66.
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N-Benzyl-5-methoxypyrido[2,3-d]pyridazin-8-amine (4b)
To a solution of 2b (50 mg, 0.185 mmol) in MeOH (1 mL) was added sodium methoxide (20 mg, 0.369 mmol). The mixture was heated in a microwave at 120 °C for 30 min. MeOH was evaporated and the residue was purified by flash chromatography (EtOAc–heptane, 50%) to afford 4b.
Yield: 86 mg (0.321 mmol, 87%); white solid; mp 96–98 °C.
1H NMR (400 MHz, CDCl3): δ = 8.95 (dd, J = 4.4, 1.4 Hz, 1 H), 8.39 (dd, J = 8.3, 1.4 Hz, 1 H), 7.68 (dd, J = 8.3, 4.4 Hz, 1 H), 7.50–7.48 (m, 2 H), 7.38–7.28 (m, 3 H), 6.51 (t, J = 6.3 Hz, 1 H), 4.86 (d, J = 5.8 Hz, 2 H), 4.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.0, 153.3, 152.4, 139.3, 137.4, 131.9, 128.7, 128.2, 127.4, 126.3, 116.7, 54.6, 45.6.
MS (ESI): m/z = 267.
Anal. Calcd for C15H14N4O: C, 67.65; H, 5.30; N, 21.04. Found: C, 67.82; H, 5.44; N, 21.37.
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N-Benzyl-8-methoxypyrido[2,3-d]pyridazin-5-amine (4c)
To a solution of 2a (50 mg, 0.185 mmol) in MeOH (1 mL) was added sodium methoxide (20 mg, 0.369 mmol). The mixture was heated at reflux at 90 °C for 15 h. MeOH was evaporated and the residue was purified by flash chromatography (MeOH–CH2Cl2, 3%) to afford 4c.
Yield: 90 mg (0.336 mmol, 91%); white solid; mp 243−245 °C.
1H NMR (400 MHz, CDCl3): δ = 9.04 (dd, J = 4.4, 1.4 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.60 (dd, J = 8.3, 4.4 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 2 H), 7.24–7.16 (m, 3 H), 5.22 (br s, 1 H), 4.70 (br s, 2 H), 4.14 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.2, 154.1, 151.3, 138.7, 137.0, 129.9, 128.6, 128.3, 127.5, 126.0, 117.1, 54.8, 46.4.
MS (ESI): m/z = 267.
Anal. Calcd for C15H14N4O: C, 67.65; H, 5.30; N, 21.04. Found: C, 67.74; H, 5.35; N, 21.33.
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Synthesis of 6-Substituted 8-(Benzylamino)pyrido[2,3-d]pyridazin-5(6H)-ones 5a–f; General Procedure
To a solution of 3a or 3b (100 mg, 0.370 mmol) in DMF (1 mL) were added K2CO3 (60 mg, 0.436 mmol) and the appropriate alkyl halide (0.436 mmol). The mixture was stirred either at r.t. for 15 h or in a microwave for 1 h at 120 °C, depending on the alkyl halide. DMF was evaporated until dryness and the residue was purified by flash chromatography to afford the target compounds.
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6-Benzyl-8-(benzylamino)pyrido[2,3-d]pyridazin-5(6H)-one (5a)
Prepared using 2b and benzyl bromide, the reaction mixture stirred at r.t. for 15 h, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 93 mg (0.270 mmol, 73%); white powder; mp 88−90 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.08 (dd, J = 4.4, 1.4 Hz, 1 H), 8.59 (dd, J = 8.3, 1.4 Hz, 1 H), 7.88 (dd, J = 8.3, 4.4 Hz, 1 H), 7.57 (t, J = 6.3 Hz, 1 H), 7.37–7.35 (m, 2 H), 7.27–7.21 (m, 8 H), 5.10 (s, 2 H), 4.48 (d, J = 6.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.2, 154.1, 144.7, 140.1, 139.8, 137.3, 135.4, 128.2, 128.1, 128.0, 127.6, 127.1, 126.8, 126.5, 123.5, 53.1, 44.0.
MS (ESI): m/z = 343.
Anal. Calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.80; H, 5.60; N, 16.40.
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8-(Benzylamino)-6-methylpyrido[2,3-d]pyridazin-5(6H)-one (5b)
Prepared using 2b and methyl iodide, the reaction mixture stirred at r.t. for 15 h, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 187 mg (0.337 mmol, 91%); yellow solid; mp 126–128 °C.
1H NMR (400 MHz, CDCl3): δ = 8.80 (dd, J = 4.4, 1.4 Hz, 1 H), 8.61 (dd, J = 8.3, 1.4 Hz, 1 H), 7.55 (dd, J = 8.3, 4.4 Hz, 1 H), 7.35–7.18 (m, 5 H), 6.19 (t, J = 5.8 Hz, 1 H), 4.50 (d, J = 5.8 Hz, 2 H), 3.64 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.6, 153.4, 145.3, 140.7, 139.0, 135.8, 128.7, 128.1, 127.5, 126.1, 124.2, 45.5, 39.0.
MS (ESI): m/z = 267.
Anal. Calcd for C15H14N4O; C, 67.65; H, 5.30; N, 21.04. Found: C, 67.69; H, 5.39; N, 21.00.
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Ethyl 2-[8-(Benzylamino)-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl]acetate (5c)
Prepared using 2b and ethyl 2-chloroacetate, the reaction mixture stirred at r.t. for 15 h, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 103 mg (0.303 mmol, 82%); white solid; mp 95–97 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.12 (dd, J = 4.4, 1.4 Hz, 1 H), 8.60 (dd, J = 8.3, 1.4 Hz, 1 H), 7.91 (dd, J = 8.3, 4.4 Hz, 1 H), 7.51 (t, J = 6.1 Hz, 1 H), 7.40–7.21 (m, 5 H), 4.71 (s, 2 H), 4.47 (d, J = 6.3 Hz, 2 H), 4.14–4.09 (m, 2 H), 1.17 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 168.0, 156.7, 154.4, 144.9, 140.5, 139.9, 135.4, 128.0, 127.7, 127.0, 126.6, 123.2, 60.8, 52.0, 43.9, 14.0.
MS (ESI): m/z = 339.
Anal. Calcd for C18H18N4O3: C, 63.89; H, 5.36; N, 16.56. Found: C, 64.00; H, 5.37; N, 16.58.
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8-(Benzylamino)-6-(2-hydroxyethyl)pyrido[2,3-d]pyridazin-5(6H)-one (5d)
Prepared using 2b and 1-chloro-2-methoxy ethane, the reaction mixture heated in a microwave for 1 h at 120 °C, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 93 mg (0.300 mmol, 81%); yellow solid; mp 86–88 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.08 (dd, J = 4.4, 1.4 Hz, 1 H), 8.58 (dd, J = 8.3, 1.4 Hz, 1 H), 7.88 (dd, J = 8.3, 4.4 Hz, 1 H), 7.53 (t, J = 5.3 Hz, 1 H), 7.41 (d, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.21 (t, J = 5.8 Hz, 1 H), 4.50 (d, J = 6.1 Hz, 2 H), 4.10 (t, J = 5.8 Hz, 2 H), 3.57 (t, J = 5.8 Hz, 2 H), 3.13 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 156.4, 154.0, 144.6, 140.0, 135.4, 128.0, 127.5, 126.8, 126.5, 123.4, 68.6, 57.6, 47.9, 44.0, 40.1.
MS (ESI): m/z = 311.
Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.99; H, 5.87; N, 18.34.
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5-(Benzylamino)-7-methylpyrido[2,3-d]pyridazin-8(7H)-one (5e)
Prepared using 2a and methyl iodide, the reaction mixture was stirred at r.t. for 15 h. Extra 1 equivalent of methyl iodide was added and the mixture was stirred at r.t. for 2 h, and purified by flash chromatography (MeOH–CH2Cl2, 5%).
Yield: 90 mg (0.337 mmol, 91%); yellow solid; mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 8.96 (dd, J = 4.4, 1.4 Hz, 1 H), 8.12 (dd, J = 8.3, 1.4 Hz, 1 H), 7.57 (dd, J = 8.3, 4.4 Hz, 1 H), 7.33–7.10 (m, 5 H), 4.99 (t, J = 5.1 Hz, 1 H), 4.46 (d, J = 5.1 Hz, 2 H), 3.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.2, 153.5, 144.3, 143.0, 138.4, 130.6, 128.6, 128.3, 127.5, 126.5, 121.1, 46.4, 39.5.
MS (ESI): m/z = 267.
Anal. Calcd for C15H14N4O: C, 67.65; H, 5.30; N, 21.04. Found: C, 67.85; H, 5.34; N, 21.33.
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5-(Benzylamino)-7-(2-methoxyethyl)pyrido[2,3-d]pyridazin-8(7H)-one (5f)
Prepared using 2a and 1-chloro-2-methoxyethane, the reaction mixture stirred at r.t. for 15 h, and purified by flash chromatography (MeOH–CH2Cl2, 3%).
Yield: 102 mg (0.329 mmol, 89%); yellow solid; mp 143–145 °C.
1H NMR (400 MHz, CDCl3): δ = 8.89 (d, J = 4.0 Hz, 1 H), 8.24 (d, J = 7.4 Hz, 1 H), 7.54 (dd, J = 7.4, 4.0 Hz, 1 H), 7.52 (d, J = 7.4 Hz, 2 H), 7.31–7.15 (m, 3 H), 5.45 (br s, 1 H), 4.45 (d, J = 5.0 Hz, 2 H), 4.24 (t, J = 5.9 Hz, 2 H), 3.68 (t, J = 5.9 Hz, 2 H), 3.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.2, 153.3, 144.2, 143.3, 138.9, 131.0, 128.4, 128.1, 127.2, 126.6, 121.2, 69.4, 58.5, 49.7, 46.3.
MS (ESI): m/z = 311.
Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.80; H, 5.82; N, 18.32.
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Suzuki–Miyaura Reaction; General Procedure
A mixture of compounds 2a or 2b (100 mg, 0.370 mmol), sodium carbonate (105 mg, 0.991 mmol), [Pd(PPh3)4] (25.4 mg, 0.022 mmol), and substituted phenyl boronic acid (0.477 mmol) in a mixture of dimethoxyethane/H2O (3 mL/1 mL) were mixed in a microwave tube and flushed with argon for 1 min. The mixture was heated in the microwave at 120 °C for 30 min. After cooling, the solvent was evaporated and the organic residue was washed with H2O (20 mL), extracted with EtOAc (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography.
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N-Benzyl-8-phenylpyrido[2,3-d]pyridazin-5-amine (6a)
Prepared using 2a and phenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 60 mg (0.192 mmol, 52%); white solid; mp 84−86 °C.
1H NMR (400 MHz, MeOD-d 4): δ = 9.03 (dd, J = 4.4, 1.6 Hz, 1 H), 8.65 (dd, J = 8.5, 1.6 Hz, 1 H), 7.85−7.83 (m, 2 H), 7.47−7.41 (m, 5 H), 7.28−7.18 (m, 3 H), 4.86 (br s, 2 H), 4.74 (dd, J = 8.5, 4.4 Hz, 1 H).
13C NMR (100 MHz, MeOD-d 4): δ = 155.9, 155.7, 154.0, 143.5, 140.6, 137.2, 132.3, 131.6, 129.7, 129.5, 129.0, 128.9, 128.1, 127.3, 116.3, 46.6.
MS (ESI): m/z = 313.
Anal. Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.86; H, 5.30; N, 17.63.
#
3-[5-(Benzylamino)pyrido[2,3-d]pyridazin-8-yl]phenol (6b)
Prepared using 2a and 3-hydroxyphenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 63 mg (0.192 mmol, 52%); white solid; mp 180−182 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.39 (br s, 1 H), 9.16 (dd, J = 4.4, 1.4 Hz, 1 H), 8.85 (dd, J = 8.4, 1.4 Hz, 1 H), 8.33 (t, J = 5.5 Hz, 1 H), 7.90 (dd, J = 8.4, 4.4 Hz, 1 H), 7.45−7.42 (m, 2 H), 7.35−7.21 (m, 6 H), 6.80 (d, J = 8.0 Hz, 1 H), 4.86 (d, J = 5.5 Hz, 2 H)
13C NMR (100 MHz, DMSO-d 6): δ = 156.2, 154.6, 153.4, 151.4, 141.2, 139.6, 137.5, 136.4, 131.0, 128.5, 127.2, 126.7, 125.9, 121.2, 117.0, 114.9, 113.7, 44.1.
MS (ESI): m/z = 329.
Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C, 73.35; H, 4.65; N, 17.08.
#
{3-[5-(Benzylamino)pyrido[2,3-d]pyridazin-8-yl]phenyl}methanol (6c)
Prepared using 2a and 3-(hydroxymethyl)phenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 90%).
Yield: 69 mg (0.200 mmol, 54%); white solid; mp 146−148 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.18 (dd, J = 4.4, 1.6 Hz, 1 H), 8.87 (dd, J = 8.5, 1.6 Hz, 1 H), 8.37 (t, J = 5.6 Hz, 1 H), 7.92 (dd, J = 8.5, 4.4 Hz, 1 H), 7.86 (br s, 1 H), 7.80 (d, J = 7.4 Hz, 1 H), 7.46−7.23 (m, 7 H), 5.23 (t, J = 5.8 Hz, 1 H), 4.88 (d, J = 5.6 Hz, 1 H), 4.57 (d, J = 5.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 154.6, 153.5, 151.5, 141.8, 141.3, 139.8, 136.3, 131.1, 128.7, 128.2, 127.4, 127.2, 126.6, 126.1, 125.9, 125.8, 113.7, 63.0, 44.3.
MS (ESI): m/z = 343.
Anal. Calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.76; H, 5.28; N, 16.59.
#
N-Benzyl-5-phenylpyrido[2,3-d]pyridazin-8-amine (6d)
Prepared using 2b and phenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 72 mg (0.229 mmol, 62%); white solid; mp 194−196 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.17 (d, J = 4.3 Hz, 1 H), 8.32 (t, J = 6.0 Hz, 1 H), 8.24 (d, J = 8.3 Hz, 1 H), 7.92 (dd, J = 8.3, 4.3 Hz, 1 H), 7.65−7.19 (m, 10 H), 4.86 (d, J = 6.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 153.6, 153.5, 150.6, 140.0, 136.0, 133.9, 133.7, 129.4, 128.4, 127.4, 127.3, 126.5, 120.4, 43.8.
MS (ESI): m/z = 313.
Anal. Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.86; H, 5.49; N, 17.59.
#
3-[8-(Benzylamino)pyrido[2,3-d]pyridazin-5-yl]phenol (6e)
Prepared using 2b and 3-hydroxyphenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 100 mg (0.303 mmol, 82%); white solid; mp 240−242 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.63 (s, 1 H), 9.14 (dd, J = 4.4, 1.6 Hz, 1 H), 8.26−8.23 (m, 2 H), 7.90 (dd, J = 8.4, 4.4 Hz, 1 H), 7.44−7.21 (m, 6 H), 7.02−6.88 (m, 3 H), 4.83 (dd, J = 5.8 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 157.4, 153.6, 153.4, 150.6, 140.0, 137.2, 134.0, 133.7, 129.4, 128.1, 127.8, 127.3, 126.5, 120.3, 120.2, 116.3, 115.5, 43.8.
MS (ESI): m/z = 329.
Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C, 73.40; H, 5.21; N, 17.20.
#
{3-[8-(Benzylamino)pyrido[2,3-d]pyridazin-5-yl]phenyl}methanol (6f)
Prepared using 2b and 3-(hydroxymethyl)phenylboronic acid, and purified by flash chromatography (EtOAc–heptane, 90%).
Yield: 82 mg (0.240 mmol, 65%); white solid; mp 172−174 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.15 (dd, J = 4.4, 1.6 Hz, 1 H), 8.30−8.22 (m, 2 H), 7.90 (dd, J = 8.4, 4.4 Hz, 1 H), 7.57−7.21 (m, 9 H), 5.25 (t, J = 5.8 Hz, 1 H), 4.84 (d, J = 6.2 Hz, 2 H), 4.59 (d, J = 5.8 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 153.7, 153.5, 150.8, 142.7, 139.9, 135.7, 135.6, 133.9, 133.6, 128.3, 128.2, 127.8, 127.4, 127.3, 126.6, 120.3, 62.6, 43.7.
MS (ESI): m/z = 343.
Anal. Calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.89; H, 5.65; N, 16.10.
#
N-Benzyl-8-styrylpyrido[3,2-d]pyridazin-5-amine (6g)
Prepared using 2a and styrylboronic acid, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 86 mg (0.255 mmol, 69%); yellow solid; mp 118−200 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.24 (dd, J = 4.4, 1.6 Hz, 1 H), 8.83 (dd, J = 8.5, 1.6 Hz, 1 H), 8.40 (t, J = 5.3 Hz, 1 H), 8.17 (d, J = 6.3 Hz, 1 H), 7.97−7.88 (m, 2 H), 7.68 (d, J = 7.4 Hz, 2 H), 7.45−7.24 (m, 8 H), 4.87 (d, J = 5.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 154.2, 152.6, 149.8, 142.0, 138.4, 137.3, 133.5, 129.5, 128.8, 128.6, 128.4, 128.2, 127.8, 127.4, 125.5, 120.1, 113.7, 46.4.
MS (ESI): m/z = 339.
Anal. Calcd for C22H18N4: C, 78.08; H, 5.36; N, 16.56. Found: C, 78.22; H, 5.39; N, 16.71.
#
N-Benzyl-5-styrylpyrido[2,3-d]pyridazin-8-amine (6h)
Prepared using 2b and styrylboronic acid, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 73 mg (0.215 mmol, 58%); yellow solid; mp 151−152 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.15 (dd, J = 5.6, 1.3 Hz, 1 H), 8.95 (dd, J = 8.4, 1.3 Hz, 1 H), 8.31 (t, J = 6.4 Hz, 1 H), 8.00−7.93 (m, 2 H), 7.80−7.74 (m, 3 H), 7.45−7.21 (m, 8 H), 4.84 (d, J = 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.7, 153.0, 147.1, 138.9, 137.0, 134.4, 132.0, 128.9, 128.8, 128.6, 128.4, 128.3, 127.6, 127.3, 126.7, 121.3, 119.6, 45.4.
MS (ESI): m/z = 339.
Anal. Calcd for C22H18N4: C, 78.08; H, 5.36; N, 16.56. Found: C, 78.12; H, 5.31; N, 16.42.
#
Sonogashira Reaction; General Procedure
A mixture of 2a or 2b (200 mg, 0.74 mmol), bis(triphenylphosphine)palladium(II) dichloride (25.8 mg, 0.037 mmol), cupper iodide (14.02 mg, 0.0741 mmol) and an appropriate alkyne (0.957 mmol) were mixed in a microwave tube, and flushed with argon for 1 min. MeCN (1.7 mL) and Et3N (1.1 mL) were added and the mixture was flushed again with argon for 1 min. The mixture was heated in a microwave for 30 min at 80 °C, then the solvent was evaporated under reduced pressure and the residue was diluted with EtOAc (20 mL) and washed with sat. NaCl (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and the residue was purified by flash chromatography.
#
N-Benzyl-8-(phenylethynyl)pyrido[2,3-d]pyridazin-5-amine (7a)
Prepared using 2a and phenylacetylene, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 110 mg (0.325 mmol, 44%); yellow solid; mp 177−179 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.85 (dd, J = 8.4, 1.4 Hz, 1 H), 8.64 (t, J = 5.6 Hz, 1 H), 7.96 (dd, J = 8.4, 4.4 Hz, 1 H), 7.65−7.62 (m, 2 H), 7.49−7.26 (m, 8 H), 4.89 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 155.6, 153.1, 142.9, 139.3, 139.2, 131.5, 131.3, 129.1, 128.8, 128.2, 127.4, 126.7, 126.6, 122.1, 113.0, 93.2, 85.8, 44.4.
MS (ESI): m/z = 337.
Anal. Calcd for C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.90; H, 4.50; N, 16.29.
#
N-Benzyl-5-(phenylethynyl)pyrido[2,3-d]pyridazin-8-amine (7b)
Prepared using 2b and phenylacetylene, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 224 mg (0.666 mmol, 90%); yellow solid; mp 153−155 °C.
1H NMR (400 MHz, CDCl3): δ = 8.97 (dd, J = 4.4, 1.7 Hz, 1 H), 8.51 (dd, J = 8.3, 1.7 Hz, 1 H), 7.76 (dd, J = 8.3, 4.4 Hz, 1 H), 7.69−7.66 (m, 2 H), 7.51−7.30 (m, 8 H), 7.01 (t, J = 5.8 Hz, 1 H), 4.99 (d, J = 5.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 153.5, 138.6, 138.0, 134.0, 133.5, 132.1, 129.3, 128.9, 128.7, 128.5, 127.7, 127.1, 123.1, 122.4, 94.7, 84.1, 45.6.
MS (ESI): m/z = 337.
Anal. Calcd for C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.65; H, 4.69; N, 16.50.
#
N-Benzyl-5-{3-[(tert-butyldiphenylsilyl)oxy]prop-1-yn-1-yl}pyrido[2,3-d]pyridazin-8-amine (7c)
Prepared using 2b and tert-butyldiphenyl(prop-2-ynyloxy)silane, and purified by flash chromatography (EtOAc–heptane, 50%).
Yield: 238 mg (0.451 mmol, 61%); colorless oil.
1H NMR (400 MHz, DMSO-d 6): δ = 9.15 (dd, J = 4.4, 1.6 Hz, 1 H), 8.59 (t, J = 6.4 Hz, 1 H), 8.12 (dd, J = 8.3, 1.6 Hz, 1 H), 7.94 (dd, J = 8.3, 4.4 Hz, 1 H), 7.74−7.71 (m, 4 H), 7.50−7.39 (m, 8 H), 7.31−7.21 (m, 3 H), 4.83 (d, J = 6.4 Hz, 2 H), 4.79 (s, 2 H), 1.03 (s, 9 H).
13C NMR (100 MHz, DMSO-d 6): δ = 154.3, 153.4, 139.6, 135.8, 135.1, 132.9, 132.5, 130.0, 128.1, 128.0, 127.9, 127.3, 126.6, 122.4, 92.4, 79.7, 48.5, 43.7, 26.5, 18.8.
HRMS: m/z calcd for C33H32N4OSi: 528.2345; found: 528.2354.
#
Benzyl 5-[8-(Benzylamino)pyrido[2,3-d]pyridazin-5-yl]pent-4-ynoate (7d)
Prepared using 2b and benzyl pent-4-ynoate, and purified by flash chromatography (EtOAc–heptane, 90%).
Yield: 253 mg (0.599 mmol, 81%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.92 (dd, J = 4.4, 1.4 Hz, 1 H), 8.35 (dd, J = 8.3, 1.4 Hz, 1 H), 7.64 (dd, J = 8.3, 4.4 Hz, 1 H), 7.48–7.26 (m, 10 H), 6.96 (t, J = 5.8 Hz, 1 H), 5.18 (s, 2 H), 4.95 (d, J = 5.8 Hz, 2 H), 2.94–2.90 (m, 4 H), 2.82–2.76 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 158.8, 153.8, 153.7, 138.9, 138.2, 136.0, 134.3, 133.7, 129.4, 129.0, 128.9, 128.6, 128.5, 127.9, 127.3, 94.1, 76.0, 67.0, 45.7, 33.7, 16.0.
HRMS: m/z calcd for C26H22N4O2: 422.1743; found: 422.1744.
#
Buchwald Reaction; General Procedure
A mixture of 2a (100 mg, 0.370 mmol), Cs2CO3 (214 mg, 0.554 mmol), palladium acetate (2.488 mg, 0.011 mmol), and BINAP (13.8 mg, 0.022 mmol) were added under argon then the appropriate amine (0.370 mmol) and dioxane (1.5 mL) were added. The mixture was kept under argon for 2 min, then heated under reflux for 15 h at 112 °C. The solvent was evaporated under reduced pressure until dryness and the residue was purified by flash chromatography.
#
N 5,N 8-Dibenzylpyrido[2,3-d]pyridazine-5,8-diamine (8a)
Prepared using 2a and benzyl amine, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 92 mg (0.270 mmol, 73%); yellow solid; mp 140−142 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (dd, J = 4.4, 1.5 Hz, 1 H), 7.98 (dd, J = 8.3, 1.5 Hz, 1 H), 7.52 (dd, J = 8.3, 4.4 Hz, 1 H), 7.39−7.16 (m, 11 H), 6.28 (t, J = 5.6 Hz, 1 H), 4.75 (d, J = 5.6 Hz, 2 H), 4.68 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 152.7, 151.0, 148.8, 139.8, 139.6, 136.6, 130.0, 128.8, 128.7, 128.6, 128.3, 127.6, 127.3, 125.8, 115.8, 46.9, 45.7.
Anal. Calcd for C21H19N5: C, 73.88; H, 5.61; N, 20.51. Found: C, 73.50; H, 5.33; N, 20.64.
#
N 5-Benzyl-N 8-phenethylpyrido[2,3-d]pyridazine-5,8-diamine (8b)
Prepared using 2a and 2-phenyl ethyl amine, and purified by flash chromatography (MeOH–CH2Cl2, 5%).
Yield: 71 mg (0.200 mmol, 54%); white solid; mp 95−97 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (dd, J = 4.4, 1.6 Hz, 1 H), 7.96 (dd, J = 8.4, 1.6 Hz, 1 H), 7.53 (dd, J = 8.3, 4.4 Hz, 1 H), 7.39−7.37 (m, 2 H), 7.29−7.12 (m, 10 H), 6.09 (t, J = 5.8 Hz, 1 H), 4.69 (br s, 2 H), 4.59 (br s, 1 H), 3.84 (q, J = 6.5 Hz, 2 H), 3.00 (t, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 152.7, 151.1, 148.6, 140.0, 139.7, 136.7, 129.9, 129.1, 128.8, 128.6, 127.6, 126.3, 125.8, 115.8, 46.9, 42.7, 35.8.
MS (ESI): m/z = 357.
Anal. Calcd for C22H21N5: C, 74.34; H, 5.96; N, 19.70. Found: C, 74.65; H, 5.59; N, 19.40.
#
2-[5-(Benzylamino)pyrido[2,3-d]pyridazin-8-ylamino]butan-1-ol (8c)
Prepared using 2a and 2-(aminomethyl)butan-1-ol, and purified by flash chromatography (MeOH–CH2Cl2, 5%).
Yield: 30 mg (0.092 mmol, 25%); yellow solid; mp 78−80 °C.
1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, J = 4.4, 1.4 Hz, 1 H), 8.02 (dd, J = 8.3, 1.4 Hz, 1 H), 7.57 (dd, J = 8.3, 4.4 Hz, 1 H), 7.73–7.20 (m, 5 H), 6.17 (d, J = 6.3 Hz, 1 H), 4.76 (br s, 1 H), 4.63 (br s, 2 H), 4.07−4.02 (m, 1 H), 3.83 (dd, J = 10.9, 2.9 Hz, 1 H), 3.64 (dd, J = 10.9, 6.9 Hz, 1 H), 3.40 (br s, 1 H), 1.75–1.61 (m, 2 H), 1.00 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 151.9, 148.8, 139.4, 136.7, 130.2, 128.8, 128.6, 127.6, 126.1, 116.1, 67.4, 56.2, 46.9, 25.0, 11.1.
MS (ESI): m/z = 324.
Anal. Calcd for C18H21N5O: C, 66.85; H, 6.55; N, 21.66; Found: C, 66.90; H, 6.55; N, 21.68.
#
N 5-Benzyl-N 8-[2-(piperidin-1-yl)ethyl]pyrido[2,3-d]pyridazine-5,8-diamine (8d)
Prepared using 2a and 2-(piperidin-1-yl)ethanamine, and purified by flash chromatography (MeOH–H2O, 5%).
Yield: 105 mg (0.289 mmol, 78%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.84 (dd, J = 4.4, 1.4 Hz, 1 H), 8.04 (dd, J = 8.3, 1.4 Hz, 1 H), 7.50 (dd, J = 8.3, 4.4 Hz, 1 H), 7.33–7.12 (m, 5 H), 6.41 (t, J = 5.1 Hz, 1 H), 4.83 (br s, 1 H), 4.64 (br s, 2 H), 3.63–3.59 (m, 2 H), 2.61 (t, J = 6.3 Hz, 2 H), 2.38 (br s, 4 H), 1.54–1.48 (m, 4 H), 1.38–1.34 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 152.6, 151.3, 148.5, 139.7, 136.7, 130.0, 128.6, 128.4, 127.3, 125.6, 115.8, 57.8, 54.5, 46.7, 38.3, 26.0, 24.6.
MS (ESI): m/z = 363.
Anal. Calcd for C21H26N6: C, 69.58; H, 7.23; N, 23.19. Found: C, 69.66; H, 7.44; N, 23.60.
#
N 5-Benzyl-N 8-(2-methoxyethyl)pyrido[2,3-d]pyridazine-5,8-diamine (8e)
Prepared using 2a and 2-methoxyethanamine, and purified by flash chromatography (MeOH–CH2Cl2, 5%).
Yield: 70 mg (0.226 mmol, 61%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.94 (dd, J = 4.4, 1.6 Hz, 1 H), 8.03 (dd, J = 8.3, 1.6 Hz, 1 H), 7.62 (dd, J = 8.3, 4.4 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.36–7.28 (m, 3 H), 6.39 (t, J = 5.4 Hz, 1 H), 4.74 (br s, 2 H), 4.61 (br s, 1 H), 3.82 (q, J = 4.9 Hz, 2 H), 3.71 (t, J = 5 Hz, 2 H), 3.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 151.3, 148.7, 139.7, 136.8, 129.8, 128.7, 127.7, 125.8, 115.8, 71.5, 60.0, 46.9, 41.2.
MS (ESI): m/z = 310.
Anal. Calcd for C17H19N5O: C, 66.00; H, 6.19; N, 22.64; O, 5.17. Found: C, 66.21; H, 6.30; N, 22.78.
#
N 5-Benzyl-N 8-isopentylpyrido[2,3-d]pyridazine-5,8-diamine (8f)
Prepared using 2a and 3-methylbutan-1-amine, and purified by flash chromatography (EtOAc–heptane, 70%).
Yield: 41 mg (0.126 mmol, 34%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.92 (d, J = 4.4 Hz, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.62 (dd, J = 8.3, 4.4 Hz, 1 H), 7.43–7.42 (m, 2 H), 7.34–7.26 (m, 3 H), 6.05 (t, J = 4.5 Hz, 1 H), 4.74 (br s, 2 H), 3.63 –3.58 (m, 2 H), 1.77–1.73 (m, 1 H), 1.66–1.60 (m, 2 H), 0.95 (d, J = 7.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 151.2, 148.4, 139.6, 136.8, 130.2, 128.8, 128.6, 127.6, 125.9, 116.0, 46.8, 39.9, 38.6, 26.3, 22.8.
MS (ESI): m/z = 322.
Anal. Calcd for C19H23N5: C, 71.00; H, 7.21; N, 21.79. Found: C, 71.20; H, 7.29; N, 21.90.
#
(E)-Benzyl 5-[8-(Benzylamino)pyrido[2,3-d]pyridazin-5-yl]pent-4-enoate (9)
To a solution of 7d (80 mg, 0.189 mmol) in EtOH (8 mL) in a hydrogenation flask, was added slowly Pd/C (10wt.%, 8 mg). The reaction mixture was kept under hydrogen at 40 psi for 14 h. The mixture was filtered through Celite, which was washed with MeOH. MeOH was evaporated under reduced pressure and the residue was purified by flash chromatography (EtOAc–heptanes, 50%) to afford 9.
Yield: 64 mg (0.151 mmol, 80%); yellow solid; mp 129–131 °C.
1H NMR (400 MHz, CDCl3): δ = 8.86 (dd, J = 4.4, 1.4 Hz, 1 H), 8.19 (dd, J = 8.3, 1.4 Hz, 1 H), 7.60 (dd, J = 8.3, 4.4 Hz, 1 H), 7.41–7.40 (m, 2 H), 7.30–7.18 (m, 8 H), 6.87–6.85 (m, 2 H), 6.78 (t, J = 5.8 Hz, 1 H), 5.06 (s, 2 H), 4.86 (d, J = 5.8 Hz, 2 H), 2.66–2.51 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 172.9, 153.8, 152.9, 147.0, 139.2, 136.1, 135.0, 134.9, 132.2, 128.8, 128.7, 128.4, 128.3, 127.6, 126.5, 123.1, 120.8, 66.5, 45.6, 33.8, 28.7.
MS (ESI): m/z = 425.
Anal. Calcd for C26H24N4O2: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.77; H, 5.80; N, 13.36.
#
5-[8-(Benzylamino)-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl]pentanoic Acid (10)
To a solution of 7d (50 mg, 0.118 mmol) in EtOH (5 mL) in a hydrogenation flask, was added slowly Pd/C (10wt.%, 8 mg). The reaction mixture was kept under hydrogen at 60 psi for 48 h. Palladium was filtered through Celite, which was washed with MeOH. MeOH was evaporated under reduced pressure and the residue was purified by flash chromatography (MeOH–H2O, 10%) to afford 10.
Yield: 37 mg (0.108 mmol, 92%); yellow solid; mp 129–131 °C.
1H NMR (400 MHz, MeOD-d 4): δ = 7.36–7.20 (m, 5 H), 4.52 (br s, 2 H), 3.48 (t, J = 5.8 Hz, 2 H), 2.74–2.68 (m, 4 H), 2.19 (t, J = 6.5 Hz, 2 H), 1.96–1.90 (m, 2 H), 1.66–1.59 (m, 4 H).
13C NMR (100 MHz, MeOD-d 4): δ = 182.1, 150.9, 147.9, 140.1, 139.8, 129.6, 129.3, 128.5, 112.9, 46.8, 41.9, 38.3, 29.7, 28.9, 26.8, 22.3, 19.9.
MS (ESI): m/z = 341.
Anal. Calcd for C19H24N4O2: C, 67.04; H, 7.11; N, 16.46. Found: C, 67.24; H, 7.15; N, 16.59.
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3-{5-(Benzylamino)pyrido[2,3-d]pyridazin-8-yl}propan-1-ol (11)
To a solution of 7c (100 mg, 0.190 mmol) in EtOH (10 mL) in a hydrogenation flask, was added slowly Pd/C (10wt.%, 10 mg). The reaction mixture was kept under hydrogen at 60 psi for 14 h. Palladium was filtered through Celite, which was washed with MeOH. The solvent was evaporated under reduced pressure to give the expected silylated compound, without any further purification.
Yield: 0.150 mmol (79%); white powder; mp 138−139 °C.
1H NMR (400 MHz, CDCl3): δ = 8.94 (d, J = 4.4 Hz, 1 H), 8.28 (d, J = 8.3 Hz, 1 H), 7.69−7.63 (m, 5 H), 7.50−7.27 (m, 11 H), 6.79 (t, J = 5.8 Hz, 1 H), 4.91 (d, J = 5.8 Hz, 2 H), 3.86 (t, J = 7.9 Hz, 2 H), 3.27 (t, J = 8.1 Hz, 2 H), 2.16−2.11 (m, 2 H), 1.10 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 162.8, 153.9, 152.8, 151.5, 139.2, 135.7, 134.0, 132.7, 129.8, 128.7, 128.3, 127.8, 127.5, 126.5, 121.5, 63.5, 45.5, 31.9, 28.6, 27.0, 19.4.
To a solution of the silylated compound (40 mg, 0.075 mmol) in MeCN (1 mL), TBAF (1 M in THF, 0.4 mL) was added dropwise. The mixture was stirred for 5 h at r.t., then the solvent was evaporated under reduced pressure. The residue was purified (MeOH–CH2Cl2, 5%) to afford compound 11.
Yield: 15 mg (0.051 mmol, 68%); white solid; mp 199–201 °C.
1H NMR (400 MHz, CDCl3): δ = 8.88 (dd, J = 4.4, 1.6 Hz, 1 H), 8.22 (dd, J = 8.4, 1.6 Hz, 1 H), 7.64 (dd, J = 8.4, 4.4 Hz, 1 H), 7.41−7.11 (m, 5 H), 6.71 (t, J = 5.6 Hz, 1 H), 3.82 (d, J = 5.6 Hz, 2 H), 3.70 (t, J = 5.9 Hz, 2 H), 3.41 (s, 1 H), 3.22 (t, J = 7 Hz, 2 H), 2.11−2.04 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 154.1, 153.1, 151.3, 139.0, 135.0, 132.6, 128.9, 128.4, 127.6, 126.7, 121.6, 62.2, 45.6, 30.7, 28.8.
MS (ESI): m/z = 295.
Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03. Found: C, 69.22; H, 6.44; N, 19.31.
#
#
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
- Supporting Information
-
References
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- 1k Loh VM, Cockcroft XL, Dillon KJ, Dixon L, Drzewiecki J, Everlsey PJ, Gomez S, Hoare J, Kerrigan F, Matthews IT. W, Menear KA, Martin NM. B, Newton RF, Paul J, Smith GC. M, Vile J, Whittle AJ. Bioorg. Med. Chem. Lett. 2005; 15: 2235
- 1l Kaminskas LM, Pyke SM, Burcham PC. Org. Biomol. Chem. 2004; 2: 2578
- 2 Pakulska W, Malinowskl Z, Szczesniak AK, Czarnecka E, Epsztajn J. Arch. Pharmacol. 2009; 342: 41
- 3 Kaizerman JA, Aaron W, An SZ, Austin R, Brown M, Chong A, Huang T, Hungate R, Jiang B, Johnson MG, Lee G, Lucas BS, Orf J, Rong MQ, Toteva MM, Wickramasinghe D, Xu GF, Ye QP, Zhong WD, McMinn DL. Bioorg. Med. Chem. Lett. 2010; 20: 4607
- 4 For a review, see: Katritzky AR, Rachwal S, Rachwal B. Tetrahedron 1996; 52: 15031
- 5 Meijer L, Flajolet M, Greengard P. Trends Pharmacol. Sci. 2004; 25: 471
- 6 Knockaert M, Greengard P, Meijer L. Trends Pharmacol. Sci. 2002; 23: 417
- 7 Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M. Cell Signal. 2005; 17: 675
- 8 Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH, Song WJ. J. Biol. Chem. 2007; 282: 34850
For selected examples, see:
-
References
- 1a Tao M, Raddatz R, Aimone LD, Hudkins RL. Bioorg. Med. Chem. Lett. 2011; 21: 6126
- 1b Sridhara AM, Reddy KR. V, Keshavayya J, Goud PS. K, Somashekar BC, Bose P, Peethambar SK, Gaddam SK. Eur. J. Med. Chem. 2010; 45: 4983
- 1c Alla MS. M. A, Hegab MI, Taleb NA. A, Hasabelnaby SM, Goudah A. Eur. J. Med. Chem. 2010; 45: 1267
- 1d Khalil AM, Berghot MA, Gouda MA. Eur. J. Med. Chem. 2009; 44: 4448
- 1e Cashman JR, Voelker T, Zhang HT, O’Donnell JM. J. Med. Chem. 2009; 52: 1530
- 1f Vina D, del Olmo E, Lopez-Perez JL, Feliciano AS. Tetrahedron 2009; 65: 1574
- 1g Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT. W, Moore S, O’Connor MJ, Smith GC. M, Martin NM. B. J. Med. Chem. 2008; 51: 6581
- 1h Strappaghetti G, Brodi C, Giannaccini G, Betti L. Bioorg. Med. Chem. Lett. 2006; 16: 2575
- 1i Cockcroft XL, Dillon KJ, Dixon L, Drzewiecki J, Kerrigan F, Loh VM, Martin NM. B, Menear KA, Smith GC. M. Bioorg. Med. Chem. Lett. 2006; 16: 1040
- 1j Piatnitski EL, Duncton MA. J, Kiselyov AS, Katoch-Rouse R, Sherman D, Milligan DL, Balagtas C, Wong WC, Kawakami J, Doody JF. Bioorg. Med. Chem. Lett. 2005; 15: 4696
- 1k Loh VM, Cockcroft XL, Dillon KJ, Dixon L, Drzewiecki J, Everlsey PJ, Gomez S, Hoare J, Kerrigan F, Matthews IT. W, Menear KA, Martin NM. B, Newton RF, Paul J, Smith GC. M, Vile J, Whittle AJ. Bioorg. Med. Chem. Lett. 2005; 15: 2235
- 1l Kaminskas LM, Pyke SM, Burcham PC. Org. Biomol. Chem. 2004; 2: 2578
- 2 Pakulska W, Malinowskl Z, Szczesniak AK, Czarnecka E, Epsztajn J. Arch. Pharmacol. 2009; 342: 41
- 3 Kaizerman JA, Aaron W, An SZ, Austin R, Brown M, Chong A, Huang T, Hungate R, Jiang B, Johnson MG, Lee G, Lucas BS, Orf J, Rong MQ, Toteva MM, Wickramasinghe D, Xu GF, Ye QP, Zhong WD, McMinn DL. Bioorg. Med. Chem. Lett. 2010; 20: 4607
- 4 For a review, see: Katritzky AR, Rachwal S, Rachwal B. Tetrahedron 1996; 52: 15031
- 5 Meijer L, Flajolet M, Greengard P. Trends Pharmacol. Sci. 2004; 25: 471
- 6 Knockaert M, Greengard P, Meijer L. Trends Pharmacol. Sci. 2002; 23: 417
- 7 Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M. Cell Signal. 2005; 17: 675
- 8 Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH, Song WJ. J. Biol. Chem. 2007; 282: 34850
For selected examples, see:
