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Herein, we describe a two-step sequential flow synthesis: Pd-catalyzed aerobic oxidation to an aldehyde 2, which is then converted by reductive amination in H-Cube® PRO into CPL302415 (3). CPL302415 is our new PI3Kδ inhibitor, which is now under evaluation for the treatment of systemic lupus erythematosus. The process was optimized using the DoE approach and generalized to other biologically active derivatives of CPL302415., Competing Interests: The authors declare the following financial interest/personal relationships which may be considered as potential competing interests. All contributors to this work at the time of their direct involvement in the project were full-time employees of Celon Pharma S.A. M. Wieczorek is the CEO of Celon Pharma S.A. Some of the authors are the shareholders of Celon Pharma S.A., (This journal is © The Royal Society of Chemistry.)

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3K δ ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.

Herein, we describe the development of a green, scalable flow Pd-catalyzed aerobic oxidation for the key step in the synthesis of CPL302415, which is a new PI3K δ inhibitor. Applying this environmental-friendly, sustainable catalytic oxidation we significantly increased product yield (up to 84%) and by eliminating of workup step, we improved the waste index and E factor (up to 0.13) in comparison with the stoichiometric synthesis. The process was optimized by using the DoE approach., Competing Interests: The authors declare the following financial interest/personal relationships which may be considered as potential competing interests. All contributors to this work (except Z. Ochal) at the time of their direct involvement in the project were full-time employees of Celon Pharma SA. M. Wieczorek is the CEO of Celon Pharma S.A. Some of the authors are the shareholders of Celon Pharma S.A. This work was financially supported by The National Centre for Research and Development (POIR.01.02.00-00-0085/18-00)., (This journal is © The Royal Society of Chemistry.)

Phosphoinositide 3-kinase δ (PI3K δ ), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5- a ]pyrimidine with IC 50 values in the low nanomolar range and high selectivity against the PI3K δ isoform. CPL302253 ( 54 ), the most potent compound of all the structures obtained, with IC 50 = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α , β , γ , δ ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5- a ]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K δ , displaying IC 50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 ( 6 ) showed the highest activity (IC 50 value of 18 nM for PI3K δ ), good selectivity (for PI3K δ relative to other PI3K isoforms: PI3K α / δ = 79; PI3K β / δ = 1415; PI3K γ / δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.

Asthma is a common chronic inflammatory disease. Although effective asthma therapies are available, part of asthmatic population do not respond to these treatment options. In this work we present the result of development of CPL302-253 molecule, a selective PI3Kδ inhibitor. This molecule is intended to be a preclinical candidate for dry powder inhalation in asthma treatment. Studies we performed showed that this molecule is safe and effective PI3Kδ inhibitor that can impact many immune functions. We developed a short, 15-day HDM induced asthma mouse model, in which we showed that CPL302-253 is able to block inflammatory processes leading to asthma development in vivo., Competing Interests: PG, KG, MB, JD, JHK, KM, DS, KD, JP, BMZ and MW are employees of Celon Pharma and received funding from Celon Pharma. AH and EGH are employees of LabMagister Training and Science Ltd. and received funding from LabMagister Training and Science Ltd. MW and JP owns stocks of Celon Pharma. The authors declare that they have no conflict of interest.