Colony-stimulating factor 1 receptor (CSF1R) is an attractive therapeutic target for triple-negative breast cancer (TNBC) because of its central role in regulating the tumor microenvironment. Structure-guided optimization of a series of 7-aminoquinazoline-based CSF1R inhibitors led to the identification of compound 28 as a next-generation lead candidate. Incorporation of an indole-containing linker effectively exploited the glycine selectivity pocket, resulting in markedly improved selectivity over c-KIT and other closely related type III receptor tyrosine kinases while maintaining subnanomolar CSF1R inhibitory activity (IC50 = 0.66 nM). Optimization of the 7-position solubilizing side chain further improved aqueous solubility, microsomal stability, and oral pharmacokinetic properties while preserving potent CSF1R inhibition. Compound 28 exhibited a favorable kinase selectivity profile together with substantially improved oral exposure and bioavailability in both rats and mice. Despite limited single-agent activity, BPR1R070 synergistically enhanced the antitumor activity of paclitaxel in MDA-MB-231 cells and produced near-complete tumor growth inhibition in an MDA-MB-231 xenograft model without overt toxicity. The combination efficacy observed in an immunodeficient xenograft model further suggests that selective CSF1R inhibition may enhance the responsiveness of TNBC cells to paclitaxel in addition to its established immunomodulatory effects. Collectively, these findings establish compound BPR1R070 as a promising preclinical development candidate and demonstrate that selective CSF1R inhibition represents a viable combination strategy for taxane-based therapy in TNBC.