Introduction of a substituent on the endocyclic NH of 3-aminoindazoles was accomplished by treating seven with an alkyl hydrazine RNHNH2 Me, HOCH2CH2) or by means of alkylation of 18, during which the 3-amino group was selectively protected in the form of a phthalimide. While ureas 22a,c,d were conveniently synthesized by means of response of anilines 21a,c,d with the corresponding aryl isocyanates, the Suzuki coupling reaction concerning iodide 20b and Veliparib urea boronate 16b was picked for your preparation of urea 22b to avoid the probable side reaction within the alcohol performance in aniline 21b with all the isocyanate. Analogs having a substituent with the 7-position in the aminoindazole were synthesized as outlined in Scheme 3. Fluoridedirected lithiation of 23a-d with lithium diisopropylamide and subsequent reaction with carbon dioxide yielded acids 24a-d, which had been then converted into amides 25a-d via the corresponding acid chlorides. Dehydration of 25a-d to form nitriles 26a-d was carried out by using thionyl chloride in warm dimethylformide. With nitriles 26a-d in hand, anilines 28a-d have been readily synthesized by way of the cyclization with hydrazine followed from the Pd-mediated coupling.
Contrary to ligand library the case of aniline 9, the 7-substituents over the indazole ring in 28a-d sterically suppressed the competitive N-acylation response at the N1-position and allowed anilines 28a-d to react with m-tolyl isocyanate to generate desired ureas 29a-d. Nitriles 26a and 26b not simply served because the intermediates for your synthesis of ureas 29a and 29b, but in addition supplied accessibility to analogs that has a selection of other substituents with the 7-position of 3-aminoindazole.
Therefore, demethylation of 26b with BBr3 followed by an O-alkylation from the developed phenol led to many O-alkylated solutions , from which ureas 34a-f were readily synthesized. Similarly, analogs with an aminomethyl-linked substituent with the 7-position of 3-aminoindazole such as 43a and 43b may very well be synthesized from bromide 39, which was prepared through benzylic bromination of 26a. Success and Discussion Kinase enzymatic assays were carried out using the homogeneous time-resolved fluorescence protocol inside the presence of a higher concentration of ATP. Offered that KDR plays a primary role in tumor angiogenesis, optimization of potency against KDR was emphasized from the SAR studies. The 1st compound of this series tested inside the KDR assay was 3-aminoindazole aniline 9. A moderate inhibitory activity 4790 nM) was measured for 9. This exercise was really very similar to that proven from the corresponding thienopyrimidine aniline 4 4600 nM), indicating the 3-aminoindazole nucleus certainly held the possible like a promising new template for RTK inhibitors. The fact is, just as was observed inside the thienopyrimidine series, the KDR potency improved remarkably when 9 was converted to an N,N?-diaryl urea. Phenyl urea 17a 64 nM) was about 75-fold alot more potent than 9. A more enhanced potency was observed for m-tolyl urea 17b 3 nM).