Synthesis of regioisomeric 2,5‐bis‐substituted‐aza‐benzothiopyranoindazoles

Abstract

The synthesis of 6‐chloro‐9‐nitro‐benzothiopyranopyridin‐5‐ones 2a, 2b and 2c has been accomplished. Chemotype 2d could not be prepared since attempts to cyclize 3‐(2‐nitro‐5‐chlorophenoxy)pyridine‐2‐carboxylic acid (1d) led to the decarboxylation product 3‐(2‐nitro‐5‐chlorothiophenoxy) pyridine (40). Analogues 2a, 2b or 2c on treatment with the respectively substituted hydrazine led to the 2‐(substituted)‐5‐nitro 7, 8‐ or 9‐aza substituted chemotypes 3a‐7a, 8b, and 9c‐13c. The reduction of the nitro groups of these substrates was effected by treatment with hydrogen gas (palladium catalyst) or by stannous chloride to yield the 5‐amino chemotypes 15a‐18a, 20b and 21c‐24c, respectively. The conversion of these derivatives to the 2,5‐bis (alkylamino)‐7‐, 8‐ and 9‐aza benzothiopyranoindazoles listed in Table 3 was accomplished by direct alkylations, acylations, followed by reduction of the amido group with Red‐Al or lithium aluminum hydride, or by reductive alkylations in the presence of sodium cyanoborohydride. The removal of the protective BOC‐group was effected by treatment of the appropriate substrates with anhydrous hydrogen chloride to afford the respective hydrochloride salts listed in Table 4.

Recent Advances in the Chemistry of Indazoles

“…A promising example is CL‐958 which is in clinical evaluation for prostate cancer treatment. In this context, aza‐bioisosters of CL‐958 were prepared 92…”

Osmium(IV) complexes with 1H- and 2H-indazoles: Tautomer identity versus spectroscopic properties and antiproliferative activity

“…Some substituted indazoles exhibit relevant biological properties for development as anticancer drugs [9–15] . One of the tetrasubstituted indazoles, namely, CI-958, entered clinical trials for prostate cancer treatment about a decade ago [16] . From the unsubstituted indazole derivatives the most prominent example is the ruthenium(III) compound (H 2 ind)[ trans -Ru III Cl 4 (Hind) 2 ] (KP1019, Hind = 1 H -indazole), which is now in clinical trials as an anticancer agent against metastatic solid tumors [17,18] .…”

One-pot synthesis of 1-alkyl-1H-indazoles from 1,1-dialkylhydrazones via aryne annulation

“…1). 7 Various methods for the synthesis of the 1H-indazole core have been developed. 8 However, most of them employ harsh reaction conditions, thus have limited the scope and applicability.…”