Functional Pyrazolo[1,5- a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

Abstract

Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.

Keywords: N-heterocyclic compounds; antitumor scaffold; enzymatic inhibitory; functionalization; organic synthesis; pyrazolo[1,5-a]pyrimidine.

Figure 1

Pyrazolo[1,5-a]pyrimidine with (a) the constituent rings and (b) the modified periphery in accordance with the retrosynthetic analysis.

Figure 2

Molecular structures of commercial compounds bearing the PP motif highlighted in brownish-red.

Scheme 1

One-pot protocol to obtain 5,7-dichloro-2-hetarylpyrazolo[1,5-a]pyrimidine 3.

Scheme 2

Synthesis examples of fluorinated pyrazolo[1,5-a]pyrimidines (a) 6 and (b) 9.

Scheme 3

Synthesis of (a) 5-aryl-12a–c and (b) 7-arylpyrazolo[1,5-a]pyrimidines 14.

Scheme 4

(a) Obtention of 16 and (b) regioselective synthesis of 17.

Scheme 5

Synthesis of pyrazolo[1,5-a]pyrimidines 20a–ac from β-enaminones 19a–l.

Scheme 6

Examples of pyrazolo[1,5-a]pyrimidines with nitrogenous groups at position 7, compounds 23a–h.

Scheme 7

Synthesis of the PP 26 by using 1-methyluracil (25) as a 1,3-biselecrophylic system.

Scheme 8

Synthesis of 7-alkynylpyrazolo[1,5-a]pyrimidines 28a–t under reflux in ethanol.

Scheme 9

Use of diarylsubstituted azidochalcones 30 in the synthesis of the 6-amino-2,5,7-triaryl-PP.

Scheme 10

Synthesis of the cyanide probe 33 from the dimethoxychalcone 32.

Scheme 11

Examples of regioselective synthesis employing ynones. Highlights the obtention of the intermediate 37.

Scheme 12

Synthesis of 5-hydroxypyrazolo[1,5-a]pyrimidines (a) 39a–f (poor yields, an opportunity for research) and (b) 39g.

Scheme 13

Synthesis of pyrazolo[1,5-a]pyrimidines 42a–c using arylidenemalononitriles 41a–c.

Scheme 14

MW-assisted synthesis of 6-(aryldiazenyl)pyrazolo[1,5-a]pyrimidines 44a–g using β-ketonitriles 43.

Scheme 15

Synthesis of pyrazolo[1,5-a]pyrimidines 46a–e using the ketene 45.

Scheme 16

Examples of multicomponent synthesis of pyrazolo[1,5-a]pyrimidines (a) 49 and (b) 51a–f.

Scheme 17

Pseudo-multicomponent synthesis of 5-amino-2,7-diarylpyrazolo[1,5-a]pyrimidines 54.

Scheme 18

Rh-catalyzed Multicomponent synthesis of variously substituted pyrazolo[1,5-a]pyrimidines 58a–at.

Scheme 19

Synthesis of 6-aryl-5-aroylpyrazolo[1,5-a]pyrimidines 60a–c by a palladation step.

Scheme 20

Synthesis of 5-aryl-7-methylpyrazolo[1,5-a]pyrimidines 64a–f via intramolecular Diels–Alder reaction.

Scheme 21

Development of fluorescent probes with biological activity via the synthesis of fused derivatives 66.

Scheme 22

MW-assisted synthesis of the hybrid system bisbenzofuran—bispyrazolopyrimidine 68.

Scheme 23

Preparation of fused pyrazolo[1,5-a]pyrimidines to (a) benzene 70 and (b) furan 72.

Scheme 24

Synthesis of tricyclic derivatives bearing cycloalkanes such as (a) cyclohexane 74 and (b) cyclooctane 77.

Scheme 25

Functionalization of the position 3 and 5 via Suzuki cross coupling reaction of (a) 36, (b) 81 and (c) 84.

Scheme 26

Synthesis of 3-arylpyrazolo[1,5-a]pyrimidines (a) 88 and (b) 91, and of (c) the 5-aryl derivative 94 by Suzuki coupling.

Scheme 27

Examples of functionalization by Suzuki coupling with the addition of (a) pyrazolic and (b) cyclopropyl moieties.

Scheme 28

Generation of a chiral carbon in coupling product 103 by a Cu-catalyzed Sonogashira reaction.

Scheme 29

Pd-Catalyzed synthesis of (a) 2-(pyridin-4-ylethynyl)PP 106 and (b) 5-(4-fluorophenylethynyl)PP 108.

Scheme 30

Pd-catalyzed synthesis of 3-aryl 109 and 7-arylpyrazolo[1,5-a]pyrimidines 110 starting from PP.

Scheme 31

Synthesis of 3-aryl-2-phenylpyrazolo[1,5-a]pyrimidines 112a–g by Pd-catalyzed C–H activation.

Scheme 32

Pd-catalyzed synthesis of 7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidines 115a–f and 116a–f.

Scheme 33

Use of Grubbs catalyst to obtain macrocycles having PP through ring closure metathesis.

Scheme 34

C–H functionalization of PP by using the 5-(diphenylphosphanyl)pyridine 118.

Scheme 35

Synthesis of the amino derivatives (a) 81 and (b) 112a via NAS reactions.

Scheme 36

Synthesis of 7-(N-arylamino)pyrazolo[1,5-a]pyrimidines 125a–e starting from the 5,7-dichloroderivative 124.

Scheme 37

Rh-catalyzed synthesis of the amides 128a–i by C–H activation.

Scheme 38

Synthesis of biologically active amides (a) 131 and (b) 134 through benzotriazole derivatives (HATU).

Scheme 39

Synthesis of 7-aryl-3-formylpyrazolo[1,5-a]pyrimidines 135a–k under Vilsmeier–Haack conditions.

Scheme 40

Synthesis of formylated pyrazolo[1,5-a]pyrimidines (a) 3-formyl 138 and (b) 6-formyl 140.

Scheme 41

Synthesis of 3-halo and 3-nitropyrazolo[1,5-a]pyrimidines 142a–i and 143a–d via aromatic substitution.

Scheme 42

Examples of (a) nitration and (b) halogenation reactions of pyrazolo[1,5-a]pyrimidines.

Scheme 43

Reduction reactions over the pyrazolo[1,5-a]pyrimidine derivatives (a) 44, (b) 143 and (c) 23a.

Scheme 44

Synthesis of the macrocyclic pyrazolo[1,5-a]pyrimidine 155.

Scheme 45

Lamie’s synthesis of (a) 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidines 158 and (b) pyrazolopyridimines 159.

Scheme 46

Synthesis of biologically active 2,7-diarylpyrazolo[1,5-a]pyrimidines 162 and 163.

Scheme 47

Synthesis of pyrazolo[1,5-a]pyrimidines with N-mustard residue.

Figure 3

Substituent positions to increase the activity of pyrazolo[1,5-a]pyridimines.

Scheme 48

Synthesis of the pyrazolo[1,5-a]pyrimidines 170a–m as novel larotrectinib analogs.

Scheme 49

Synthesis of pyridine-fused pyrazolo[1,5-a]pyrimidines 174a–q starting from the pyrazolo[3,4-b]pyridine 17.

Scheme 50

Synthesis of amides 176a–u having the 7-arylpyrazolo[1,5-a]pyrimidine fragment.

Scheme 51

Synthesis of pyrazolo[1,5-a]pyrimidines derivatives 178 with potential activity against CDK2 enzyme.

Scheme 52

Synthesis of the 2-(benzothiazol-2-yl)pyrazolo[1,5-a]pyrimidine 181 with great cytotoxic activity.

Scheme 53

Synthesis sequence of PP derivative 187a starting from the 3-aminopyrazole 5.

Figure 4

Main interactions that improve the activity of compound 187a within the PDE2A enzyme.

Scheme 54

(a) Synthesis of pyrazolo[1,5-a]pyrimidine salt 190a. (b) Analysis of better amino group for the cellular activity.

Scheme 55

(a) Synthesis of potent RET kinase inhibitor 193. (b) Mains substitutions to find the better activity.

Scheme 56

Synthesis of pyrazolo[1,5-a]pyrimidines 195a–g that were able to inhibit tyrosine kinase in cancer cells.

Scheme 57

Synthesis of pyrazolo[1,5-a]pyrimidines with potential activity against histone lysine d methylases.