Privileged Structures in Drug Discovery: Medicinal Chemistry and Synthesis

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 α,β-Unsaturated Ketones 33 2.4.1.3 Condensation of o-Phenylenediamines with Alkynes 34 2.4.2 Reductive Condensation of α-Substituted Nitrobenzenes with Ketones and α,β-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 [3+3] Cycloaddition Reactions 132 4.4.3.2 [4+2] Cycloaddition Reactions 132 4.4.3.3 [2+2+2] 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 0003364809.INDD 7 12/18/2017 9:40:53 PM viii Contents 6.4.2 Azaspiro[5.5]alkane Systems 218 6.4.3 Diazaspiro[5.5]alkane 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 α-Functionalized Ketones and Thioureas 306 8.4.2 Hantzsch Synthesis from Ketones and Thioureas 306 8.4.3 Synthesis from α-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 α-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 β-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 α,β-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 [3+2] 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 β-Ketoesters 509 13.6.2.3 From 2-Aminopyridines and Miscellaneous Ketones 510 13.6.2.4 From Pyridines and 2-Aminopyridines with α-Haloketones or α-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 α,β-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

About the Author :
Larry Yet, PhD, is an Assistant Professor in the Department of Chemistry at the University of South Alabama. He has authored or coauthored more than 40 publications, is an inventor on several non-provisional and issued patents, and has written multiple invited book chapters and review articles in synthetic organic and medicinal chemistry.