Table Of ContentDrug Discovery with Privileged
Building Blocks
Drug Discovery with Privileged
Building Blocks
Tactics in Medicinal Chemistry
Jie Jack Li and Minmin Yang
First edition published 2022
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Library of Congress Cataloging-in-Publication Data
Names: Li, Jie Jack, author. | Yang, Minmin, author.
Title: Drug discovery with privileged building blocks : tactics in medicinal chemistry / Jie Jack Li, Minmin Yang.
Description: Boca Raton : CRC Press, 2021. | Includes bibliographical references and index.
Identifiers: LCCN 2021006031 | ISBN 9781032041735 (hardback) | ISBN 9781032041681 (paperback) |
ISBN 9781003190806 (ebook)
Subjects: LCSH: Pharmaceutical chemistry. | Drugs—Design. | Drug development.
Classification: LCC RS403 .L52 2021 | DDC 615.1/9—dc23
LC record available at https://lccn.loc.gov/2021006031
ISBN: 978-1-032-04173-5 (hbk)
ISBN: 978-1-032-04168-1 (pbk)
ISBN: 978-1-003-19080-6 (ebk)
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by codeMantra
Contents
Preface...............................................................................................................................................xi
Authors ...........................................................................................................................................xiii
Chapter 1 Alkynes ........................................................................................................................1
Alkyne-Containing Drugs ...........................................................................................1
Alkynes in Drug Discovery .........................................................................................3
Synthesis of Some Alkyne-Containing Drugs ...........................................................11
References ..................................................................................................................14
Chapter 2 Azaindoles ..................................................................................................................17
Azaindole-Containing Drugs .....................................................................................17
Azaindoles in Drug Discovery ...................................................................................19
Synthesis of Some Azaindole-Containing Drugs ......................................................21
Bartoli Reaction .....................................................................................................21
Batcho–Leimgruber Reaction ...............................................................................22
Radical Aromatization ..........................................................................................23
Suzuki Coupling ....................................................................................................24
Sonogashira Reaction ............................................................................................25
References ..................................................................................................................26
Chapter 3 Azetidines ...................................................................................................................29
Azetidine-Containing Drugs ......................................................................................29
Azetidines in Drug Discovery ....................................................................................29
Synthesis of Some Azetidine-Containing Drugs .......................................................31
References ..................................................................................................................32
Chapter 4 Bicyclic Pyridines Containing Ring-Junction N ........................................................33
Bicyclic Pyridine-Containing Drugs ..........................................................................33
Bicyclic Pyridines in Drug Discovery ........................................................................34
Synthesis of Some Bicyclic Pyridines ........................................................................37
References ..................................................................................................................39
Chapter 5 Bicyclo[1.1.1]pentyl (BCP) as an sp3 Carbon-Rich Bioisostere
for para-Phenyl and tert-Butyl Groups ......................................................................41
There is Something about BCP ..................................................................................41
Bicyclo[1.1.1]pentanes in Drug Discovery ..................................................................44
Synthesis of Some Bicyclo[1.1.1]pentane-Containing Drugs .....................................46
References ..................................................................................................................48
Chapter 6 Bicyclo[2.2.2]octane (BCO) as a 3D-Rich Bioisostere
for the para-Phenyl Group .........................................................................................49
Merits of sp3-Rich Carbon Bioisosteres—Escape from Flatland ..............................49
v
vi Contents
Bicyclo[2.2.2]octanes in Drug Discovery ..................................................................50
Synthesis of Some Bicyclo[2.2.2]octane-Containing Drugs ......................................53
References ..................................................................................................................55
Chapter 7 Bicyclo[3.1.0]hexanes .................................................................................................57
Bicyclo[3.1.0]hexane-Containing Drugs ....................................................................57
Bicyclo[3.1.0]hexanes in Drug Discovery ..................................................................59
Bicyclo[3.1.0]hexanes as Bioisosteres of Cyclohexanes ........................................59
Utility of Bicyclo[3.1.0]hexanes in Medicinal Chemistry .....................................61
Synthesis of Some Bicyclo[3.1.0]hexane-Containing Drugs ......................................63
References ..................................................................................................................65
Chapter 8 Bridge-Fused Rings as m-Phenyl Bioisosteres ...........................................................67
3-D-Rich Bioisosteres for the Phenyl Ring in Drug Discovery .................................68
Synthesis of Some Drugs Containing 3-D-Rich Bioisosteres
for the m-Phenyl Ring ................................................................................................71
References ..................................................................................................................73
Chapter 9 Cubanes, Are We There Yet? .....................................................................................75
Cubane-Containing Drugs .........................................................................................75
Cubanes in Drug Discovery .......................................................................................75
Synthesis of Some Cubane-Containing Building Blocks ..........................................80
References ..................................................................................................................82
Chapter 10 Cyclobutanes ..............................................................................................................85
Cyclobutane-Containing Drugs .................................................................................85
Cyclobutanes in Drug Discovery ...............................................................................86
Synthesis of Some Cyclobutane-Containing Drugs ..................................................89
References ..................................................................................................................90
Chapter 11 Cyclohexanes ..............................................................................................................93
Cyclohexane-Containing Drugs .................................................................................93
Cyclohexanes in Drug Discovery ...............................................................................96
Synthesis of Some Cyclohexane-Containing Drugs ................................................101
References ................................................................................................................104
Chapter 12 Cyclopentanes ..........................................................................................................107
Cyclopentane-Containing Drugs ..............................................................................107
Cyclopentanes in Drug Discovery ............................................................................108
Synthesis of Some Cyclopentane-Containing Drugs ...............................................110
References ................................................................................................................112
Chapter 13 Cyclopropane Derivatives as Metabolically More Robust Bioisosteres
for Linear Alkyl Substituents ...................................................................................113
References ................................................................................................................116
Contents vii
Chapter 14 Deazapurines ............................................................................................................117
References ................................................................................................................120
Chapter 15 Furopyridines ...........................................................................................................121
Furopyridine-Containing Drugs ..............................................................................121
Furopyridines in Drug Discovery ............................................................................123
Synthesis of Some Furopyridine-Containing Drugs ................................................126
References ................................................................................................................127
Chapter 16 Indazoles ..................................................................................................................129
Indazole-Containing Drugs ......................................................................................129
Indazoles in Drug Discovery ....................................................................................130
Synthesis of Some Indazole-Containing Drugs .......................................................137
References ................................................................................................................140
Chapter 17 Indoles ......................................................................................................................143
Indole-Containing Drugs .........................................................................................143
Indoles in Drug Discovery .......................................................................................146
Representative Bioisosteres .................................................................................146
Possible Liabilities of Drugs Containing 3-Methylindole ...................................148
Synthesis of Some Indole-Containing Drugs ...........................................................149
References ................................................................................................................151
Chapter 18 Oxetanes ...................................................................................................................153
Oxetane-Containing Drugs ......................................................................................153
Oxetanes in Drug Discovery ....................................................................................153
Synthesis of Some Oxetane-Containing Drugs .......................................................157
References ................................................................................................................158
Chapter 19 Piperidine, the Enchanted Ring ...............................................................................159
Piperidine-Containing Drugs ...................................................................................159
Piperidine Improves Aqueous Solubility of Drugs ..................................................160
Piperidine Addresses Drug-Resistance Issues .........................................................161
Synthesis of Some Piperidine-Containing Drugs ....................................................161
References ................................................................................................................162
Chapter 20 Pyrazines ..................................................................................................................163
Pyrazine-Containing Drugs .....................................................................................163
Pyrazines in Drug Discovery ...................................................................................165
Synthesis of Some Pyrazine-Containing Drugs.......................................................168
References ................................................................................................................171
Chapter 21 Pyrazoles ..................................................................................................................173
Pyrazole-Containing Drugs .....................................................................................173
viii Contents
Pyrazoles in Drug Discovery ...................................................................................175
Pyrazole as a Bioisostere of Arenes and Hetarenes ............................................175
Pyrazole as Hydrogen Bond Donor and Acceptor ...............................................178
Synthesis of Some Pyrazole-Containing Drugs .......................................................180
References ................................................................................................................185
Chapter 22 Pyridazines ...............................................................................................................187
Pyridazine-Containing Drugs ..................................................................................187
Pyridazines in Drug Discovery ................................................................................189
Boost a Drug’s Aqueous Solubility .....................................................................189
Facilitate Formation of Crystalline, Water-Soluble Solid Salts ..........................190
As a Bioisostere of Hetaryl Rings .......................................................................191
Synthesis of Some Pyridazine-Containing Drugs ...................................................192
References ................................................................................................................195
Chapter 23 Pyridines—The Magic of Phenyl–Pyridyl Switch ...................................................197
Pyridine-Containing Drugs ......................................................................................197
Pyridines in Drug Discovery ....................................................................................199
Boosting Biochemical Potency ............................................................................199
Fixing CYP450 Liability .....................................................................................200
Elevating Permeability ........................................................................................200
Addressing Protein Binding Issue .......................................................................201
Synthesis of Some Pyridine-Containing Drugs .......................................................202
Loratadine (Claritin, 1) ........................................................................................202
Nevirapine (Viramune, 2) ....................................................................................203
Omeprazole (Prilosec, 3) .....................................................................................203
Netupitant (4) .......................................................................................................204
Abemaciclib (Verzenio, 5) ...................................................................................205
Lorlatinib (Lorbrena, 6) ......................................................................................205
Apalutamide (Erleada, 7) ....................................................................................206
References ................................................................................................................207
Chapter 24 Pyrimidines ..............................................................................................................209
Pyrimidine-Containing Drugs .................................................................................209
Pyrimidines in Drug Discovery ...............................................................................213
Pyrimidine as a Bioisostere .................................................................................213
Interactions with Target Proteins.........................................................................214
Synthesis of Some Pyrimidine-Containing Drugs ...................................................216
References ................................................................................................................218
Chapter 25 Pyrrolidines ..............................................................................................................219
Pyrrolidine-Containing Drugs .................................................................................219
Pyrrolidines in Drug Discovery ...............................................................................224
Synthesis of Some Pyrrolidine-Containing Drugs...................................................228
References ................................................................................................................231
Contents ix
Chapter 26 Pyrrolotriazines ........................................................................................................233
Pyrrolotriazine-Containing Drugs ...........................................................................233
Pyrrolotriazines in Drug Discovery .........................................................................235
Synthesis of Some Pyrrolotriazine-Containing Drugs ............................................238
References ................................................................................................................240
Chapter 27 Spiroazetidines .........................................................................................................243
Spiroazetidines in Drug Discovery ..........................................................................243
Spiroazetidines as Bioisosteres............................................................................243
Utility of Spiroazetidines in Medicinal Chemistry .............................................246
Synthesis of Some Spiroazetidines ..........................................................................248
References ................................................................................................................250
Chapter 28 Spirocyclic Piperidines .............................................................................................251
Spirocyclic Piperidine-Containing Drugs ................................................................251
Spirocyclic Piperidines in Drug Discovery ..............................................................251
Synthesis of Some Spirocyclic Piperidines ..............................................................254
References ................................................................................................................256
Chapter 29 Spirocyclic Pyrrolidines ...........................................................................................259
Spirocyclic Pyrrolidine-Containing Drugs ..............................................................259
Spirocyclic Pyrrolidines in Drug Discovery ............................................................260
Synthesis of Some Spirocyclic Pyrrolidine-Containing Drugs ...............................263
References ................................................................................................................267
Chapter 30 Spirooxetanes ...........................................................................................................269
Spirooxetanes in Drug Discovery ............................................................................269
Synthesis of Some Spirooxetane-Containing Drugs ................................................272
References ................................................................................................................273
Chapter 31 Tetrahydropyrans ......................................................................................................275
Tetrahydropyran-Containing Drugs .........................................................................275
Tetrahydropyrans in Drug Discovery .......................................................................277
Synthesis of Some Tetrahydropyran-Containing Drugs ..........................................281
References ................................................................................................................285
Chapter 32 Trifluoromethylpyridines ..........................................................................................287
Trifluoromethylpyridine-Containing Drugs .............................................................288
Trifluoromethylpyridines in Drug Discovery ...........................................................289
Synthesis of Some Trifluoromethylpyridine-Containing Drugs ..............................292
References ................................................................................................................295
Index ..............................................................................................................................................297
