Heterocyclic Chemistry in Drug Discovery

JIE JACK LI, PhD, is a chemist at Bristol-Myers Squibb Company. He has authored or edited several books published by Wiley, including Name Reactions in Heterocyclic Chemistry, Name Reactions for Functional Group Transformations, Name Reactions for Homologations (Part I and Part ll ), Name Reactions for Carbocyclic Ring Formations, Contemporary Drug Synthesis, The Art of Drug Synthesis, and Modern Drug Synthesis.

• Chapter 1 Introduction 11.1 Nomenclature of Heterocycles 11.2 Aromatic Heterocycles 41.3 Importance of Heterocycles in Life 51.4 Importance of Heterocycles in Drug Discovery 8PART I FIVE-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 17Chapter 2 Pyrroles 182.1 Introduction 182.2 Reactivity 222.3 Construction of the Pyrrole Rings 342.4 Palladium Chemistry of Pyrroles 442.5 Possible Liabilities of Pyrrole-Containing Drugs 462.6 Problems 492.7 References 51Chapter 3 Indoles 543.1 Introduction 543.2 Reactivity of the Indole Ring 583.3 Construction of the Indole Rings 643.4 Oxindole-Containing Drug Synthesis 883.5 Cross-coupling Reactions for Indoles 913.6 Azaindole 1043.7 Possible Liabilities of Drugs Containing 3-Methylindole 1093.8 Problems 1113.9 References 113Chapter 4 Furans, Benzofurans, Thiophenes, and Benzothiophenes 1194.1 Introduction 1194.2 Furans and Benzofuran 1264.3 Thiophenes and Benzothiophenes 1584.4 Possible Liabilities of Furan and Thiophene-Containing Drugs 1854.5 Problems 1874.6 References 191PART II FIVE-MEMBERED HETEROCYCLES WITH TWO OR MORE HETEROATOMS 197Chapter 5 Pyrazoles, Pyrazolones, and Indazoles 1985.1 Introduction 198 viii5.2 Reactivity of the Pyrazoles and Indazoles 2025.3 Construction of the Pyrazole and Indazole Rings 2065.4 Pyrazolone-containing Drugs 2175.5 Indazole-containing Drugs 2205.6 Problems 2235.7 References 226Chapter 6 Oxazoles, Benzoxazoles, and Isoxazoles 2316.1 Introduction 2316.2 Construction of the Heterocyclic Ring 2356.3 Reactivity 2446.4 Cross-Coupling Reactions 2506.5 Selected Reactions of Isoxazoles 2696.6 Possible Liabilities of Oxazole-Containing Drugs 2706.6 Problems 2716.7 References 278Chapter 7 Thiazoles and Benzothiazoles 2837.1 Introduction 2837.2 Reactions of the Thiazole Ring 290 ix7.3 Palladium Chemistry Undergone by Thiazoles and Benzothiazoles 3007.4 Construction of the Thiazole Ring 3077.5 Construction of the Benzothiazole Ring 3157.6 Possible Liabilities of Drugs Containing Thiazoles and Benzothiazoles 3217.7 Thiazoles and Benzothiazoles as Bioisosteres 3237.8 Problems 3257.9 References 328Chapter 8 Imidazoles and Benzimidazoles 3338.1 Introduction to Imidazole 3338.2 Reactivity of the Imidazole Ring 3358.3 Construction of the Imidazole Ring 3418.3.1 Debus 3428.4 Conversion of Imidazolines to Imidazoles 3538.5 Possible Liabilities of Imidazole-Containing Drugs 3538.6 Introduction to Benzimidazole 3548.7 Synthesis of Benzimidazoles: Classical Approaches 3578.8 Construction of the Benzimidazole Core Using Transition Metal- Mediated Approaches 3618.9 Alternative Cyclization Approach toward Benzimidazoles: Process Route toward BYK405879 3678.10 Problems 3688.11 References 370Chapter 9 Triazoles and Tetrazoles 3739.1 Introduction 3739.2 Reactivity of the Triazole and Tetrazole Ring 3759.3 Construction of the Triazole Ring 3849.4 Possible Liabilities of Triazole-Containing Drugs 3929.5 Problems 3939.6 References 394PART III SIX-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 397Chapter 10 Pyridines 39810.1 Introduction 39810.2 Reactivity of the Pyridine Ring 40410.3 Construction of the Pyridine Ring 42510.4. Problems 45710.5 References 459Chapter 11 Quinolines and Isoquinolines 47111.1 Introduction 47111.2 Reactivity of the Quinoline and Isoquinoline Ring 47411.3 Construction of Quinoline Core 49211.4 Construction of Isoquinoline Core 51311.5 Possible Liabilities of Drugs Containing Quinoline and Isoquinoline Ring 52611.6 Problems 52711.7 References 528PART IV SIX-MEMBERED HETEROCYCLES WITH TWO HETEROATOMS 535Chapter 12 Pyrazines and Quinoxalines 53612.1 Introduction 53612.2 Formation of Diazines 53912.3 Reactivity of the Molecules 54512.4 Coupling Reactions 55312.5 Problems 56212.6 References 565Chapter 13 Pyrimidines 56913.1 Introduction 56913.2 Construction of the Pyrimidine Ring 57313.3 Synthesis of Pyrimidine-Containing Drugs 59013.4 Problems 60813.5 References 611Chapter 14 Quinazolines and Quinazolones 61514.1 Introduction 61514.2 Reactions of Quinazolines and Quinazolinones 61814.3 Quinazoline and Quinazolinone Synthesis 62514.4 Synthesis of Quinazoline- and Quinazolinone-Containing Drugs 63614.5 Problems 64114.6 References 644Subject Index 647

“The book can also serve as a textbook for undergraduates and graduates, which is highlighted by the inclusion of interesting problem sets.”  (Angew. Chem. Int. Ed, 1 February 2014)“In summary, both students and experts in the field would find useful information in this book.”  (ChemMedChem, 1 January 2014)“[Li] has assembled a team of 20 contributing authors from academia and the industry to write this book, which … comes across as a successful fusion of heterocyclic chemistry and drug discovery, from which intending medicinal chemists will derive much benefit, or as Li puts it, a ‘jump-start’ on the competition!.”  (Chemistry in Australia, 1 July 2013)