Pyrazolo pyridine-5 -carboxamides

In the pyrazolo [ 1,5-a]pyridine series, the reaction of hydrazine with the 2,3-dimethoxycarbonyl derivative afforded the corresponding 2-hydrazide, whereas saponification and decarboxylation gave the 3-carboxylic acid.169 Further, several 2-substituted 3-carboxamides, -hydrazides, and -carboxylic acids were obtained,169,239 using standard methods. Decarboxylation was also reported.169 A number of transformations of py razolo [3,4-h]pyridine... 

The formamide reaction has been successfully used to convert a 2-amino-pyridine-3-carboxamide to pyrido[2,3-d]pyrimidin-4-ones (see 3)220 3-aminopyrazole-4-carboxamide (see 15) to pyrazolo[3,4-rf ] pyrimidin-4-ones (see 16)118 4-aminopyrazole-3-carboxamide to pyrazolo[4,3-d]pyrimi-din-7-ones (see 17)221 many 4-amino-1,2,3-triazole-5-carboxamides (see 20) to 8-azapurin-6-ones (see 21)157,217-222—226 and 4-aminoimidazole-5-car-boxamides (see 18) to purin-6-ones (see 19).124-202-227 228 Secondary amines are suitable starting materials, as in the conversion of 4-amino-l,2,3-triazole-5-(jV-methyl)carboxamide and its 3-benzyl63 and... 

The l-aryl-3-trifluorometylpyrazole-5-carboxamide group is present in many of the orally available blood coagulation factor Xa inhibitors. Pinto and co-workers found in their medicinal chemistry program that a fluorinated pyrazole was an optimal five-membered heterocyclic core. Thus, two members of the 3-trifluoromethylpyrazole-5-carboxamide series were advanced to preclinical development (Fig. 2a) [81]. An additional structural modification, the incorporation of an aminobenzisoxazole moiety at N1 instead of the benzylamine group, led to the discovery of razaxaban (Fig. 2b), a potent, selective, and orally bioavailable inhibitor of factor Xa with in vivo efficacy in antithrombotic models [82], The amide hydrolysis observed in vivo could be modulated by introducing bicyclic core variants at the carboxamide portion, such as l/f-pyrazolo[4,3-rf pyrimidin-7(6//)-oneor 1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridine-7-one [83]. 

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