Synthesis and Structure-Activity Relationship of Tetra-Substituted Cyclohexyl Diol Inhibitors of Proviral Insertion of Moloney Virus (PIM) Kinases

J Med Chem. 2020 Dec 10;63(23):14885-14904. doi: 10.1021/acs.jmedchem.0c01279.

Wooseok Han ¹ ², Yu Ding ¹ ³, Zheng Chen ¹ ⁴, John L Langowski ¹ ⁵, Cornelia Bellamacina ¹ ⁶, Alice Rico ¹ ⁷, Gisele A Nishiguchi ¹ ⁸, Jiong Lan ¹ ⁹, Gordana Atallah ¹ ¹⁰, Mika Lindvall ¹ ¹¹, Song Lin ¹ ¹², Richard Zang ¹ ¹³, Paul Feucht ¹, Tatiana Zavorotinskaya ¹ ¹⁴, Yumin Dai ¹ ¹⁵, Pablo Garcia ¹ ¹⁶, Matthew T Burger ¹ ¹⁷

Affiliations

1 Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
2 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
3 BeiGene, Ltd., San Mateo, California 94403, United States.
4 Boston Analytical, Salem, New Hampshire 03079, United States.
5 Kite, a Gilead Company, Emeryville, California 94608, United States.
6 Crystallographic Consulting, Berkeley, California 94704, United States.
7 Exelixis, Alameda, California 94502, United States.
8 St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
9 Genfleet Therapeutics, Inc., Pudong District, Shanghai 201203, China.
10 Pharmacyclics, an AbbVie Company, Sunnyvale, California 94085, United States.
11 Recursion Pharmaceuticals, Salt Lake City, Utah 84101, United States.
12 Astex Pharmaceuticals Inc., Pleasanton, California 94588, United States.
13 Global Blood Therapeutics, South San Francisco, California 94080, United States.
14 ORIC Pharmaceuticals, South San Francisco, California 94080, United States.
15 Bristol Myers Squibb, Redwood City, California 94158, United States.
16 Circle Pharma, Inc., South San Francisco, California 94080, United States.
17 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

PMID: 33258605 DOI: 10.1021/acs.jmedchem.0c01279

Abstract

Overexpression of Pim 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.

Name
Email *

	Sorry, but the email address you supplied was invalid.