Simon Maechling

Synthesis and Biochemical Testing of 3-(Carboxyphenylethyl)imidazo[2,1-f][1,2,4]triazines as Inhibitors of AMP Deaminase

C-Ribosyl imidazo[2,1-f][1,2,4]triazines and 3-[2-(3-carboxyphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ols represent two classes of known AMP deaminase inhibitors. A combination of the aglycone from the former class with the ribose phosphate mimic from the latter led to the 3-[2-(3-carboxyphenyl)ethyl]imidazo[2,1-f][1,2,4]triazines, which represent a new class of AMP deaminase inhibitors. The best compound, 3-[2-(3-carboxy-5,6,7,8-tetrahydronaphthyl)ethyl]imidazo[2,1-f][1,2,4]triazine (8), was a good inhibitor of all three human AMPD recombinant isozymes (AMPD1, AMPD2, and AMPD3; IC50 = 0.9-5.7 μM) but a poor inhibitor of the plant recombinant enzyme (Arabidopsis FAC1; IC50 = 200 μM).

Synthesis of a solid-phase amino imidazotriazine library via palladium catalyzed direct arylation.

Heteroarenes, including imidazoles and triazines, are important structural units frequently found in natural products, pharmaceuticals, and agrochemicals. The biological importance and structural variation of heterocyclic derivatives provide a significant synthetic challenge, particularly when concerned with efficiently synthesizing large numbers of discrete analogues. Modern combinatorial chemistry plays a key role in the search for lead structures displaying biological activity and represents a powerful methodology for the synthesis of compound libraries for biological evaluation. Considering the frequent occurrence of heterocyclic frameworks in known pharmaceutical and agrochemical biologically active entities, they make an attractive target for diversification utilizing combinatorial synthetic approaches. Of particular importance to lead discovery is the incorporation of novel heterocyclic cores into library design and production. A good example is the imidazo[2,1-f ][1,2,4]triazine core 1 (Figure 1), which represents a currently little known heterocylic system but which clearly has an interesting biological potential as illustrated by the adenosine deaminase inhibitor 5, the antiviral agent 6, the GABA agonist 7, and the tyrosine kinase inhibitor 8. In the current work, we focused our attention on the use of the 7-amino-imidazo[2,1-f][1,2,4]triazine (2) (Figure 1) as an attractive core structure that we envisaged could be derivatized to give a protein kinase targeted library of general structure 3. For the production of the library, we planned to use a Hecklike direct arylation reaction to functionalize the C-3 position (Scheme 1). The direct arylation reaction of imidazotriazines and of many other heterocyclic systems has been previously reported but has, to the best of our knowledge, not been used to functionalize resin bound imidazole based heterocycles. This reaction has some advantages over traditional cross-coupling methods (e.g., Stille, Suzuki, and Negishi), in that there is no need to synthesize heterocyclic halides or organometallic intermediates (B, Sn, Zn). In addition, undesired side reactions such as protodehalogenation and protodemetalation do not affect the purity of the final products, thus simplifying or even avoiding the need for postsynthesis purification. This paper discloses the synthesis and characterization of a sample solidphase library of 20 compounds prepared using IRORI MicroKan technology. Our synthesis program started from the amide 11 (Scheme 1), which we envisaged could be directly transformed into a resin-bound amine 12 by adaptating recently published solution-phase chemistry. The starting heterocyclic amide 11 can be synthesized in three steps from the imidazole 9 or in four steps from the triazine 10 (Scheme 1). Four simple alkyamines were chosen for the first diversity point R1 (Figure 2). These amines were attached to a 2-(4formyl-3-methoxyphenoxy)ethyl (FMPE) polystyrene resin by reductive amination to give resins 14 (contained in 20 MicroKans) (Scheme 2). The substitution reaction to attach the heterocycle to the resin was carried out by treating the resins 14 and the heterocyclic amide 11 in DMF with DBU, followed by addition of PyBOP and heating to 60 °C for 66 h. Filtration and thorough washing of the MicroKans afforded the resin-bound intermediates 16. Cleavage of trial MicroKans at this stage afforded good yields of products 4 which are also of interest as potential kinase inhibitors. Five simple aryl bromides were chosen for the second diversity point R2 (Figure 2). The key palladium catalyzed arylation coupling step to generate intermediate 17 on the solid phase (Scheme 2) was performed under a nitrogenatmosphere with reagent grade solvents. No extensive drying or degassing protocols were necessary. A 5-fold excess of aryl halide and base was used to drive the reaction to completion. Since workup and purification involved a simple filtration, this did not cause any postsynthesis purification problems. Following arylation the products were cleaved from the resin using 50% TFA in CH2Cl2 to afford the products 3 listed in Table 1 and shown in Figure 3. The products were isolated in modest to good yield and in high purity demonstrating an advantage of this approach when compared to conventional coupling methodologies. The purities of the compounds were measured using 1H NMR and both evaporative light scattering (ELS) and diode array detectors (DAD, 220 and 260 nm). There was a good overall agreement between compound purities determined by 1H NMR, ELS, and UV at 260 nm. The 1H NMR and mass spectra for all compounds were entirely in agreement with the assigned structures (see Supporting Information). The electron-deficient aryl halide 15{1} reacted as a very efficient electrophile in the arylation reaction affording products 3{1,1}, 3{2,1}, 3{3,1}, and 3{4,1} in excellent purity >97% as determined by 1H NMR (Table 1, entries 1, 6, 11, 16). The deactivated aryl halides 15{2} and 15{4} also gave the products in excellent purity >95% (Table 1). The direct arylation reaction also proved highly successful with the relatively sterically hindered substrate 15{3}, affording 3{1,3}, 3{2,3}, 3{3,3}, 3{4,3} (Table 1, entries 3, 8, 13, 18) although some nonarylated product could be detected after cleavage (<5%). Utilization of the relatively more electron rich aryl halide 15{5} afforded the products with the lowest average purity in the test subset, although even here the purity was mostly good, laying at around 90% * To whom correspondence should be addressed. E-mail: simon.maechling@ bayercropscience.com (S.M.) or stephen.lindell@bayercropscience.com (S.D.L.). J. Comb. Chem. 2010, 12, 818–821 818