Phosphodiesterase type 4 (PDE4) is a cAMP-specific hydrolase; its inhibition is beneficial for treating inflammatory diseases like asthma and COPD but limited by side effects such as nausea and emesis. Targeting the PDE4B subtype may improve the therapeutic index. Building on the pyrazole-based PDE4 inhibitor ibudilast A and our previous 7-(hetero)aryl substituted pyrazolopyrimidine B, we designed the fused heterocyclic scaffold D. Herein, we report a (Pd/C-mediated)coupling–iodocyclization–coupling strategy and a new H3PO3-mediated condensation reaction for pyrazolopyrimidine synthesis to generate a D-based compound library. Key compound 1 was prepared from ethyl 3-amino-1H-pyrazole-4-carboxylate via N-acylation, bromination, and deacylation. 2-Bromopyrazolo[1,5-a]pyrimidines 3 were synthesized by H3PO3-mediated condensation of 1 and aryl ketone-derived reactants 2, then reacted with terminal alkynes under Sonogashira conditions to yield 2-alkynyl derivatives 5. Intramolecular iodocyclization of 5 gave 7-iodo derivatives 6, which underwent further Sonogashira/Heck/Suzuki coupling to produce 7-alkynyl/aryl/alkenyl derivatives 7. Among tested compounds, 7c, 7d, 7g, 7h, and 7i showed significant PDE4B inhibition (85%, 93%, 66%, 74%, 74% at 30μM, respectively). Compound 7d was promising in cell-based assays: it modulated cAMP levels in HEK 293 cells and inhibited LPS-induced TNF-α production in RAW 264.7 cells (vs. reference compound rolipram). Preliminary safety evaluation in zebrafish embryos showed no mortality for 7d (10/20μM) and only mild locomotor effects, whereas rolipram (10/20μM) caused mortality and lordosis. Thus, 7d was identified as a novel and potentially safe PDE4 inhibitor candidate.