(PDF) Privileged Structures in Drug Discovery by Larry Yet

This is the PDF eBook version for Privileged Structures in Drug Discovery – Medicinal Chemistry and Synthesis by Larry Yet

Table of Contents

1 Introduction 1

1.1 The Original Definition of Privileged Structures 1

1.2 The Role of Privileged Structures in the Drug Discovery Process 1

1.3 The Loose Definitions of “Privileged Structures” 2

1.4 Synthesis and Biological Activities of Carbocyclic and Heterocyclic Privileged Structures 2

1.4.1 Synthesis and Biological Activities of Three?] and Four?]Membered Ring Privileged Structures 2

1.4.2 Synthesis and Biological Activities of Five-Membered Ring Privileged Structures 2

1.4.3 Synthesis and Biological Activities of Six-Membered Ring Privileged Structures 4

1.4.4 Synthesis and Biological Activities of Bicyclic 5/5 and 6/5 Ring Privileged Structures 4

1.4.5 Synthesis and Biological Activities of Bicyclic 6/6 and 6/7 Ring Privileged Structures 4

1.4.6 Synthesis and Biological Activities of Tricyclic and Tetracyclic Ring Privileged Structures 4

1.5 Combinatorial Libraries of “Privileged Structures” 4

1.6 Scope of this Monograph 9

References 10

2 Benzodiazepines 15

2.1 Introduction 15

2.2 Marketed BDZ Drugs 15

2.2.1 1,4-Benzodiazepine Marketed Drugs 15

2.2.2 1,5-Benzodiazepine Marketed Drugs 16

2.2.3 Linearly Fused BDZ Marketed Drugs 16

2.2.4 Angularly Fused-1,4-Benzodiazepine Marketed Drugs 17

2.3 Medicinal Chemistry Case Studies 17

2.3.1 Cardiovascular Applications 17

2.3.2 Central Nervous System Applications 19

2.3.3 Gastrointestinal Applications 23

2.3.4 Infectious Diseases Applications 24

2.3.5 Inflammation Applications 25

2.3.6 Metabolic Diseases Applications 27

2.3.7 Oncology Applications 28

2.4 Synthesis of BDZs 30

2.4.1 Condensation of o-Phenylenediamines to 1,5-Benzodiazepines 31

2.4.1.1 Condensation of o-Phenylenediamines with Ketones 31

2.4.1.2 Condensation of o-Phenylenediamines with a,ß-Unsaturated Ketones 33

2.4.1.3 Condensation of o-Phenylenediamines with Alkynes 34

2.4.2 Reductive Condensation of a-Substituted Nitrobenzenes with Ketones and a,ß-Unsaturated Ketones 35

2.4.3 Intramolecular Cyclizations to 1,4-Benzodiazepines 35

2.4.3.1 Intramolecular Cyclizations—Path A 36

2.4.3.2 Intramolecular Cyclizations—Path B 37

2.4.3.3 Intramolecular Cyclizations—Path C 39

2.4.3.4 Intramolecular Cyclizations—Path D 40

2.4.3.5 Intramolecular Cyclizations—Path E 42

2.4.3.6 Intramolecular Cyclizations—Path F 42

2.4.3.7 Intramolecular Cyclizations—Path G 42

2.4.3.8 Intramolecular Cyclizations—Path H 42

2.4.4 Ugi Multicomponent Synthesis 42

2.4.5 Elaboration of 1,4-Benzodiazepines 44

2.4.6 Pyrrolo[2,1-c]benzodiazepines 45

2.4.7 Fused BDZ Ring Systems 45

2.4.8 Solid-Phase Synthesis of BDZs 47

References 47

3 1,4-Dihydropyridines 59

3.1 Introduction 59

3.2 Marketed 1,4-Dihyropyridine Drugs 59

3.3 Medicinal Chemistry Case Studies 59

3.3.1 Cardiovascular Applications 59

3.3.2 Central Nervous System Applications 61

3.3.3 Infectious Diseases Applications 62

3.3.4 Inflammation Applications 63

3.3.5 Men’s and Women’s Health Issues Applications 64

3.3.6 Metabolic Diseases Applications 65

3.3.7 Oncology Applications 65

3.4 Synthesis of 1,4-Dihydropyridines 66

3.4.1 Classical Hantzsch Synthesis 66

3.4.2 Modified Hantzsch Conditions 66

3.4.3 1,4-Disubstituted-1,4-Dihydropyridines 69

3.4.4 Organometallic Additions to Pyridinium Salts 69

3.4.5 From Imines and Enamino Compounds 71

3.4.6 Multicomponent Synthesis 72

3.4.6.1 Three-Component Synthesis of 1,4-Dihydropyridines 72

3.4.6.2 Four-Component Synthesis of 1,4-Dihydropyridines 74

3.4.7 Organocatalytic Synthesis of 1,4-Dihydropyridines 74

3.4.8 Miscellaneous Preparations 75

3.4.9 Elaboration of 1,4-Dihydropyridines 76

References 77

4 Biaryls 83

4.1 Introduction 83

4.2 Marketed Biaryl Drugs 83

4.3 Medicinal Chemistry Case Studies 87

4.3.1 Cardiovascular Applications 87

4.3.2 Central Nervous System Applications 89

4.3.3 Infectious Diseases Applications 95

4.3.4 Inflammation Applications 98

4.3.5 Men’s and Women’s Health Issues Applications 102

4.3.6 Metabolic Diseases Applications 103

4.3.7 Oncology Applications 109

4.4 Synthesis of Biaryls 114

4.4.1 Transition Metal-Catalyzed Cross-Coupling Synthesis 114

4.4.1.1 Suzuki–Miyaura Cross-Coupling Reactions with Boronic Acids 114

4.4.1.2 Suzuki–Miyaura Cross-Coupling Reactions with Boronate Esters 114

4.4.1.3 Metal-Catalyzed Homocoupling Reactions 121

4.4.1.4 Uhlmann Coupling Reactions 122

4.4.1.5 Kumada–Tamao–Corriu Cross-Coupling Reactions 123

4.4.1.6 Negishi Cross-Coupling Reactions 124

4.4.1.7 Hiyama Cross-Coupling Reactions 124

4.4.1.8 Stille Cross-Coupling Reactions 125

4.4.1.9 Miscellaneous Cross-Coupling Reactions 126

4.4.1.10 Metal-Catalyzed Functional Group Removal Cross-Coupling Reaction 127

4.4.2 C„ŸH Functionalization Reactions 127

4.4.2.1 Oxidative Coupling Reactions 127

4.4.2.2 Direct C„ŸH Arylations 127

4.4.2.3 C„ŸH Functionalization with Directing Groups 127

4.4.3 Cycloaddition Reactions 132

4.4.3.1 33 Cycloaddition Reactions 132

4.4.3.2 42 Cycloaddition Reactions 132

4.4.3.3 222 Cycloaddition Reactions 133

4.4.3.4 Tandem Cycloaddition Reactions 133

4.4.4 Biaryl Phenol Syntheses 133

4.4.5 Miscellaneous Syntheses 134

References 135

5 4-(Hetero)Arylpiperidines 155

5.1 Introduction 155

5.2 Marketed 4-(Hetero)Arylpiperidine Drugs 155

5.3 Medicinal Chemistry Case Studies 159

5.3.1 Cardiovascular Applications 159

5.3.2 Central Nervous System Applications 159

5.3.3 Infectious Diseases Applications 168

5.3.4 Inflammation Applications 169

5.3.5 Men’s and Women’s Health Applications 174

5.3.6 Metabolic Diseases Applications 175

5.3.7 Oncology Applications 177

5.4 Synthesis of 4-(Hetero)Arylpiperidines 179

5.4.1 Preparation from 4-Piperidinones 179

5.4.2 Preparation from 4-Prefunctionalized-3-alkenylpiperidines 180

5.4.3 Preparation from Negishi Cross-Coupling of 3-Zincated Piperidines 180

5.4.4 Preparation from 4-Funtionalized Piperidines 181

5.4.5 Conjugated Addition to Unsaturated Piperidines 181

5.4.6 Miscellaneous Syntheses 183

References 185

6 Spiropiperidines 194

6.1 Introduction 194

6.2 Marketed Spiropiperidine Drugs 194

6.3 Medicinal Chemistry Case Studies 195

6.3.1 Cardiovascular Applications 195

6.3.2 Central Nervous System Applications 197

6.3.3 Infectious Diseases Applications 203

6.3.4 Inflammation Applications 205

6.3.5 Men’s and Women’s Health Applications 210

6.3.6 Metabolic Diseases Applications 211

6.3.7 Oncology Applications 216

6.4 Synthesis of Spiropiperidines 218

6.4.1 Quinolinylspiropiperidines 218

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6.4.2 Azaspiro5.5alkane Systems 218

6.4.3 Diazaspiro5.5alkane Derivatives 221

6.4.4 1,4-Benzodioxinylspiropiperidines 222

6.4.5 Spirobenzooxazinylspiropiperidines 223

6.4.6 (Iso)Quinolinylspiropiperidines 223

6.4.7 Indenospiropiperidines 225

6.4.8 Indolin(on)ylspiropiperidines 225

6.4.9 Cyclohexadienonylspiropiperidines 226

6.4.10 Cyclopenta[b]pyrrolospiropiperidines 226

6.4.11 Chromanylspiropiperidines 226

6.4.12 (Iso)Benzofuran(on)ylspiropiperidines 227

6.4.13 Indenospiropiperidines 227

References 228

7 2-Aminopyrimidines 237

7.1 Introduction 237

7.2 Marketed 2-Aminopyrimidine Drugs 237

7.3 Medicinal Chemistry Case Studies 239

7.3.1 Cardiovascular Applications 239

7.3.2 Central Nervous System Applications 241

7.3.3 Infectious Diseases Applications 245

7.3.4 Inflammation Applications 248

7.3.5 Metabolic Diseases Applications 254

7.3.6 Miscellaneous Applications 255

7.3.7 Oncology Applications 256

7.4 Synthesis of 2-Aminopyrimidines 267

7.4.1 Aminations with 2-Halo or 2,4-Dihalopyrimidines 267

7.4.2 Cross-Coupling Reactions with 2-Aminopyrimidines 270

7.4.3 Aminations with 2-Sulfonylpyrimidines 270

7.4.4 Cyclizations with Guanidines 272

References 272

8 2-Aminothiazoles 284

8.1 Introduction 284

8.2 Marketed 2-Aminothiazole Drugs 284

8.3 Medicinal Chemistry Case Studies 286

8.3.1 Cardiovascular Diseases Applications 286

8.3.2 Central Nervous System Applications 288

8.3.3 Infectious Diseases Applications 292

8.3.4 Inflammation Applications 296

8.3.5 Metabolic Diseases Applications 299

8.3.6 Oncology Applications 301

8.3.7 Miscellaneous Applications 305

8.4 Synthesis of 2-Aminothiazoles 306

8.4.1 Hantzsch Synthesis from a-Functionalized Ketones and Thioureas 306

8.4.2 Hantzsch Synthesis from Ketones and Thioureas 306

8.4.3 Synthesis from a-Haloketones and Thiocyanates 308

8.4.4 Synthesis from Vinyl Azides and Thiocyanates 308

8.4.5 Synthesis from Amidines and Thiocyanates 309

8.4.6 Synthesis from Alkenyl and Alkynyl Compounds with Thiocyanates or Thioureas 309

8.4.7 Miscellaneous Syntheses 309

8.4.8 Elaboration of 2-Aminothiazoles 311

References 311

9 2-(Hetero)Arylindoles 321

9.1 Introduction 321

9.2 Marketed 2-Arylindole Drugs 321

9.3 Medicinal Chemistry Case Studies 321

9.3.1 Cardiovascular Applications 321

9.3.2 Central Nervous System Applications 322

9.3.3 Infectious Diseases Applications 323

9.3.4 Inflammation Applications 325

9.3.5 Men’s and Women’s Health Applications 326

9.3.6 Metabolic Diseases Applications 328

9.3.7 Miscellaneous Applications 328

9.3.8 Oncology Applications 328

9.4 Synthesis of 2-(Hetero)Arylindoles 332

9.4.1 Functionalization to the Preformed Indole System 332

9.4.1.1 2-Functionalized Metallated Indoles with Aryl Halides (Strategy 1) 332

9.4.1.2 2-Halogenated or 2-Triflated Indoles with Functionalized Arenes (Strategy 1) 332

9.4.1.3 Direct Arylation of Indole with Functionalized Arenes (Strategy 2) 334

9.4.1.4 Direct Oxidative Coupling of Indoles with (Hetero)Arenes (Strategy 3) 334

9.4.2 Fischer Indole Synthesis 334

9.4.3 Bischler–Mohlau Indole Synthesis 334

9.4.4 Metal-Catalyzed Approach with Alkynes 334

9.4.4.1 Intramolecular Cyclizations of o-Alkynylanilines (Strategy A) 336

9.4.4.2 Intramolecular Cyclizations of o-Alkynylanilines with Other Groups (Strategy B) 336

9.4.4.3 Intramolecular Cyclizations of o-Haloanilines with Alkynes (Strategy C) 337

9.4.4.4 Intramolecular Cyclizations of o-Alkynylhaloarenes with Primary Amines (Strategy D) 340

9.4.4.5 Miscellaneous Transition Metal-Catalyzed Reactions 340

9.4.4.6 Reductive Cyclizations of o-Nitroalkynylarenes 342

9.4.5 Intracmolecular Reductive Cyclizations of o-Nitro (or Azido)alkenylarenes 342

9.4.6 Cyclizations of Arylamido and Arylimine Precursors 343

9.4.7 Cyclizations of o-Vinylaminoarenes 344

9.4.8 Cyclizations with N-Arylenamines or N-Arylenaminones 344

9.4.9 Multicomponent Synthesis 345

9.4.10 Radical Cyclization Reactions 346

9.4.11 Miscellaneous Cyclizations with o-Substituted Anilines 346

References 348

10 Tetrahydroisoquinolines 356

10.1 Introduction 356

10.2 Marketed THIQ Drugs 356

10.3 Medicinal Chemistry Case Studies 357

10.3.1 Cardiovascular Applications 357

10.3.2 Central Nervous System Applications 359

10.3.3 Infectious Diseases Applications 365

10.3.4 Inflammation Applications 366

10.3.5 Men’s and Women’s Health Applications 369

10.3.6 Metabolic Diseases Applications 369

10.3.7 Miscellaneous Applications 370

10.3.8 Oncology Applications 372

10.4 Synthesis of THIQs 376

10.4.1 Pictet–Spengler Reactions 376

10.4.1.1 Classical Pictet–Spengler Reactions 376

10.4.1.2 Pictet–Spengler Reactions with Masked Carbonyl Compounds 377

10.4.1.3 Modified Pictet–Spengler Reactions 377

10.4.1.4 Pictet–Spengler-Type Reactions 377

10.4.1.5 Pictet–Spengler Synthesis of Tic 378

10.4.2 Transition Metal-Catalyzed Reactions 379

10.4.2.1 Intramolecular a-Arylation Reactions 379

10.4.2.2 Intramolecular Cyclizations of N-Propargylbenzylamines 379

10.4.2.3 Intramolecular Heck Cyclizations 379

10.4.2.4 Intramolecular Nucleophilic Additions 379

10.4.2.5 One-Pot Multistep Metal-Catalyzed Cyclization Reactions 380

10.4.3 Multicomponent Synthesis of THIQs 382

10.4.4 Synthesis of 3-Aryltetrahydroisoquinolines 382

10.4.5 Synthesis of 4-Aryltetrahydroisoquinolines 383

10.4.6 Miscellaneous Intramolecular Cyclizations 386

10.4.7 Asymmetric Reduction of 1-Substituted-3,4-

Dihydroisoquinolines 387

10.4.7.1 Iridium-Catalyzed Hydrogenations of Dihydroisoquinolines, Isoquinoline Salts, and Isoquinolines 388

10.4.7.2 Ruthenium- and Rhodium-Catalyzed Reductions of Dihydroisoquinolines 389

10.4.7.3 Asymmetric Additions to Dihydroisoquinolines, Dihydroisoquinoline

Salts, and Dihydroisoquinoline N-Oxides 389

10.4.7.4 Asymmetric Intramolecular Cyclizations 391

10.4.7.5 Asymmetric Intramolecular Cyclizations with Chiral Sulfoxides 391

10.4.7.6 Miscellaneous Asymmetric Preparations 392

10.4.8 Arylations of THIQs 393

10.4.9 C„ŸH Functionalization of THIQs 395

10.4.9.1 Direct C-1 (Hetero)Arylations of THIQs 395

10.4.9.2 Oxidative C-1 CDC Reactions 395

10.4.9.3 Oxidative C-1 CDC with ß-Ketoesters 396

10.4.9.4 Oxidative C-1 CDC with Ketones 397

10.4.9.5 Oxidative C-1 CDC with Indoles 397

10.4.9.6 Oxidative C-1 CDC with Aliphatic Nitro Compounds 398

10.4.9.7 Oxidative C-1 CDC with Alkynes 399

10.4.9.8 Oxidative C-1 CDC with Alkenes 399

10.4.9.9 Oxidative C-1 Cross-Dehydrogenative Phosphonations 400

10.4.9.10 Miscellaneous Oxidative C-1 CDC Reactions 400

References 401

11 2,2-Dimethylbenzopyrans 414

11.1 Introduction 414

11.2 Marketed 2,2-Dimethylopyran Drugs 414

11.3 Medicinal Chemistry Case Studies 415

11.3.1 Cardiovascular Applications 415

11.3.2 Central Nervous System Applications 416

11.3.3 Infectious Diseases Applications 418

11.3.4 Inflammation Applications 419

11.3.5 Metabolic Diseases Applications 419

11.3.6 Oncology Applications 419

11.3.7 Cannabinoid Receptors 421

11.4 Synthesis of 2,2-Dimethylbenzopyrans 423

11.4.1 Annulations of Phenol Derivatives with Unsaturated Systems 423

11.4.1.1 Annulations of Phenol Derivatives with Simple Alkenes 423

11.4.1.2 Annulations of Phenol Derivatives with a,ß-Unsaturated Systems 424

11.4.1.3 Annulations of Phenol Derivatives with Nitroalkenes 424

11.4.1.4 Annulations of Phenol Derivatives with Allylic Alcohols 424

11.4.1.5 Annulations of Phenol Derivatives with Propargyl Alcohols 425

11.4.2 Replacement of the Methyl Group of 2,2-Dimethylbenzopyrans 425

11.4.3 Functionalization of 2,2,-Dimethylbenzopyrans 426

11.4.4 Fused 2,2-Dimethylbenzopyran Ring Systems 428

11.4.5 Solid-Phase Synthesis of 2,2-Dimethylbenzopyrans 428

References 429

12 Hydroxamates 435

12.1 Introduction 435

12.2 Marketed Hydroxame Drugs 435

12.3 Medicinal Chemistry Case Studies 436

12.3.1 Central Nervous System Applications 436

12.3.2 Infectious Diseases Applications 436

12.3.3 Inflammation Applications 439

12.3.4 Men’s and Women’s Health Applications 452

12.3.5 Metabolic Diseases Applications 453

12.3.6 Oncology Applications 453

12.4 Synthesis of Hydroxamates 466

12.4.1 Synthesis of Hydroxamates from Carboxylic Acids 466

12.4.2 Synthesis of Hydroxamates from Carboxylic Acid Derivatives 466

12.4.2.1 Synthesis of Hydroxamates from Esters 466

12.4.2.2 Synthesis of Hydroxamates from Acid Chlorides 468

12.4.2.3 Synthesis of Hydroxamates from Oxazolidinones 468

12.4.3 Miscellaneous Syntheses of Hydroxamates 469

12.4.4 Solid-Phase Synthesis of Hydroxamates 469

References 470

13 Bicyclic Pyridines Containing Ring-Junction Nitrogen 481

13.1 Introduction 481

13.2 Marketed Bicyclic Ring-Junction Pyridine Drugs 481

13.3 Medicinal Chemistry Case Studies 482

13.3.1 Cardiovascular Applications 482

13.3.2 Central Nervous System Applications 483

13.3.3 Gastrointestinal Applications 487

13.3.4 Infectious Diseases Applications 488

13.3.5 Inflammation Applications 491

13.3.6 Metabolic Diseases Applications 493

13.3.7 Miscellaneous Applications 494

13.3.8 Oncology Applications 494

13.4 Synthesis of Pyrazolo[1,5-a]pyridines 498

13.4.1 32 Dipolar Cycloadditions 498

13.4.2 Intramolecular Cyclizations 499

13.4.3 From N-Aminopyridinium Ylides 500

13.4.4 From 2-Substituted Pyridines 500

13.4.5 Thermal and Radical Cyclizations 500

13.5 Synthesis of Imidazo[1,5-a]pyridines 501

13.5.1 From 2-Methylaminopyridines 501

13.5.2 From 2-Methylaminopyridine Amides 502

13.5.3 From 2-Methylaminopyridine Thioamides or Thioureas 503

13.5.4 From Pyridine-2-Carbaldehydes (Picolinaldehydes) 503

13.5.5 From 2-Cyanopyridines 503

13.5.6 From Pyridine-2-Esters 504

13.5.7 From Di-2-Pyridyl Ketones 504

13.5.8 From Pyridotriazoles 504

13.5.9 Miscellaneous Syntheses 504

13.5.10 Chemical Elaborations of Imidazo[1,5-a]pyridines 505

13.6 Synthesis of Imidazo[1,2-a]pyridines 507

13.6.1 Ugi Three-Component Reactions 507

13.6.1.1 Classical Ugi Three-Component Reactions of 2-Aminopyridines, Aldehydes, and (Iso)Nitriles 507

13.6.1.2 Modified Ugi Three-Component Reactions 507

13.6.2 From 2-Aminopyridines and Carbonyl Compounds 509

13.6.2.1 From 2-Aminopyridines and Methyl Ketones 509

13.6.2.2 From 2-Aminopyridines and ß-Ketoesters 509

13.6.2.3 From 2-Aminopyridines and Miscellaneous Ketones 510

13.6.2.4 From Pyridines and 2-Aminopyridines with a-Haloketones or a-Haloaldehydes 511

13.6.3 From 2-Aminopyridines and Alkynes 512

13.6.3.1 From 2-Aminopyridines and Alkynes 512

13.6.3.2 From 2-Aminopyridines, Alkynes, and Aldehydes 513

13.6.4 From 2-Aminopyridines and a,ß-Unsaturated Systems 513

13.6.5 From 2-Aminopyridines and Nitroolefins 515

13.6.6 Cyclizations from 2-Aminopropargylpyridines 515

13.6.7 Cyclizations from Pyridyl Enamines(ones) 517

13.6.8 From Other Heterocycles 517

13.6.9 Miscellaneous Syntheses 518

13.6.10 Chemical Elaboration of Imidazo[1,2-a]pyridines 520

13.6.10.1 Cross-Coupling Reactions of Pre-functionalized Imidazo[1,2-a]pyridines 520

13.6.10.2 C„ŸH Functionalization of Imidazo[1,2-a]pyridines 521

13.6.11 Fused Imidazo[1,2-a]pyridine Ring Systems 523

References 525

Index