Liverpool ChiroChem Technical Overview

1. Liverpool ChiroChem Technical Overview Chief Executive Officer: Dr. Paul Colbon (paul.colbon@liverpoolchirochem.co.uk) Chief Scientific Officer: Dr. Jiwu Ruan (jiwu.ruan@liverpoolchirochem.co.uk) www.liverpoolchirochem.com

2. Our expertise The founding team consists of chemists with academic and industrial experience that have developed state-of-the-art synthetic methods in asymmetric hydrogenation /transfer hydrogenation and palladium chemistry. The team is also experienced in process development and tech transfer. • Asymmetric Hydrogenation /Transfer Hydrogenation (AH /ATH) • – Offering access to a wide variety of chiral products or APIs J. Am. Chem. Soc. 2008,130, 14450. J. Am. Chem. Soc. 2008, 130, 13208. J. Am. Chem. Soc.2009, 131, 6967. J. Am. Chem. Soc.2014, 136, 4031. Angew. Chem. Int. Ed. 2006, 45, 6718. Angew. Chem. Int. Ed. 2009, 48, 6524. Angew. Chem. Int. Ed. 2010, 49, 7548. Angew. Chem. Int. Ed.2011, 123, 1104. Angew. Chem. Int. Ed. 2013, 52, 1668 .

3. Our expertise • Pd-Catalysed Coupling Reactions – powerful strategy for construction of new C–C and C–X bonds, widely applied in APIs synthesis Acc. Chem. Res. 2011, 44, 614. J. Am. Chem. Soc. 2005, 127, 751. J. Am. Chem. Soc. 2008, 130, 2424. J. Am. Chem. Soc. 2008, 130, 10510. J. Am. Chem. Soc. 2010, 132, 16689. Angew. Chem. Int. Ed. 2006, 45, 4152.

4. Our products and services • Building blocks; • Fragment /Screening libraries; • Hit-to-lead optimisation; • Process development for APIs or key intermediates synthesis; • Custom synthesis; • Fee-for-service (FFS) and Full-time-equivalent (FTE) projects.

5. Specialist product ranges: sp3-rich chiral N-heterocycles – Production of sp3-rich chiral N-heterocycles that can be used as building blocks, fragments or screening compounds:

6. Recent examples:

7. Project example: Hit-to-lead optimisation • One of our customers got a hit with a 4-heteroarylpiperidine core: • Problems encountered when attempting to make building blocks for hit-to-lead optimisation; • LCC designed the synthetic route which was tolerant of the functionality our customer wanted to incorporate on the aryl ring; • New process was used to supply ~20 building blocks that allowed efficient analogue synthesis to explore SAR.

8. Project example: Process development 1 • Niraparib Tosylate: Phase III candidate for the treatment of ovarian and breast cancer: • LCC’s process chemistry team developed a highly efficient synthetic route to the key chiral piperidine intermediates which provide access to Niraparib in >99.9% ee and has already been piloted on kilogram scale; • LCC can also provide the piperidine intermediate analogues to aid the new drug discovery.

9. Project example: Process development 2 • LOXO-101 (ARRY-470): Phase II candidate for the treatment of cancer: • LCC’s process chemistry team developed a highly efficient synthetic route to the key chiral pyrrolidine intermediate which provides access to LOXO-101 in >99.9% ee and has already been piloted on kilogram scale; • LCC can also provide the pyrrolidine intermediate analogues to aid the new drug discovery.

10. Project example: Process development 3 • A key intermediate of a early stage drug candidate for one of our customers: • LCC’s process chemistry team developed a highly efficient synthetic route to this key chiral 1,4-dioxane intermediate in >99.5% ee and has already been piloted on kilogram scale; • LCC can also provide the 1,4-dioxane intermediate analogues to aid the new drug discovery.

11. Project example: Process development 4 • PPDA-001: pre-clinical candidate for the treatment of cancer: • LCC’s process chemistry team developed an efficient asymmetric hydrogenation procedure via DKR for synthesis of the key di-substituted chiral piperidine intermediate in >95% ee and >90% de. To the best of our knowledge, our procedure is the best procedure so far for producing this intermediate. It is now being scaled up in our kilo-lab.