Synthetic Approaches To The New Drugs 2012

Bioorganic & Medicinal Chemistry 22 (2014) 2005–2032 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Review Synthetic approaches to the 2012 new drugs Hong X Ding a, , Carolyn A Leverett b,à, Robert E Kyne Jr b,§, Kevin K.-C Liu c,–, Subas M Sakya d,k, Andrew C Flick b,  , Christopher J O’Donnell b,⇑ a PharmaPhase Co., Ltd, Beijing 100193, China Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States c Lilly China Research and Development Center, Shanghai 201203, China d BioDuro Co., Ltd, Shanghai 200131, China b a r t i c l e i n f o Article history: Received 27 December 2013 Revised 11 February 2014 Accepted 13 February 2014 Available online 25 February 2014 Keywords: Synthesis New drug molecules New chemical entities Medicine Therapeutic agents a b s t r a c t New drugs introduced to the market every year represent a privileged structure for a particular biological target These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011 Ó 2014 Elsevier Ltd All rights reserved Contents Introduction Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ, Bretaris GenuaiÒ) Allisartan isoproxil Anagliptin (BeskoaÒ, SuinyÒ) Axitinib (InlytaÒ) Azilsartan (AzilvaÒ) Bedaquiline fumarate (SirturoÒ) 2006 2006 2006 2006 2009 2010 2012 Abbreviations: 1,2-DAP, 1,2-diaminopropane; 1,2-DCE, 1,2-dichloroethane; Ac, acetyl; aq, aqueous; B2(pin)2, bis(pinacolato)diboron; BINAP, 2,20 -bis(diphenylphosphino)1,10 -binaphthyl; BOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophospate; CDI, N,N0 -carbonyldiimidazole; DAP, diaminopropane; DBU, 1,5-diazabicycolo[4.3.0]non-5-ene; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DIC, 1,3-diisopropylcarbodiimide; DIEA/DIPEA, diisopropylethylamine; DMA, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDC, N-(3-dimethylaminopropal)-N0 -ethylcarbodiimide; Fmoc, 9-fluorenylmethoxycarbonyl; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOBT, 1-hydroxybenzotriazole hydrate; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; LDA, lithium diisopropylamide; MEK, methyl ethyl ketone; MIBK, 4-methyl-2-pentanone; NBS, N-bromosuccinimide; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidone; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2, [1,10 -bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4, tetrakis(triphenylphosphine)palladium(0); pin, pinacol; Py, pyridine; RT, room temperature; STAB-H, sodium triacetoxyborohydride; TBAF, t-butyl ammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMSCl, trimethylsilyl chloride; XantPhos, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene ⇑ Corresponding author Tel.: +1 860 715 4118 E-mail addresses: Hongxia.ding@gmail.com (H.X Ding), carolyn.a.leverett@pfizer.com (C.A Leverett), robert.kynejr@pfizer.com (R.E Kyne), Liu_kang_zhi_kevin@lilly.com (K.K.-C Liu), subas.sakya@bioduro.com (S.M Sakya), andrew.flick@pfizer.com (A.C Flick), christopher.j.odonnell@pfizer.com (C.J O’Donnell)   Tel.: +86 10 8484 8357 Tel.: +1 860 441 3936 § Tel.: +1 860 441 1510 – Tel.: +86 21 2080 5590 k Tel.: +86 38139788x3904    Tel.: +1 860 715 0228 http://dx.doi.org/10.1016/j.bmc.2014.02.017 0968-0896/Ó 2014 Elsevier Ltd All rights reserved 2006 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 Bosutinib hydrate (BosulifÒ) Cabozantinib (S)-malate (CometriqÒ) 10 Carfilzomib (KyprolisÒ) 11 Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ, EdistrideÒ, AppebbÒ) 12 Enzalutamide (XtandiÒ) 13 Iguratimod (CareramÒ, IremodÒ) 14 Imrecoxib (HengyangÒ) 15 Ingenol mebutate (PicatoÒ) 16 Ivacaftor (KalydecoÒ) 17 Lorcaserin hydrochloride hydrate (BelviqÒ) 18 Omacetaxine mepesuccinate (SynriboÒ) 19 Pasireotide (SigniforÒ) 20 Perampanel hydrate (FycompaÒ) 21 Pixantrone dimaleate (PixuvriÒ) 22 Ponatinib hydrochloride (IclusigÒ) 23 Radotinib hydrochloride (SupectÒ) 24 Regorafenib hydrate (StivargaÒ) 25 Tafamidis meglumine (VyndaqelÒ) 26 Teneligliptin hydrobromide hydrate (TeneliaÒ) 27 Teriflunomide (AubagioÒ) 28 Tofacitinib citrate (XeljanzÒ) 29 Vismodegib (ErivedgeÒ) References and notes Introduction ‘The most fruitful basis for the discovery of a new drug is to start with an old drug.’ – Sir James Whyte Black, winner of the 1988 Nobel Prize in medicine.1 This annual review was inaugurated eleven years ago2–11 and presents synthetic methods for molecular entities that were launched in various countries during the past year Given that drugs tend to have structural homology across similar biological targets, it is widely believed that the knowledge of new chemical entities and their syntheses will greatly enhance the ability to design new drugs in shorter periods of time The pharmaceutical industry enjoyed a banner year in 2012, with a total of 36 new products, including new chemical entities, biological drugs and diagnostic agents having reached the worldwide market for the first time Although an additional 22 new products were approved for the first time in 2012, these were not launched before year end,12 and therefore this review focuses on the syntheses of 26 drugs that were launched or approved in 2012 and two additional drugs that was launched at the end of 2011 (Fig 1) New indications for previously launched medications, new combinations, new formulations of existing drugs, and drugs synthesized purely via bio-processes or peptide synthesizers have been excluded from this review Although the scale of the synthetic routes were not explicitly disclosed in most cases, this review covers, perceptibly, the most scalable routes based on published or patent literature Drugs are covered in alphabetical order by the drug’s generic name Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ, Bretaris GenuaiÒ) Aclidinium bromide was approved by the U.S Food and Drug Administration (FDA) in July 2012 for the treatment of chronic obstructive pulmonary disease (COPD).13 Marketed by Forest Pharmaceuticals, aclidinium bromide selectively binds to five human muscarinic receptors (M1–M5), and posesses a subnanomolar binding affinity for these particular targets Administered by inhalation, this medicine has demonstrated favorable onset and duration of action, and its safety profile is an improvement over competitor therapies.14 While no manufacturing route has been disclosed to date,15 the most scalable published synthesis is described in 2013 2015 2015 2016 2016 2017 2019 2020 2021 2021 2022 2022 2024 2024 2025 2026 2026 2027 2028 2028 2029 2029 2029 Scheme 1.16 Dimethyl oxalate (1) was initially treated with two equivalents of Grignard to give bis-thiophenoate in 36% yield Subsequent transesterification with (R)-quinuclidinol (4) gave rise to the quinuclidine-containing ester in 50% yield Aclidinium bromide (I) could be accessed by two different methods involving bromoalkyl phenyl ether 6: an excess of bromide in the presence of an acetonitrile/chloroform mixture gave the drug in 89% isolated yield, or with fewer equivalents of electrophile (1.25 equiv) during exposure to refluxing acetophenone, has reportedly delivered (I) quantitatively on multi-gram scale.17 From commercial 2,18 the multi-gram synthesis of Aclidinium bromide (I) was completed in 17.8% over three steps Allisartan isoproxil Allisartan isoproxil, a member of a new class of selective angiotensin II-1 receptor antagonists, was approved by the Chinese Food and Drug Administration (CFDA) for the treatment of hypertension in July 2012.19 At time of publication, there is no trade name associated with this drug Allisartan was discovered and developed by the Chinese biomedical company Allist Pharmaceuticals Allisartan isoproxil is a prodrug which is readily hydrolyzed to active metabolite EXP3174, which is also the active metabolite of losartan (des-triphenylmethyl-9, Scheme 2).20 Although several synthetic routes have been reported within two patents,21,22 the most likely scalable process route is described in Scheme Commercial 2-butyl-4-chloro-5-(hydroxymethyl)-imidazole (7) was alkylated with N-triphenylmethyl-5-(40 -bromomethylbiphenyl-2-yl)tetrazole (8) under basic conditions in warm DMF, providing alcohol in 90% yield This alcohol was then oxidized to the corresponding carboxylic acid 10 with KMnO4 in 88% yield Etherification of acid 10 with isopropyl chloromethyl carbonate (11) followed by de-tritylation of the tetrazole group under acidic conditions gave allisartan isoproxil (II) in 69% yield.22 Anagliptin (BeskoaÒ, SuinyÒ) Anagliptin, which is marketed as Beskoa or Suiny, is a dipeptidyl peptidase-IV (DPP-4) inhibitor which was approved in September 2012 and launched in November 2012 in Japan for the treatment of Type II diabetes The drug was co-developed by three Japanese 2007 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 Cl N S O O O N N H N O CN N N N N Br - O H N O OH S O N+ O O O N N NH I Aclidinium bromide O II Allisartan isoproxil III Anagliptin N NH S CO2 H N H N O N N HO O O O N H Ph HO2 C NH H3 C OH O N N Br IV Axitinib V Azilsartan Cl VI Bedaquiline fumarate Cl HN H N O O O O CN H N O F O N O O HO N O N OH N O H 2O VII Bosutinib hydrate OH VIII Cabozantinib (S)-malate Cl H N N O O H N N H O O O N H O O HO OH HO O OH OH OH H 2O O IX Carfilzomib F F3C NC O N H S N X Dapagliflozin propanediol hydrate S O N H N O O O O O S O O N H N H O O XI Enzalutamide XII Iguratimod XIII Imrecoxib OH O O O H Cl N H O O HO HO NH HCl 1/2 H 2O N H HO XIV Ingenol mebutate XV Ivacaftor XVI Lorcaserin hydrochloride hydrate Figure Structures of 28 NCEs marketed/approved in 2012 2008 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 OBn O N O H2 N ( )3 HN H O O O O O HN O Ph H N O OH O O O O O HN NH N H O N H2 N Ph H N HO XVII Omacetaxine mepesuccinate N XVIII Pasireotide O N NH2 HN COOH O CN 3/4 H2O N COOH O XIX Perampanel hydrate HN NH2 XX Pixantrone dimaleate N N N N N HCl N N H N N N H N N H N O N O HCl CF3 CF3 XXI Ponatinib hydrochloride CF3 XXII Radotinib dihydrochloride O Cl O O N H N H N F O Cl O N H OH N OH HO OH XXIII Regorafenib hydrate NH OH XXIV Tafamidis meglumine O N N N OH S N N OH Cl H 2O 2.5 HBr x H 2O CN XXV Teneligliptin hydrobromide hydrate CF3 O N H XXVI Teriflunomide N N N CN O N HOOC N N H Cl O OH COOH HOOC Cl N H SO 2Me XXVII Tofacitinib citrate XXVIII Vismodegib Fig (continued) H N 2009 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 S MeO OH MgBr O OMe S Et2 O, −30 °C 36% O OH S MeO S S OPh Br OH S O N NaH, toluene, ↑↓ 50% O N O OH O CH3 CN : CHCl3 (2:3), RT 89% N+ O O Br S - I Aclidinium bromide OPh , Acetophenone, ↑↓ Br 99% Scheme Synthesis of aclidinium bromide (I) Cl Br N Cl OH N OH N K2 CO3 , DMF, 90 °C + N N N N N H 90% N CPh3 N N N CPh3 Cl O Cl OH N O N N K2 CO 3, DME, RT 11, 50 °C O 1% KMnO O N O O N HCl, dioxane, RT 69% °C to 50 °C, 88% N N N N N CPh3 Cl O O O 10 11 N N NH II Allisartan isoproxil Scheme Synthesis of allisartan isoproxil (II) companies; Kowa, Sanwa Kagaku and JW pharmaceutical Anagliptin, which is more selective against several recombinant human proteases by comparison to sitagliptin and vildagliptin,23 has more than 10,000-fold selectivity over the structurally homologous DPP8 and DPP-9 enzymes The most likely process-scale synthesis is depicted in Scheme 3.24 Commercially available (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile (12) was alkylated with t-butyl (2-amino-2-methyl-1-propyl) carbamate (13), giving rise to (S)-t-butyl (2-((2-(2-cyanopyrrolidin-1yl)-2-oxoethyl)amino)-2-methylpropyl)carbamate (14) This Boc-protected system was subsequently treated with strong acid to give the ethylene diamine derivative 15 in 96% yield Activation of 15 with CDI followed by coupling with commercially available 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid (16) gave anagliptin (III) in 90% yield Axitinib (InlytaÒ) Sold under the brand name InlytaÒ by Pfizer, Inc., axitinib was approved by the FDA in January 2012 for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments.25 Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway In particular, axitinib is a potent inhibitor of VEGF/RTK 1–3, which selectively slows angiogenesis, vascular permeability, and blood flow in solid tumors.26,27 While numerous patents and papers have been disclosed on the synthesis of axitinib,28–37 a recently published manuscript details the development of the manufacturing route, and this route is depicted in Scheme 4.38 The synthesis began with Migita coupling of commercial iodide 17 with thiophenol 18 2010 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 O Cl O CN 13, NaI, K2CO3 , acetone N N H O °C to RT, 91% 12 O H N CN N HCl/Dioxane N °C to RT, 96% 14 O O H N H 2N CN N 16, CDI, THF N Et 3N, THF, °C to RT 90% O H N N H CN N N N III Anagliptin 15 O O O OH N NH N H N N 13 16 Scheme Synthesis of anagliptin (III) O H N I NH O NH Pd 2(dba)3 , XantPhos SH N 17 NaHCO3, NMP, 50 °C 18 H N S N 19 O O I2, NMP, aq KOH Ac 2O, DIPEA, NMP, 60 °C Pd(OAc)2 , 2-vinylpyridine XantPhos, 90 °C NH H N S 85-90% f or steps N NH S H N N 1,2-DAP, THF, polishing filter NMP, THF, 62% for steps I N 20 IV Axitinib Scheme Synthesis of axitinib (IV) Interestingly, this transformation’s efficiency relied upon attention to the number of equivalents of base and an inert atmosphere in the reaction vessel, conditions which minimized catalyst poisoning during the reaction Without isolation, indazole 19 was iodinated to afford diarylthioether 20 in 85–90% yield over the two steps Protection of the indazole within 20 as its acetamide preceeded a Heck reaction with 2-vinylpyridine, and then subsequent removal of the indazole protection followed by a series of recrystallizations yielded axitinib (IV) in a combined 62% yield over the final steps Azilsartan (AzilvaÒ) Azilsartan is an orally active angiotensin II blocker which was approved and launched in Japan for the treatment of arterial hypertension in May 2012.39 Azilsartan, which is marketed under the trade name AzilvaÒ, was discovered and developed by Takeda—the same firm which had developed and launched a prodrug of azilsartan (azilsartan kamedoxomil, EdarbiÒ) in 2010 Azilsartan exhibits higher potency and slower off-rate kinetics for type angiotensin II receptors, which contributes to azilsartan’s comparatively improved blood pressure lowering effect.40 The most likely process-scale synthetic route mimics that which is disclosed in Takeda’s patents, and this is described in Scheme 541,42 Commercially available benzoic acid 21 was activated as the corresponding acyl azide and underwent a Curtius rearrangement to give carbamate 22 in 57% yield (three steps from compound 21) The resulting aniline 22 was alkylated with commercial 4-(bromomethyl)-2’-cyanobiphenyl (23) to give benzylamine 24 in 85% yield Nitroamine 24 was then exposed to mildly acidic conditions to affect Boc-removal prior to reduction via ferric chloride hydrate in the presence of hydrazine hydrate The resulting diamine 25 arose in 64% yield across the two-step sequence Interestingly, it was found that metal catalysts under conventional hydrogenation conditions caused partial debenzylation, which led the authors to arrive at the hydrazine/ferric chloride conditions Next, benzimidazole formation was achieved upon treatment of diamine 25 with ethyl orthocarbonate in acetic acid The resulting ethoxylbenzimidazole 26 was procured in 86% yield, and this benzonitrile was further reacted with hydroxylamine hydrochloride and sodium methoxide to provide amidoxime 27 in 90% as a white powder Next, activation with ethyl chlorocarbonate gave 28 followed by heating in refluxing xylene to give 2011 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 NO NO2 SOCl2, DMF, toluene, ↑↓ CO 2H O NHBoc NaN 3, H2 O, °C t-BuOH, ↑↓, 57% for steps O O O 22 21 Br CN NO2 Boc N 23 O K2 CO3, CH CN, ↑↓, 85% NH2 1 N HCl EtOAc, RT, 77% O CN NH O FeCl3•6 H2 O °C, THF/MeOH ↑↓; NH 2NH2 •H2 O ↑↓, 64% O CN 25 24 N N O N (EtO)4 C, AcOH O O 80 °C, 86% CN O N NHOH•HCl, NaOMe/MeOH O OH N O DMSO, 90 °C, 90% NH2 27 26 O N O N ClCO2 Et, CH 2Cl2, THF O O N O Et3N, RT OEt NH2 28 N N O N xylenes, ↑↓ O 23% for steps O O O N NH N N LiOH, MeOH, ↑↓ HO O O 84% 29 V Azilsartan Scheme Synthesis of azilsartan (V) N N O O N O O OH N NH2 NaOMe, O O N O O O DMSO, RT, 85-90% 30 29 N N aq NaOH HO O O O O N 50 °C, 88-90% V Azilsartan Scheme Improved synthesis of azilsartan (V) NH O O N NH O O N NH 2012 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 oxadiazolone 29 in 23% yield from hydroxyamidine 27 Finally, ester 29 was saponified with N LiOH in methanol to give azilsartan (V) in 84% yield An improved scalable route (Scheme 6) to azilsartan was reported and features reproducibly better yields.43 Hydroxyamidine 30 was treated with dimethyl carbonate and sodium methoxide, which triggered they key cyclization along with concomitant transesterification to deliver 29 Milder aqueous sodium hydroxide hydrolysis converted this methyl ester 29 to azilsartan (V) in 88–90% yield Bedaquiline fumarate (SirturoÒ) Bedaquiline fumarate is a diarylquinone drug developed by Janssen Pharmaceutical which is marketed under the trade name SirturoÒ.44 The drug, which was approved in 2012 for the • HCl N O O N O aq NaOH, 60 °C OH P 98% O 31 32 O 34 N N CO2 H Ph OH Ph HO2 C Br N O LDA, THF, -70 °C 32, THF, -70 °C AcOH, THF, -10 °C CH3 H3 C O 34, DMSO, ↑↓ 10% aq K2CO3 toluene, 85 °C 33 H 3C fumaric acid, i-PrOH 50-80 °C N • Ph H O N 82% Br Br 35 VI Bedaquiline fumarate 39% for five steps Scheme Synthesis of bedaquiline fumarate (VI) H3 CO Cl Br 37 i-PrOH, N NaOH H 3CO HO NO2 Cl 70 °C, 82% N NH 39 NO2 NaI, DME, ↑↓, 77% 38 N H2 , Pd/C O ↑↓, 93% for steps O NO2 40 Cl Cl NH O NC O N H N NH 41 Cl O 42, HC(OEt) 3, i-PrOH O N i-PrOH, RT O N N O 36 N O Cl HN O POCl3, sulfolane 70 °C to 105 °C 75-82%, >99% purity N O CN O N N H 2O VII Bosutinib monohydrate 43 O Cl Cl H2 N O NC OH 45 OH Cl O Cl N H O NC DIC, THF, ↑↓, 88% 42 44 Scheme Synthesis of bosutinib hydrate (VII) 2013 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 treatment of multidrug-resistant tuberculosis (MDR-TB), was developed in partnership with Johnson & Johnson and represents the first new tuberculosis therapy approved in over four decades.44 Bedaquiline is the first member of a new class of diarylquinoline compounds whose mechanism of action inhibits Mycobaterium tuberculosis ATP synthase which deprives bacterium of energy.44 Of the relatively few synthetic approaches to bedaquiline (or its fumarate salt) that have been reported,45–47 the most likely process-scale route is that described by Porstmann and co-workers from Janssen Pharmaceutical, and this route is outlined in Scheme 7.48 The synthesis was initiated by first treating commercially available dimethylaminoketone 31 with sodium hydroxide to provide naphthylone 32 in nearly quantitative yield Treatment of commercially available quinoline 33 with LDA and subsequent trapping with naphthylone 32 provided a mixture of diastereomers, whereby the major diastereomer obtained from this reaction corresponded to the bedaquiline geometry The minor diastereomer was resolved through multiple recrystallizations and seeding techniques.48 This racemate of the major diastereomer subsequently underwent a chiral resolution upon treatment with BINAP derivative 34 in refluxing DMSO Cooling and subjection to aqueous base in warm toluene furnished bedaquiline 35, bearing the requisite (R,S)-configuration of the two vicinal chiral centers corresponding to that of the drug The overall yield of the conversion of 33 to enantiopure 35 was 39% Aminoquinolinol 35 was then prepared as the corresponding fumarate salt upon treatment with fumaric acid in the presence of isopropanol, and this salt formation delivered bedaquiline fumarate (VI) in 82% yield.49 Bosutinib hydrate (BosulifÒ) BosulifÒ (Bosutinib hydrate), also known as (SKI-606), is a novel 4-phenylamino-3-quinolinecarbonitrile kinase inhibitor approved for treatment of adults with chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML).50 Bosutinib is an orally-dosed, dual Src/Abl kinase inhibitor51,52 which provides an alternative treatment to patients exhibiting immunity to imatinib and other kinase inhibitors utilized for this treatment.53,54 In contrast to competitor tyrosine inhibitors, bosutinib inhibits autophosphorylation of both Srs and Abl kinases, leading to decreased cell growth and apoptosis.51 Bosutinib was originally developed by Wyeth and continues to be marketed by Pfizer after the merger of Wyeth and Pfizer in 2009.55 Several synthetic routes to bosutinib have been reported, including synthetic work for scale up and processing to obtain pure salt forms of bosutinib for pharmaceutical applications.56–59 The current manufacturing route begins with reaction of 2-methoxy5-nitrophenol (36) and 1-bromo-3-chloropropane (37) to provide aryl chloroether 38 in 82% yield.58 Reaction of 38 with N-methylpiperazine (39) and NaI in refluxing DME provided the functionalized aryl-nitro-piperazine 40 (77% yield), which was converted directly NH OH Cl POCl3 , CH CN O N OH O O 77 °C, 70% O H 2N O N t-BuONa, DMA, 105 °C 72% O O 46 N 48 47 H N 51, K2CO3 , THF, H 2O, RT O O 96% H N O F O O N 52 H N (S)-malic acid O O MEK, H 2O, 55 °C to RT H N O F O O HO 75% O N OH O OH VIII Cabozantinib (S)-malate O O HO OH F 49 O SOCl2, Et N, THF, °C H 2N , THF, 10 °C HO F O O oxalyl chloride N H DMF, THF, RT 50 70% for two steps Scheme Synthesis of cabozantinib (S)-malate (VIII) F O Cl N H 51 2014 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 (93% over steps).58,59 Finally, conversion of 43 to bosutinib was facilitated by a POCl3-promoted cyclization in the presence of sulfolane As shown in Scheme 8, employment of carefully optimized conditions for the isolation of bosutinib hydrate (VII) provided material in 75–82% yields and >99% purity.59 to aniline 41 under hydrogenolysis conditions Aniline 41 was then reacted with triethyl orthoformate and aryl cyanoamide 42, which was generated in one step from 2,4-dichloro-5-methoxy-aniline (44), 1,3-diisopropylcabodiimide (DIC), and cyanoacetic acid (45) under refluxing conditions, to yield advanced intermediate 43 H N BOP, HOBT, DMF BocHN DIPEA, °C, 93% H2 N BocHN CO2 Me 53 CO2 Me O CO2H 54 55 O BocHN TFA, DCM, °C H N N H CO2 Me O Boc-Homophe-OH, BOP HOBT, DMF, DIPEA, °C 85% for steps 56 Cl H N O N H TFA, DCM ClCH2C(O)Cl DMF, DIPEA, °C 67% for steps H N O CO2 Me O KI, THF morpholine N LiOH, MeOH °C to °C 87% for steps O H N O H N N H O 57 O 58 59, HBTU, HOBT, DMF, DIPEA, °C N O Recrystallization from MeOH/H O 75% for steps O H N H N N H O O O O N H O O TFA IX Carfilzomib H2 N O 59 Scheme 10 Synthesis of carfilzomib (IX) i-BuOC(O)Cl, DCM BocHN CO2H MeONHMe•HCl, NMM Et3N, −20 °C, 94% OMe N BocHN 54 MgBr THF, °C, 81% BocHN O O 60 62 Ca(OCl)2 , NMP, H2 O −10 °C to −5 °C, 41% TFA, CH Cl2 , °C, 92% 61 O TFA H N O 59 Scheme 11 Synthesis of fragment 59 of carfilzomib (IX) CO2 H 2018 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 O O H H acetone, cat p-TsOH, RT 69% HO HO HO HO HO O HO O 87; ingenol O 88 O O O 89 O H O LHMDS, THF, RT, 73% H H3 PO4, RT O 71% O HO O O HO HO O HO 90 XIV Ingenol mebutate Scheme 16 Synthesis of ingenol mebutate (XIV) O OH O O EtO EtO O H2 SO4 , HNO DCM, °C to RT Cl EtO O O Cl 57% Et3N, EtOAc °C to RT, 99% N H 94 O2 N 91 O 92 93 O OH EtO Pd/C, H 2, MeOH O O KOH, MeOH O 94, Et3N, DCM, RT 53% f or steps O O N H 96% N H N H N H 95 XV Ivacaftor Scheme 17 Synthesis of ivacaftor (XV) OH 95% Cl 1-amino-2-propanol, 85 °C to 100 °C SOCl2 , DMA, PhCH3 , 65 °C 71% for steps Cl 96 97 AlCl3, 1,2-dichlorobenzene, 128 °C aq NaOH, cyclohexane NH • HCl Cl Br PBr 3, °C to 85 °C L-(+)-tartaric acid, acetone /H2 O Recrystallization from acetone/H 2O 27% for steps Cl O OH 99 NH • HCl HCl (gas), °C to °C 90% for steps Cl • 1/2 H 2O XVI Lorcaserin hydrochloride hydrate Scheme 18 Synthesis of lorcaserin hydrochloride hydrate (XVI) OH HO Cl 98 K2 CO3, H2O, RT EtOAc OH NH • O 2019 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 Br i Mg, THF ii diethyl oxalate, ↑↓, 70% HO CH 2CO2 Me 101 , LHMDS, THF -78 °C, 72% 100 O O O R* O MeO 2C O MeO2 C 106a (desired) 103 106b (undesired) OMe Cl OMe O O R* + 105 , RT, 84% (2 diastereomers, 1:1) MeO2 C BF3, MeOH, RT, 69% 102 104 , Et3N, DMAP, toluene, RT CO2 H p-TsOH, toluene, 65 °C, 69% KOH, EtOH, ↑↓, 98% CO2 Et N N R* = Cl O OH O Cl 101 Cl N N 104 105 quinine Scheme 19 Synthesis of fragment 106a of omacetaxine mepesuccinate (XVII) O O H2 , Pd/C 106a EtOAc, RT, 50% N O H OH 104 , Et N, toluene , 30 °C O 108 , RT, 43% O OMe O O MeO2C CO2Me 107 109 O N O H O N O HBr/HOAc, DCM, -10 °C, 87% OMe O 5% aq NaHCO3 , acetone, RT, 47% O O H O OH HO OMe 108 cephalotaxine HO XVII Omacetaxine mepesuccinate Scheme 20 Synthesis of omacetaxine mepesuccinate (XVII) H N O O Fmoc-OSu, aq Na2CO3 , THF, RT triphosgene, N-Boc-diaminoethane THF, RT 0.1 N HCl in THF 49% f or steps HO Fmoc N OH O BocHN N H 110 O O 111 Scheme 21 Synthesis of fragment 111 of pasireotide (XVIII) 14 Imrecoxib (HengyangÒ) Imrecoxib, a new non-steroid anti-inflammtory drug (NSAID), was launched in China with the trade name of HengyangÒ for the treatment of osteoarthritis in 2012 It was originally designed and synthesized by Guo and co-workers at the Institute of Materia Medica (IMM) of the Chinese Academy of Medical Sciences in collaboration with Hengrui Pharmaceuticals.88 Imrecoxib, which is a moderately selective COX-2 inhibitor (with IC50 values against COX-1 and COX-2 being 115 ± 28 and 18 ± nM, respectively),89 is the subject of two synthetic routes reported across several publications.90–93 2020 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 OBn OBn O O Fmoc-Lys(Boc)-OH DIC/HOBt, DMF, RT, 16 h O 20% piperidine in DMF, ºC to RT, 0.25 h O Fmoc-DTrp(Boc)-OH DIC/HOBt, DMF, RT, 16 h O O O O O HN R 20% piperidine, DMF, ºC to rt, 0.25 h ( )4 BocHN NH NH Fmoc 112; R = Fmoc 113; R = H OBn 114 O O O OBn 20% piperidine in DMF, ºC to RT, 0.25 h O O Fmoc-PhG-OH DIC/HOBt, DMF, RT, 16 h O O O NH O O O NH NHFmoc ( )4 N H BocHN Boc N O ( )4 N H BocHN Boc N Ph H N NHFmoc O 115 116 Scheme 22 Synthesis of pasireotide intermediate 116 (XVIII) The most likely process-scale route to this drug is described in Scheme 15,93 which began with 2-bromo-40 -(methylsulfonyl)-acetophenone (84) and p-tolylacetic acid (85) as starting materials In the presence of base, a-bromoketone 84 was treated with acid 85 which resulted in lactone 86 in 72% yield across the two-step sequence Exposure of lactone 86 with propylamine triggered a ring-opening-ring closing reaction, which resulted in imrecoxib (XIII) directly in 85% yield.93 15 Ingenol mebutate (PicatoÒ) Ingenol mebutate is a diterpene ester which was approved in the U.S., EU, Australia, and Brazil for the treatment of actinic keratosis, a disease stage associated with sun exposure which can potentially develop into cancer.94 The drug, which is marketed by LEO Pharma A/S as PicatoÒ, is administered as a topical gel (0.015%, 0.05%) which has been proven effective in treating face-, scalp-, and trunk-localized actinic keratosis in four randomized, double-blind, vehicle-controlled, multicenter studies.94 The drug exhibits mild side effects limited to application-site conditions (e.g irritation, pain, pruritus), and no detectable concentrations of ingenol mebutate or two of its metabolites were found in blood samples.94 Traditionally used as a home remedy for various skin conditions, the ingenol mebutate, also referred to as ingenol 3-angelate, is the main active constituent of sap from the plant Euphorbia pelpus.95 From natural extractions, 17 kg of fresh E pelpus afforded g of ingenol 3-angelate as an oil, which upon further purification was deemed insufficient for process-scale production.96 Although several synthetic approaches to the ingenol family of terpenes have been reported,97–113 Liang and coworkers at LEO Pharma have reported a semisynthesis of the API from naturallyoccurring ingenol This natural product’s accessibility from the seeds of E lathyris renders it widely commercial on scale The conversion of ingenol to ingenol mebutate involves a protection, esterification, and deprotection strategy to procure scale quantities of the drug (Scheme 16).114 Conversion of ingenol (87) to the corresponding 5, 20-acetonide 88 proceeded in good yield using a protocol modified from the original conditions described by Hecker.115 A considerable amount of study was conducted by Liang to affect efficient angeloylation with minimal isomerization of the doublebond to the corresponding Z-isomer (tiglate) It was found that angelic anhydride 89 (which is a commercially available reagent, but for process scale was prepared immediately prior to usage from the self-condensation of 99.5% pure angelic acid with 0.5 equivalents of DCC) in the presence of LHMDS gave acetonide 90 in over 95% conversion and was practically free of the undesired tiglate biproduct after recrystallization (73% yield).96 Deprotection of the acetonide 90 was affected using phosphoric acid and after three recrystallizations, ingenol mebutate (XIV) was produced on multigram scale in a combined yield of 37% starting from ingenol 87.96 2021 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 16 Ivacaftor (KalydecoÒ) 17 Lorcaserin hydrochloride hydrate (BelviqÒ) Vertex’s ivacaftor was granted breakthrough therapy designation by the FDA in January 2012 for cystic fibrosis (CF) patients who bear the G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene This CFTR mutation occurs in roughly 4% of the 30,000 people living with CF in the United States While the compound has been identified as a potentiator in cell-based assays, its mechanism of action is currently unknown.116–118 While several patents describe a synthesis of ivacaftor,119–133 only one demonstrates the synthesis on scale and includes yields, which is depicted in Scheme 17.134 Beginning with treatment of commercial di-tert-butylphenol derivative 91 with ethyl chloroformate, the synthesis of carbonate 92 was achieved in quantitative yield Nitration of 92 provided the desired nitroarene regioisomer 93 in 57% yield which was isolated by recrystallization Reduction of the newly-installed nitro group and subsequent amide bond formation via reaction with commercially available acid chloride 94 produced amide 95 in 53% yield over the two step sequence Finally, cleavage of the carbonate unmasked the phenol to furnish ivacaftor (XV) in 96% yield Lorcaserin hydrochloride is a selective serotonin 5HT2C agonist approved in the U.S for the treatment of obesity Lorcaserin hydrochloride was discovered and developed by Arena Pharmaceuticals, Inc and licensed to Eisai Lorcaserin hydrochloride is reported to be approximately 100 fold more active at the 5HT2C receptor than the 5HT2B receptor.135 The significance of this selectivity is that 5HT2B activation is hypothesized to be associated with the cardiac valvulopathy side effect of the infamous ‘fen–phen’ (fenfluramine + dexfenfluramine) combination treatment for obesity.136 Numerous syntheses of lorcaserin hydrochloride have been reported135,137,138 and the process scale route is highlighted in Scheme 18.139 Commercial 2-(40 -chlorophenyl)ethanol (96) was treated with phosphorus tribromide to give 2-(40 -chlorophenyl)ethyl bromide (97) in 95% yield Alkylation of 1-amino-2-propanol with 97 followed by treatment of the corresponding alcohol with thionyl chloride gave chloroamine 98 in 71% yield Friedel–Crafts acylation of 98 with aluminum trichloride followed by a classical resolution with L-(+)-tartaric acid gave the desired (R)-enantiomer tartrate salt of lorcaserin 99 in 27% overall yield from 98 The free base of 99 was liberated upon treatment with aqueous potassium carbonate and this material was then immediately extracted into ethyl OBn O 20% piperidine in DMF, ºC to RT, 0.25 h O Fmoc-Phe-OH, DIC/HOBt, DMF, RT, 16 h O 20% piperidine in DMF, ºC to RT, 0.25 h 20% piperidine in DMF, ºC to RT, 0.25 h O O 111, DIC/HOBt DMF, RT, 16 h 116 NH ( )4 N H BocHN Boc N O Ph H N O N H O 2% TFA in CH2 Cl2 RT, h Fmoc N (S) (R) O HN O BocHN 117 OBn OBn O OH O NH ( )4 N H BocHN Boc N O O Ph H N O NH O Ph N N H DPPA, DIEA, DMF, ºC, 16 h aq TFA, RT, 40 mins H2 N ( ) HN HN O BocHN 119 O O O O O O O 20% from 112 N H HN H N Ph H N N O O HN NH Ph H2 N XVIII Pasireotide Scheme 23 Conversion of pasireotide intermediate 116 to pasireotide (XVIII) 2022 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 acetate and treated with HCl gas to give lorcaserin hydrochloride hydrate (XVI) in 90% yield 18 Omacetaxine mepesuccinate (SynriboÒ) SynriboÒ (Omacetaxine mepesuccinate) was approved by the FDA for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) exhibiting resistance or intolerance to tyrosine kinase inhibitors (TKI’s) Omacetaxine mepesuccinate inhibits protein synthesis and prevents aminoacyl-tRNA binding during the elongation phase and targets myeloma-promoting molecules Mcl-1, XIAP, and b-catenin,140–142 which are particularly important in the survival of myeloma cells.143 Omacetaxine mepesuccinate is also known as homoharringtonine, an alkaloid originally discovered144 and structurally identified145–147 from Cephalotaxus harringtonia, which occurs naturally in Japan and eastern Asia Because of its leukemic activity and interesting chemical structure, the core and ester side chains of the cephalotaxine alkaloids have been the focus of numerous synthetic studies.148 However, large-scale production often utilizes a semisynthetic route which relies upon cephalotaxine (CET) derived from natural sources149 coupled with a synthetically obtained ester side chain.150,151 The challenges associated with direct esterification of cephalotaxine with the homoharringtonine and other related ester side chains are the basis of ongoing research aimed at identification of improved side-chain coupling methods.148,152 The most likely process-scale synthetic route features the coupling of the homoharringtonine side chain with the cephalotaxine core, and a subsequent conversion of the a-hydroxy moiety to a bridged heterocyclic species Following this coupling, ring opening N Br2 , NaOAc, EtOAc OMe Br OMe 120 19 Pasireotide (SigniforÒ) Pasireotide, also known as SOM230, is a cyclic, hexameric peptide developed by Novartis which exhibits somatostatin-like activity as an antisecretory agent used in the treatment of Cushing’s disease.154 Pasireotide activates a broad range of somatostatin receptors, and in particular displays a significantly n-BuLi, hexanes THF, –76 °C N 10 °C to 50 °C, 86% provided the active homoharringtonine product, which is described in Scheme 19.152,153 The method for large scale synthesis of homoharringtonine begins with derivatization of commercial 5-bromo-2-methyl-pent-2ene (100) with diethyl oxalate and the pre-formed enolate of methyl acetate (101), generating diester 102 in 50% overall yield (Scheme 19).153 Acid-promoted pyran formation, followed by universal ester saponification and selective re-esterification provided the desired racemic pyran acid 103 Activation of acid 103 with 2,4,6-trichlorobenzoyl chloride (104) and subsequent addition of quinine (105) led to a mixture of diastereomers 106a/106b (1:1) in 84% yield, which were separable by chromatographic methods Diastereomer 106a was then carried on to the synthesis of homoharringtonine (Omacetaxine mepesuccinate) as described in Scheme 20.153 From isomer 106a, hydrogenolysis with Pd/C and H2 provided acid 107 in 50% yield Activation of 107 with 2,4,6-trichlorobenzoyl chloride (104) followed by addition of cephalotaxine (CET) (108) provided the desired cephalotaxine-coupled product 109 in 43% yield Sequential treatment with HBr/HOAc and 5% aqueous NaHCO3 completed the synthesis, providing omacetaxine mepesuccinate (XVII) in 41% yield (over two steps).153 125, Cu(OAc)2 , H2 O NH N ↑↓, 60% O 123 N 30 °C O O Br 126 128, Pd(OAc) 2, PPh 3, CuI K2CO3 , DME, ↑↓ N NBS, DMF N pyridine, DMF 28 °C to 40 °C, 91% 124 N N N O CN Recrystallization from acetone /H2 O 86% for steps 127 3/4 H2 O XIX Perampanel hydrate B O O S O B N B O B O O 122 N OMe 121 HCl, H 2O N N 122 125 128 Scheme 24 Synthesis of perampanel hydrate (XIX) O 2023 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 higher binding affinity for somatostatin receptors 1, 3, and than its competitor somatostatin-mimic octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2.154 Pasireotide is more potent than somatostatin in inhibiting the secretion of human growth hormone (HGH), glucagon, and insulin.155 The synthesis of pasireotide is relatively straightforward, given that the chemical entity is a cyclic peptide The most likely scalable route closely mimics that described by the discovery authors involving a series of conventional couplings and deprotection steps to arrive at a linear peptide which then underwent sequential release from solid support, macrocyclization, and a global deprotection step.156 O O Ac 2O OH OH N ↑↓, 76% Beginning from (2S,4R)-4-hydroxyproline methyl ester (110) in Scheme 21 above, this pyrrolidine nitrogen was first Fmoc-protected in 85% yield, followed by treatment with triphosgene and N-Boc diaminoethane to provide the prolino carbamate 111 in 49% yield over the two step sequence after a recrystallization with ethyl acetate.156 Next, commercially available Fmoc-Tyr(Bzl)-O-CH2-Ph(3OCH3)-O-CH2-SASRIN157 resin (112) was used as starting material in a manually operated reactor and carried through a standard protocol consisting of repetitive cycles of Na deprotection (piperidine/DMF, 2:8), repeated washings with DMF, and coupling using DIC/HOBT in DMF (Schemes 22 and 23) The following amino acid derivatives were sequentially coupled: Fmoc-Lys(Boc)-OH, F 129 AlCl3, ↑↓, 84% F CO2 H 20% H 2SO4 N 140 °C, 81% O O NH2 134 HN 133b NH2 O OH OH •2 N AcOH, H 2O 3 M aq maleic acid 40 °C to 50 °C 92% for steps F CO2 H F 132a H2N THF, 55 °C HN O 133 O NH XX Pixantrone dimaleate Scheme 25 Synthesis of pixantrone dimaleate (XX) N Si(CH 3) 136 N N N N N TBAF, THF N RT, 94% Pd(PPh3) 4, CuI, DIPEA CH CN RT, 71% Br N N Si(CH 3) 135 137 138 N N N HCl 139, Pd(PPh3 )4 , CuI EtOAc, Et3 N, RT N H N EtOH, HCl, RT 53% for steps N O CF3 XXI Ponatinib hydrochloride I I SOCl2, DCM, RT OH H 2N O 140 O CF N HN N 141 CF3 F N + 130 O O N O O F 131 O N O F N 139 DCM, DIPEA, DMAP, RT, 65% Scheme 26 Synthesis of ponatinib hydrochloride (XXI) N F 2024 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 Fmoc-D-Trp(Boc)-OH, Fmoc-PhG-OH, proline derivative 111 above, and finally Fmoc-Phe-OH Couplings were continued or repeated until complete disappearance of residual amino groups as monitored with a ninhydrin stain test Before cleavage of the protected linear peptide from its resin support, the Fmoc group was removed After washings with dichloromethane, the peptide resin was transferred into a column and the peptide fragment was cleaved from solid support upon subjection to 2% TFA in dichloromethane The eluant was immediately neutralized with a saturated NaHCO3 solution which resulted in the side chain protected fragment 119 (Scheme 23) This material was obtained in 93% homogeneity and cyclized without further purification For cyclization, the linear fragment was dissolved in DMF and subsequently treated with DIPEA and 1.5 equiv of diphenylphosphoryl azide, resulting in the protected cyclized product in good yield For complete deprotection, the residue was dissolved at °C in aqueous TFA, and the mixture was stirred at this temperature for 30 The product was then precipitated with ether containing ca 10 equiv of HCl, then filtered and washed with ether, and finally dried The entire sequence produced pasireotide (XVIII) in 20% yield from resin-bound 112.156 Bromination of commercial 2-methoxypyridine (120) gave 5-bromo-2-methoxypridine 121 in 86% yield (Scheme 24) Lithium halogen exchange was then accomplished by treating 121 with nbutyllithium, followed by reaction with 2-benzenesulfonylpyridine (122) to provide bi-aryl 123 Hydrolysis of 123 under acidic conditions gave pyridinone 124 in 60% overall yield N-Arylation with triphenylboroxine (125) in the presence of copper acetate afforded N-aryl pyridinone 126 in 91% yield Pyridone 126 was reacted with N-bromosuccinimide to give bromopyridine 127, which was coupled with 2-(1,3,2-dioxaborinan-2-yl)benzonitrile (128) under palladium-catalyzed conditions to give perampanel hydrate (XIX) in 86% yield after recrystallization from acetone/H2O 21 Pixantrone dimaleate (PixuvriÒ) Pixuvri (Pixantrone dimaleate) is a novel aza-anthracenedione derivative approved in Europe for the treatment of adult patients with non-Hodgkin B-cell lymphoma.163 It is also being pursued as a treatment for various cancers, and specifically as an alternative to other structurally-related drugs like mitoxantrone, employed for treatment of breast cancer, acute myeloid leukemia (AML), and non-Hodgkins lymphoma.164 Pixantrone dimaleate has been designed to maintain antitumor efficacy while decreasing highly cardiotoxic side effects observed during treatment with other related anti-tumor anthracenedione derivatives.164–166 Like many anthracenedione drugs, the mechanism of action for pixantrone dimaleate likely includes a number of pathways and processes, with studies suggesting intercalation into DNA and/or interference with DNA—Topoisomerase II activity, leading to subsequent protein associated-DNA strand breaks and eventually to cell death.167,168 Pixantrone dimaleate, also known as BBR 2778, was originally 20 Perampanel hydrate (FycompaÒ) Perampanel is a selective, non-competitive a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist approved for partial-onset seizures in patients with epilepsy.158,159 Perampanel was discovered and developed by Eisai A number of synthetic routes to perampanel have been reported160 and the process scale route is described herein.161,162 O N O O O N N Et N, 110 °C, 81% N N 142 143 N N N N N 144, NaOH, i-PrOH, ↑↓ N O N H O N 146, t -BuOK, THF N -25 °C to RT, 85% N N H N N H N O CF3 145 147 N N N N 35% aq HCl, acetone 0°C to RT H N N H N O N HCl CF3 XXII Radotinib dihydrochloride N NH H 2N H2N N O N H HNO 144 O CF3 146 Scheme 27 Synthesis of radotinib dihydrochloride (XXII) 2025 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 synthesized by Professors Krapcho and Hacker at the University of Vermont,169 and determination of in vitro tumor cell cytotoxicity was co-identified by the Boehringer Mannheim Italia research center and the University of Vermont.170 After the merger of Boehringer Mannheim with La-Roche, Novuspharm, and Cell Therapeautics, Inc., pixantrone dimaleate has been developed and marketed by Cell Therapeutics, Inc The manufacturing scale synthesis of pixantrone dimaleate relies on several process modifications171,172 from the original synthesis reported by Krapcho in 1994.169 This modified procedure has provided active pharmaceutical ingredient (API) in high purity (>99%) and is acceptable for use in pharmaceutical applications (Scheme 25).171 Beginning with pyridine 3,4-dicarboxylic acid (129), generation of the corresponding anhydride 130 proceeded in 76% yield upon treatment with refluxing Ac2O Next, an O 148 Ponatinib hydrochloride (IclusigÒ), previously known as AP24534, is a multi-targeted tyrosine kinase inhibitor approved in the U.S as an oral treatment for resistant or intolerant chronic Cl methylamine toluene, H 2O, 20 °C acetyl chloride EtOH, toluene, RT, quant N 22 Ponatinib hydrochloride (IclusigÒ) O SOCl2, DMF, chlorobenzene 70 °C to 90 °C OH AlCl3-promoted Friedel–Crafts reaction of 1,4-difluorobenzene (131) with 130 under reflux conditions provided a mixture of nicotinic acid isomers 132a/132b in 84% yield, which were carried directly to the next step Cyclization with fuming H2SO4 yielded the desired difluorobenzo-isoquinoline-dione core 133, which was further functionalized with ethylenediamine (134) to provide the free base of pixantrone Subjection of the pixantrone free base to aqueous acetic anhydride and maleic acid provided pixantrone dimaleate (XX) in 92% yield over steps.171 N toluene, NaOH N H HCl 150, t-BuOK, NMP 100 °C, 84% 149 CF3 Cl 152 O O H 2N N C O N H N CF3 O Cl O THF, RT, 83% N H F 151 O N H N N H H2 O F XXIII Regorafenib hydrate O H 2N OH N OH cyclohexane, ↑↓ F F 150 153 Scheme 28 Synthesis of regorafenib hydrate (XXIII) Cl Cl H2 N O O CO2Me pyridine, DCM HN Cl HO Cl Cl 154 HO 156 155 Cl O p-TsOH, toluene , ↑↓ N Cl CO2 Me LiOH, THF, H2 O, 40 °C N-methyl-D-glucamine i-PrOH, H2 O, 82% 157 O Cl O OH N OH OH Cl HO OH H N OH XXIV Tafamidis meglumine Scheme 29 Synthesis of tafamidis meglumine (XXIV) CO2Me 2026 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).173 Ponatinib hydrochloride was designed for treatment of tumors containing the T351I mutation which are present in some forms of CML and resistant to traditional therapies such as imatinib.173–175 Ponatinib hydrochloride was developed by Ariad Pharmaceauticals, and operates by a similar mechanism of action as other tyrosine kinase inhibitors, inhibiting the enzymatic activity of BCR-ABL, an abnormal tyrosine kinase responsible for unregulated and excess white blood cell production by bone marrow.176 However, the ability of ponatinib hydrochloride to target isoforms of the BCR-ABL gene typically leading to resistance in other known tyrosine kinase inhibitors provides an alternate form of therapy not previously available.175 A significant amount of research has been devoted towards identification of a manufacturing synthesis of ponatinib hydrochloride.177–180 A majority of methods rely on two key Sonagashira couplings to generate the imidazo[1,2-b]pyridazin-3-ylethynyl framework The most likely process-scale method begins with 3bromo-imidazo[1,2-b]pyridazine (135) (Scheme 26).177,180 Direct Sonogashira coupling of (135) with ethynyltrimethylsilane (136) in the presence of Pd(PPh3)4 and CuI, followed by treatment with TBAF/THF led to the desired alkynyl imidazo[1,2-b]pyridazine 138 in 71% and 94% yields, respectively Alkyne 138 was then coupled under similar Sonogashira conditions with functionalized aryl iodide 139 (generated in two steps from 3-iodo-4-methylbenzoic acid (140) and commercially available piperazinyl aniline 141) providing ponatinib free base, which was then immediately treated with EtOH/HCl at room temperature to ultimately furnish ponatinib hydrochloride (XXI).177,180 23 Radotinib hydrochloride (SupectÒ) In January 2012, radotinib hydrochloride (marketed as SupectÒ) obtained its approval from the KFDA (Korea Food and Drug Administration) for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who have become resistant to existing drugs such as Gleevec, Tasigna and Sprycel.181 Originally developed by IL-YANG pharmaceuticals of South Korea as an oral second-generation tyrosine kinase inhibitor, the drug inhibits both Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR).182 Because of the structural similarity of radotinib to that of nilotinib (TasignaÒ), the processscale synthetic route (which is depicted in Scheme 27) is capable of furnishing both drugs.183–185 Claisen condensation of commerical 2-acetylpyrazine (142) with N,N-dimethylformamide dimethylacetal gave rise to the enamino ketone 143 in 81% yield.186 Under basic conditions, vinylogous amide 143 was coupled with commercial guanidine nitrate 144187 to produce aminopyridine 145.184 Subsequent condensation with commercial aniline (146) by means of potassium t-butoxide in THF constructed radotinib 147 in 85% yield as the free base, and this material could be converted to the radotinib dihydrochloride (XXII) upon exposure to concentrated hydrochloric acid in chilled acetone.185 24 Regorafenib hydrate (StivargaÒ) Regorafenib was approved by the U.S Food and Drug Administration (FDA) in September 2012 for the treatment of metastatic O O Boc N O 159 Boc N NH N NHNH O MsOH, RT pyridine, POCl3 , RT, 12% DMF, RT, 86% 158 160 N N N N Boc TFA, DCM N N N NH 88% NaBH(OAc)3 , AcOH 161 Boc N 162 H O OH H Boc HOBt, EDC, DMF, RT, 62% HN + S 1,2-DCE, RT, 50% O N N S DMSO, SO3 Py, RT, 55% HO O 165 164 163 Boc N O N NH N N N O N N S N N TFA, DCM, RT, 93% 48% HBr, ↑↓, EtOH, 90% 166 N N S 2.5 HBr x H 2O XXV Teneligliptin hydrobromide hydrate Scheme 30 Synthesis of teneligliptin hydrobromide hydrate (XXV) 2027 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 colorectal cancer in patients who have previously undergone fluoropyrimidine-, oxaliplatin-, and irinotecan-based therapies.188 The FDA expanded the approved use of the drug to include patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to imatinib and sunitinib, two other drugs approved for treatment of GIST Regorafenib, marketed under the trade name StivargaÒ, was discovered and developed by Bayer Pharmaceuticals and marketed jointly with Onyx Pharmaceuticals.189 The active metabolites of the drug inhibit multiple targets within a variety of kinase families including those in the RET, VEGF, FGFR, PTK, and Abl pathways.190,191 Among several published synthesis,192,193 the most likely process scale synthesis will be highlighted from the two published syntheses, and this is described in Scheme 28.194 Commercially available picolinic acid (148) was heated with thionyl chloride to provide the crude intermediate 4-chloro-2-pyridyl acid chloride CF3 O O + H 2N O 167 25 Tafamidis meglumine (VyndaqelÒ) Tafamidis meglumine is a transthyretin amyloid inhibitor that was approved for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN) and transthyretin familial amyloid polyneropa- O Br CF3 O KBr, H 2O 2, toluene N H ↑↓, 51% 168 HCl (conc.), RT, 67% 169 CF3 O O xylene which was subsequently reacted with aqueous methylamine in toluene to give 4-chloro-2-methylcarboxamide as its hydrochloride salt 149 in quantitative yield after treatment with acetyl chloride in toluene and ethanol Conversion of 149 to its free base form was performed with sodium hydroxide, and this intermediate was immediately reacted with imine 150 (formed upon exposure to 4-amino-3-fluorophenol (153) in refluxing 3-methyl-2-butanone) in base to provide diaryl ether 151 in 85% yield Reaction of amine 151 with the commercially available isocyanate 152 ultimately delivered regorafenib hydrate (XXIII) in 83% yield NaCN, DMSO, RT N H 85% CN 170 CF3 OH O N H XXVI Teriflunomide Scheme 31 Synthesis of teriflunomide (XXVI) N H 2N H2 , 5% Rh/C (JM C101023-5) AcOH O KOt -Bu, (MeO 2C)2 O 2-MeTHF, toluene 20 °C to 35 °C, 87% N H O 171 N O PhCHO, NaHB(OAc) toluene, 73% NBn N H O 172 173 O N NaOH, i-PrOH, MeOH LAH, THF, RT HCl, i-PrOH, 87% NBn N H di-p-toluoyl-L-tartaric acid 42% for steps 2HCl HO2 C O HO2 C O NBn N H O 175 98.6% ee 174 Cl N Cl 176 N N H NBn N N K2 CO 3, H O, 95 °C to 105 °C quant Cl N H N H2 , Pd(OH)2 /C H O, 70 °C to 75 °C N DBU, MeOCCH 2CN 1-butanol, 40 °C citric acid, 90% Cl POCl3, DIPEA N 178 N H HOOC HOOC XXVII Tofacitinib citrate OH N N H N OH CN O 177 HO N N toluene, 106 °C 52% N Cl N N H 176 Scheme 32 Synthesis of tofacitinib citrate (XXVII) COOH 2028 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 thy (TTR-FAP).195–197 These diseases represent a rare autosomal neurodegenerative disorder characterized by autonomic, sensory and motor impairment which are typically fatal Tafamidis was discovered at The Scripps Research Institute and developed by Pfizer Numerous synthetic routes have been reported including the use of direct CH activation to form the key biaryl bond.198,199 Although only reported on small scale, the most likely production route is detailed in Scheme 29.200–202 Condensation of methyl 4-amino-3-hydroxybenzoic acid (154) with 3,5-dichlorobenzoyl chloride (155) in refluxing pyridine gave intermediate amide 156, which underwent cyclization upon treatment with p-TsOH in refluxing toluene, producing benzoxazole 157 Saponification of the methyl ester with LiOH (aq) afforded tafamidis The free acid was treated with N-methyl-D-glutamine to provide tafamidis meglumine (XXIV) in 82% yield give pyrazole 161 in 12% yield The t-butyl carbamate was then removed with TFA in dichloromethane to give amine 162 in 88% yield This amine was then subjected to butyrolactam 165 (which was prepared from N-Boc-trans-4-hydroxy-L-proline (163) coupled with thiazolidine (164) under conventional amide-forming conditions using EDC) in the presence of sodium triacetoxy borohydride (STAB-H) in acetic acid.205 This reductive amination reaction afforded the cis-aminopyrrolidine 166 exclusively in 50% yield Removal of the t-butyl carbamate group with TFA afforded the teneligliptin free amine in 93% yield, which was then subsequently treated with 48% hydrobromic acid in refluxing ethanol to give teleligliptin hydrobromide hydrate (XXV) in 90% yield 27 Teriflunomide (AubagioÒ) Teriflunomide (AubagioÒ), also known as A77 1726, is an immunosupressant marketed by Sanofi for the teatment of multiple sclerosis (MS).206 Teriflunomide is the active metabolite of leflunomide, used for treatment of patients diagnosed with rheumatoid arthritis, and therefore simultaneously can be used as a treatment for rheumatoid arthritis.207 Teriflunomide acts as an inhibitor of the mitochondrial enzyme dihydrorotate dehydrogenase,208–210 inhibiting pyrimidine formation,211 and resulting in reduced B and T cell proliferation.210 Numerous syntheses of teriflunomide have been developed to date,212–217 most relying on the use of 4-trifluoromethyl aniline (167).212 The current optimized method for scale-up synthesis of teriflunomide, developed by Keshav and coworkers, begins with reaction of commercial 4-trifluoromethyl aniline 167 and ethylacetoacetate (168) in refluxing xylenes, providing acetoamidate 169 in 51% yield (Scheme 31).215 The resulting acetoamidate 169 was 26 Teneligliptin hydrobromide hydrate (TeneliaÒ) Teneligliptin is a DPP-4 inhibitor which was approved in Japan in 2012 for the treatment of type II diabetes.203 It was discovered and developed by Mitsubishi Tanabe Pharma under the trade name TeneliaÒ Similar to other marketed DPP-4 inhibitors, teneligliptin was well tolerated in all studies and QD dosing produced a longlasting inhibitory action against DPP-4 and an increase in active GLP-1 levels, with very low rates of renal excretion.204 The only reported synthesis of teneligliptin is described in Scheme 30.203 Reaction of commercially available N-Boc-piperazine (158) with diketene (159) in DMF at room temperature gave acetoacetamide 160 in 86% yield, and this material was immediately condensed with phenylhydrazine in methanesulfonic acid followed by a cyclodehydration with phosphorus oxychloride to I I Cl H2 SO4 (conc.), NaIO4 , KI, RT t-BuOH, DPPA Cl N H CO2 H 179 180 O B2(pin) , Pd(dppf)Cl B N 2-bromopyridine, Pd(PPh )4 N H 182 Cl NaHCO3 , H 2O, DME ↑↓, quant O 185 , Et 3N, DCM Cl 183 Cl O 0°C to °C, 99% Cl N H NH2 SO 2Me 184 XXVIII Vismodegib O Cl HO 2C O N H Ot-Bu N N TFA, DCM, °C Ot-Bu 181 O Cl KOAc, DMSO, 110 °C, 91% 98% O Et N, ↓↑, 84% 73% CO2 H Cl 10% NaOH, toluene, Et3 N Cl Cl DMF, SOCl2 , °C to 50 °C SO2 Me 186 SO2 Me 185 Scheme 33 Synthesis of vismodegib (XXVIII) Ot-Bu H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 then treated with H2O2, KBr, and concentrated HCl at room temperature, providing bromide 170 in 67% yield Bromide 170 was reacted with NaCN in DMSO, generating teriflunomide (XXVI) in 85% yield.215 28 Tofacitinib citrate (XeljanzÒ) Tofacitinib, a pan-Janus Kinase (JAK) inhibitor, was approved by the FDA for the treatment of moderate to serious cases of rheumatoid arthritis (RA) in patients that have not responded to mono therapy with methotrexate therapy.188 Tofacitinib, which was discovered and developed by Pfizer Inc.,218 is a potent and selective inhibitor of the JAK family of kinases and has shown potential for treating psoriasis and organ transplant in addition to RA.219 Both the initial discovery synthetic route220,221 and the process scale synthetic route have been disclosed in the chemical literature, and the process approach is described in Scheme 32 below.222,223 Commercially available aminopyridine 171 was reacted with dimethyl dicarbonate in the presence of potassium t-butoxide to give the methyl carbamate 172 in 87% yield Hydrogenation of this carbamate 172 in the presence of 20 wt % of 5% Rh/C (JM type C101023-5) in acetic acid followed by reductive amination with benzaldehyde and sodium triacetoxy borohydride furnished the cis-benzyl protected piperidine 173 in 73% yield Reduction of the methyl carbamate within 173 with lithium aluminum hydride (LAH) in THF gave the corresponding methyl amino piperidine which was isolated as the dihydrochloride salt 174 in 87% yield Enantiomeric resolution of the methyl amino piperidine was achieved by preparation of the free base of 174 with sodium hydroxide, conversion to the di-toluol-L-tartaric acid salt, and subsequent crystallization to give 175 in 42% yield and 98.6% ee The enantioenriched tartrate salt 175 was then directly reacted with dichloride 176 (obtained from reaction of commercial 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride) in the presence of potassium carbonate in water to give the coupled product 177 in essentially quantitative yield Hydrogenation of intermediate 177 with DeGussa’s catalyst triggered concomitant debenzylation and chloride removal, and this was followed by installation of the cyanoacetate group and subsequent treatment with citric acid to provide tofacitinib citrate (XXVII) in 90% yield.224 References and notes 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Vismodegib (ErivedgeÒ) Until the approval of Genentech’s visomodegib, the only treatment options for patients with advanced or metastatic basal-cell carcinoma (BCC) were surgery or radiation therapy Because it represented a first-in-class treatment, vismodegib received priority review from the FDA as the drug progressed through clinical trials The drug, which is marketed as ErivedgeÒ, derives its efficacy through inhibition of the hedgehog signaling pathway which exists in most BCC’s.225,226 While there are several patents that cover the synthesis of vismodegib,227–229 the scale route has been published, and this route is depicted in Scheme 33.230 The synthesis began with selective iodination of commercial carboxylic acid 179, affording trisubstituted arene 180 in 73% yield A Curtius reaction then converted 180 to carbamate 181 in 84% yield, and this was followed by a palladium(0)-catalyzed borylation of 181 which furnished Suzuki coupling partner 182 in 91% yield Pinacol borane 182 was exposed to commercial 2-bromopyridine under conventional cross-coupling conditions to furnish biaryl 183, which underwent Boc-deprotection in quantitative conversion to generate 184 Amide bond formation with acid chloride 185 (readily available from the corresponding commercial acid)231 produced vismodegib (XXVIII) in 99% yield 2029 29 30 31 32 33 34 35 36 37 38 39 40 Raju, T N K Lancet 2000, 355, 1022 Li, J.; Liu, K K.-C Mini-Rev Med Chem 2004, 4, 207 Liu, K K.-C.; Li, J.; Sakya, S Mini-Rev Med Chem 2004, 4, 1105 Li, J.; Liu, K K.-C.; Sakya, S Mini-Rev Med Chem 2005, 5, 1133 Sakya, S M.; Li, J.; Liu, K K.-C Mini-Rev Med Chem 2007, 7, 429 Liu, K K.-C.; Sakya, S M.; Li, J Mini-Rev Med Chem 2007, 7, 1255 Liu, K K.-C.; Sakya, S M.; O’Donnell, C J.; Li, J Mini-Rev Med Chem 2008, 8, 1526 Liu, K K.-C.; Sakya, S M.; O’Donnell, C J.; Li, J Mini-Rev Med Chem 2009, 9, 1655 Liu, K K.-C.; Sakya, S M.; O’Donnell, C J.; Flick, A C.; Li, J Bioorg Med Chem 2011, 19, 1136 Liu, K K.-C.; Sakya, S M.; O’Donnell, C J.; Flick, A C.; Ding, H X Bioorg Med Chem 2012, 20, 1155 Ding, H X.; Liu, K K.; Sakya, S M.; Flick, A C.; O’Donnell, C J Bioorg Med Chem 2013, 21, 2795 Graul, A I.; Lupone, B.; Cruces, E.; Stringer, M Drugs Today (Barc) 2013, 49, 33 FDA approves Tudorza Pressair to treat chronic obstructive pulmonary disease http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm313052.htm; 2012, [Access Date: 2012-July-23] Gavalda, A.; Miralpeix, M.; Ramos, I.; Otal, R.; Carreno, C.; Vinals, M.; Domenech, T.; Carcasona, C.; Reyes, B.; Vilella, D.; Gras, J.; Cortijo, J.; Morcillo, E.; Llenas, J.; Ryder, H.; Beleta, J J Pharmacol Exp Ther 2009, 331, 740 Fernandez Forner, D.; Prat Quinones, M.; Buil Albero, M A WO Patent 01/ 04118 A2, 2001 Prat, M.; Fernandez, D.; Antonia Buil, M.; Crespo, M I.; Casals, G.; Ferrer, M.; Tort, L.; Castro, J.; Monleon, J M.; Gavalda, A.; Miralpeix, M.; Ramos, I.; Domenech, T.; Vilella, D.; Anton, F.; Huerta, J M.; Espinosa, S.; Lopez, M.; Sentellas, S.; Gonzalez, M.; Alberti, J.; Segarra, V.; Cardenas, A.; Beleta, J.; Ryder, H J Med Chem 2009, 52, 5076 Busquets Baque, N.; Pajuelo Lorenzo, F WO Patent 2008/009397 A1, 2008 Nyberg, K.; Östman, B.; Wallerberg, G Acta Chem Scand 1970, 24, 2012 China Drug Review Annual Report, 2013, http://www.cde.org.cn/linshi/ regulatEn/newsShow.jsp Wu, M Y.; Ma, X J.; Yang, C.; Tao, X.; Liu, A J.; Su, D F.; Liu, J G Acta Pharmacol Sin 2009, 30, 307 Guo, J H.; An, D WO Patent 2007/095789 A1, 2007 An, D.; Guo, J H CN Patent 101367795 B, 2012 Tsubamoto, Y.; Goto, M Folia Pharmacol Jpn 2013, 141, 339 Kato, N.; Oka, M.; Murase, T.; Yoshida, M.; Sakairi, M.; Yamashita, S.; Yasuda, Y.; Yoshikawa, A.; Hayashi, Y.; Makino, M.; Takeda, M.; Mirensha, Y.; Kakigami, K Bioorg Med Chem 2011, 19, 7221 Yang, L P H.; McKeage, K Drugs 2012, 72, 2375 Hu-Lowe, D D.; Zou, H Y.; Grazzini, M L.; Hallin, M E.; Wickman, G R.; Amundson, K.; Chen, J H.; Rewolinski, D A.; Yamazaki, S.; Wu, E Y.; McTigue, M A.; Murray, B W.; Kania, R S.; O’Connor, P.; Shalinsky, D R.; Bender, S L Clin Cancer Res 2008, 14, 7272 Rini, B I.; Escudier, B.; Tomczak, P.; Kaprin, A.; Szczylik, C.; Hutson, T E.; Michaelson, M D.; Gorbunova, V A.; Gore, M E.; Rusakov, I G.; Negrier, S.; Ou, Y.-C.; Castellano, D.; Lim, H Y.; Uemura, H.; Tarazi, J.; Cella, D.; Chen, C.; Rosbrook, B.; Kim, S.; Motzer, R J Lancet 2011, 378, 1931 Kania, R S.; Bender, S L.; Borchardt, A J.; Braganza, J F.; Cripps, S J.; Hua, Y.; Johnson, M D.; Johnson, T O., Jr.; Luu, H T.; Palmer, C L.; Reich, S H.; Tempczyk-russell, A M.; Teng, M.; Thomas, C.; Varney, M D.; Wallace, M B WO Patent 01/02369 A2, 2001 Kania, R S.; Bender, S L.; Borchardt, A J.; Cripps, S J.; Palmer, C L.; Tempczykrussell, A M.; Varney, M D.; Collins, M R US Patent 6531491 B1, 2003 Bender, S.; Kania, R.; Mctigue, M.; Palmer, C.; Pinko, C.; Wickersham, J WO Patent 2004/092217 A1, 2004 Flahive, E.; Ewanicki, B.; Yu, S.; Higginson, P D.; Sach, N W.; Morao, I QSAR Comb Sci 2007, 26, 679 Ewanicki, B L.; Flahive, E J.; Kasparian, A J.; Mitchell, M B.; Perry, M D.; O’Neill-Slawecki, S A.; Sach, N W.; Saenz, J E.; Shi, B.; Stankovic, N S US Patent 2006/0094881 A1, 2006 Ye, Q.; Hart, R M.; Kania, R.; Ouellette, M.; Wu, Z P.; Zook, S E US Patent 2006/0094763 A1, 2006 Babu, S.; Dagnino Jr, R.; Ouellette, M.; Shi, B.; Tian, Q.; Zook, S WO Patent 2006/048745 A1, 2006 Friesen, D T.; Lorenz, D A.; Smith, S W WO Patent 2006/123223 A1, 2006 Flahive, E J.; Ewanicki, B L.; Sach, N W.; O’Neill-Slawecki, S A.; Stankovic, N S.; Yu, S.; Guinness, S M.; Dunn, J Org Process Res Dev 2008, 12, 637 Ewanicki, B L.; Flahive, E J.; Kasparian, A J.; Mitchell, M B.; Perry, M D.; O’Neill-Slawecki, S A.; Sach, N W.; Saenz, J E.; Shi, B.; Stankovic, N S.; Srirangam, J K.; Tian, Q.; Yu, S EP Patent 2163544 A1, 2010 Chekal, B P.; Guinness, S M.; Lillie, B M.; McLaughlin, R W.; Palmer, C W.; Post, R J.; Sieser, J E.; Singer, R A.; Sluggett, G W.; Vaidyanathan, R.; Withbroe, G J Org Process Res Dev 2013 Buclin, T.; Biollaz, J.; Kung, S.; Appenzeller, M.; Nussberger, J.; Higgins, T.; Obayashi, M.; Brunner, H R Clin Pharmacol Ther 1995 Westline Industrial Dr, St Louis, MO 63146-3318, Abstract 204 Ojima, M.; Igata, H.; Tanaka, M.; Sakamoto, H.; Kuroita, T.; Kohara, Y.; Kubo, K.; Fuse, H.; Imura, Y.; Kusumoto, K.; Nagaya, H J Pharmacol Exp Ther 2011, 336, 801 2030 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 Naka, T.; Inada, Y US Patent 5583141 A, 1996 Naka, T.; Inada, Y EP Patent 0520423 A2, 2003 Ra´dl, S.; Cerny´, J.; Stach, J.; Gablíkova´, Z Org Process Res Dev 2013, 17, 77 Jones, D Nat Rev Drug Disc 2013, 12, 175 Van Gestel, J F E.; Guillemont, J E G.; Venet, M G.; Poignet, H J J.; Decrane, L F B.; Vernier, D F J.; Odds, F C US Patent 2005/0148581 A1, 2005 Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M J Am Chem Soc 2010, 132, 7905 Shibazaki, M.; Kanai, M.; Saga, H JP patent 2011–168519 A, 2011 Porstmann, F R.; Horns, S.; Bader, T WO Patent 2006/125769 A1, 2006 Hegyi, J F., Alexandre, Lucas; Aelterman, W., Albert, Alex; Lang, Y L.; Stokbroekx, S., Carl, Maria; Leys, C.; Van Remoortere, P., Jozef, Maria; Faure, A WO Patent 2008/068231 A1, 2008 Keller-von Amsberg, G.; Koschmieder, S OncoTargets Ther 2013, 6, 99 Golas, J M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D H.; Boschelli, F Cancer Res 2003, 63, 375 Boschelli, D H.; Wang, Y D.; Johnson, S.; Wu, B.; Ye, F.; Sosa, A C B.; Golas, J M.; Boschelli, F J Med Chem 2004, 47, 1599 Khoury, H J.; Cortes, J E.; Kantarjian, H M.; Gambacorti-Passerini, C.; Baccarani, M.; Kim, D.-W.; Zaritskey, A.; Countouriotis, A.; Besson, N.; Leip, E.; Kelly, V.; Brummendorf, T H Blood 2012, 119, 3403 Cortes, J E.; Kantarjian, H M.; Brummendorf, T H.; Kim, D.-W.; Turkina, A G.; Shen, Z.-X.; Pasquini, R.; Khoury, H J.; Arkin, S.; Volkert, A.; Besson, N.; Abbas, R.; Wang, J.; Leip, E.; Gambacorti-Passerini, C Blood 2011, 118, 4567 Keller, G.; Schafhausen, P.; Bruemmendorf, T H Recent Results Cancer Res 2010, 184, 119 Yin, X J.; Xu, G H.; Sun, X.; Peng, Y.; Ji, X.; Jiang, K.; Li, F Molecules 2010, 15, 4261 Li, F.; Yin, X J.; Jiang, K.; Sun, X.; Xu, G H CN Patent 101792416 A, 2010 Sutherland, K W.; Feigelson, G B.; Boschelli, D H.; Blum, D M.; Strong, H L US Patent 2005/0043537 A1, 2005 Withbroe, G J.; Seadeek, C.; Girard, K P.; Guinness, S M.; Vanderplas, B C.; Vaidyanathan, R Org Process Res Dev 2013, 17, 500 Hart, C D.; De Boer, R H OncoTargets Ther 2013, 6, Traynor, K Am J Health Syst Pharm 2013, 70, 88 Bentzien, F.; Zuzow, M.; Heald, N.; Gibson, A.; Shi, Y.; Goon, L.; Yu, P.; Engst, S.; Zhang, W.; Huang, S.; Zhao, L.; Vysotskaia, V.; Chu, F.; Bautista, R.; Cancilla, B.; Lamb, P.; Joly, A H.; Yakes, F M Thyroid 2013 Bannen, L C.; Chan, D S.-M.; Chen, J.; Dalrymple, L E.; Forsyth, T P.; Huynh, T P.; Jammalamadaka, V.; Khoury, R G.; Leahy, J W.; Mac, M B.; Mann, G.; Mann, L W.; Nuss, J M.; Parks, J J.; Takeuchi, C S.; Wang, Y.; Xu, W WO Patent 2005/030140 A2, 2005 St Clair Brown, A.; Lamb, P.; Gallagher, W P WO Patent 2010/083414 A1, 2010 Wilson, J A WO Patent 2012/109510 A1, 2012 Wilson, J A.; Naganathan, S.; Pfeiffer, M.; Andersen, N G WO Patent 2013/ 059788 A1, 2013 Kim, K B.; Crews, C M Nat Prod Rep 2013, 30, 600 Davies, S.; Pandian, R.; Bolos, J.; Castaner, R Drugs Future 2009, 34, 708 Sin, N.; Kim, K B.; Elofsson, M.; Meng, L.; Auth, H.; Kwok, B H B.; Crews, C M Bioorg Med Chem Lett 1999, 9, 2283 Elofsson, M.; Splittgerber, U.; Myung, J.; Mohan, R.; Crews, C M Chem Biol 1999, 6, 811 Phiasivongsa, P.; Sehl, L C.; Fuller, W D.; Laidig, G J WO Patent 2009/045497 A1, 2009 Laidig, G J.; Radel, P A.; Smyth, M S US Patent 2005/0256324 A1, 2005 Ptaszynska, A.; Chalamandaris, A.-G.; Sugg, J.; Johnsson, K.; Parikh, S.; List, J F European Association for the Study of Diabetes Annual Meeting 2012 (48th), 2012, Berlin, German, Abstract 242 Meng, W.; Ellsworth, B A.; Nirschl, A A.; McCann, P J.; Patel, M.; Girotra, R N.; Wu, G.; Sher, P M.; Morrison, E P.; Biller, S A.; Zahler, R.; Deshpande, P P.; Pullockaran, A.; Hagan, D L.; Morgan, N.; Taylor, J R.; Obermeier, M T.; Humphreys, W G.; Khanna, A.; Discenza, L.; Robertson, J G.; Wang, A.; Han, S.; Wetterau, J R.; Janovitz, E B.; Flint, O P.; Whaley, J M.; Washburn, W N J Med Chem 2008, 51, 1145 Deshpande, P P.; Ellsworth, B A.; Singh, J.; Lai, C.; Crispino, G.; Randazzo, M E.; Gougoutas, J Z.; Denzel, T W WO Patent 2004/063209 A2, 2004 FDA approves new treatment for a type of late stage prostate cancer, http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317838.htm, [Access Date: 2012-Aug-31] Tran, C.; Ouk, S.; Clegg, N J.; Chen, Y.; Watson, P A.; Arora, V.; Wongvipat, J.; Smith-Jones, P M.; Yoo, D.; Kwon, A.; Wasielewska, T.; Welsbie, D.; Chen, C D.; Higano, C S.; Beer, T M.; Hung, D T.; Scher, H I.; Jung, M E.; Sawyers, C L Science (New York, N.Y.) 2009, 324, 787 Sawyers, C L.; Jung, M E.; Chen, C D.; Ouk, S.; Welsbie, D.; Tran, C.; Wongvipat, J.; Yoo, D WO Patent 2006/124118 A1, 2006 Jung, M.; Yoo, D.; Sawyers, C L.; Tran, C US Patent 2007/0254933 A1, 2007 Jung, M E.; Ouk, S.; Yoo, D.; Sawyers, C L.; Chen, C.; Tran, C.; Wongvipat, J J Med Chem 2010, 53, 2779 Chen, Y WO Patent 2013/087004 A1, 2013 Jain, R P.; Angelaud, R.; Thompson, A.; Lamberson, C.; Greenfield, S WO Patent 2011/106570 A1, 2011 Eisai and Toyama Chemical Receive Approval to Market Anti-rheumatic Agent Iguratimod in Japan, 2012, http://www.eisai.com/news/news201239.html, [Access Date: 2012-July-29] 84 Tanaka, K.; Shimotori, T.; Makino, S.; Aikawa, Y.; Inaba, T.; Yoshida, C.; Takano, S Arzneim.-Forsch 1992, 42, 935 85 Tanaka, K.; Makino, S.; Shimotori, T.; Aikawa, Y.; Inaba, T.; Yoshida, C Arzneim.-Forsch 1992, 42, 945 86 Takano, S.; Yoshida, C.; Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Shimotori, T.; Makino, S US Patent 4954518 A, 1990 87 Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Yoshida, C.; Takano, S Chem Pharm Bull 2000, 48, 131 88 Guo, Z R Chin J New Drugs 2012, 21, 223 89 Chen, X H.; Bai, J Y.; Shen, F.; Bai, A P.; Guo, Z R.; Cheng, G F Acta Pharmacol Sin 2004, 25, 927 90 Bai, A P.; Guo, Z R.; Hu, W H.; Shen, F.; Cheng, G F Chin Chem Lett 2001, 12, 775 91 Guo, Z.; Cheng, G.; Chu, F.; Yang, G.; Xu, B CN Patent 1134413 C, 2001 92 Guo, Z.; Cheng, G.; Chu, F US Patent 2004/0029951 A1, 2004 93 Zhang, F Y.; Shen, X M.; Sun, P Y CN Patent 102206178 A, 2011 94 Keating, G M Drugs 2012, 72, 2397 95 Aylward, J H.; Parsons, P G.; Suhrbier, A.; Turner, K A US Patent 7449492 B2, 2008 96 Liang, X.; Grue-Sørensen, G.; Petersen, A K.; Högberg, T Synlett 2012, 2647 97 Liang, X.; Grue-Sørensen, G.; Mansson, K.; Vedsø, P.; Soor, A.; Stahlhut, M.; Bertelsen, M.; Engell, K M.; Högberg, T Bioorg Med Chem Lett 2013, 23, 5624 98 Jørgensen, L.; McKerrall, S J.; Kuttruff, C A.; Ungeheuer, F.; Felding, J.; Baran, P S Science (New York, N.Y.) 2013, 341, 878 99 Winkler, J D.; Lee, E C Y.; Nevels, L I Org Lett 2005, 7, 1489 100 Kuwajima, I.; Tanino, K Chem Rev 2005, 105, 4661 101 Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P D.; Greene, B.; Yusuff, N.; Wood, J L J Am Chem Soc 2004, 126, 16300 102 Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I J Am Chem Soc 2003, 125, 1498 103 Winkler, J D.; Rouse, M B.; Greaney, M F.; Harrison, S J.; Jeon, Y T J Am Chem Soc 2002, 124, 9726 104 Winkler, J D.; Harrison, S J.; Greaney, M F.; Rouse, M B Synthesis 2002, 2002, 2150 105 Wood, J L.; Tang, H Abstracts of Papers, 221st ACS National Meeting, San Diego, CA, United States, April 1–5, 2001, ORGN 106 Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Kuwajima, I Conference proceedings from the 43rd Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 2001, 85 107 Tang, H.; Yusuff, N.; Wood, J L Org Lett 2001, 3, 1563 108 Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D Tetrahedron Lett 2000, 41, 3927 109 Kim, S.; Winkler, J D Chem Soc Rev 1997, 26, 387 110 Winkler, J D.; Hong, B C.; Bahador, A.; Kazanietz, M G.; Blumberg, P M Bioorg Med Chem Lett 1993, 3, 577 111 Rigby, J H.; Moore, T L.; Rege, S J Org Chem 1986, 51, 2398 112 Satoh, T.; Kaneko, Y.; Okuda, T.; Uwaya, S.; Yamakawa, K Chem Pharm Bull 1984, 32, 3452 113 Seip, E H.; Hecker, E Planta Med 1982, 46, 215 114 Grue-Sørensena, G.; Liang, X.; Högberga, T.; Mansson, K.; Vedsø, P.; Vifian, T WO Patent 2012/083953 A1, 2012 115 Sorg, B.; Hecker, E Z Naturforsch., B: Anorg Chem Org Chem 1982, 37B, 1640 116 FDA approves Kalydeco to treat rare form of cystic fibrosis, http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm, [Access Date: 2012-Jan-31] 117 Van Goor, F.; Hadida, S.; Grootenhuis, P D.; Burton, B.; Stack, J H.; Straley, K S.; Decker, C J.; Miller, M.; McCartney, J.; Olson, E R.; Wine, J J.; Frizzell, R A.; Ashlock, M.; Negulescu, P A Proc Natl Acad Sci U.S.A 2011, 108, 18843 118 Eckford, P D W.; Li, C.; Ramjeesingh, M.; Bear, C E J Biol Chem 2012, 287, 36639 119 Van Goor, F F.; Burton, W L WO Patent 2011/050325 A1, 2011 120 Hadida Ruah, S S.; Hazlewood, A R.; Grootenhuis, P D J.; Van Goor, F F.; Singh, A K.; Zhou, J.; Mccartney, J WO Patent 2006/002421 A2, 2006 121 Singh, A.; Van Goor, F.; Worley III, J F.; Knapp, T WO Patent 2007/075946 A1, 2007 122 Hurter, P WO Patent 2007/079139 A2, 2007 123 Young, C R.; Rowe, C W WO Patent 2007/134279 A2, 2007 124 Young, C R.; Rowe, C W US Patent 2008/0090864 A1, 2008 125 Demattei, J.; Feng, Y.; Harrison, C.; Looker, A.; Mudunuri, P.; Roeper, S.; Zhang, Y WO Patent 2009/038683 A2, 2009 126 Sheth, U.; Fanning, L T D.; Numa, M M D.; Binch, H.; Hurley, D.; Zhou, J.; Hadida Ruah, S S.; Hazlewood, A.; Silina, A.; Vairagoundar, R US Patent 2010/ 0184739 A1, 2010 127 Demattei, J.; Looker, A R.; Neubert-Langille, B.; Trudeau, M.; Roeper, S.; Ryan, M P.; YAP, D M L.; Krueger, B R.; Grootenhuis, P.; Vac Goor, F F.; Botfield, M C.; Zlokarnik, G WO Patent 2010/108162 A1, 2010 128 Sheth, U.; Fanning, L T D.; Numa, M.; Binch, H.; Hurley, D J.; Zhou, J.; Hadida Ruah, S S.; Hazlewood, A R.; Silina, A.; Vairagoundar, R.; Van Goor, F F.; Grootenhuis, P D J.; Botfield, M C WO Patent 2011/072241 A1, 2011 129 Arekar, S G.; Johnston, S C.; Krawiec, M.; Medek, A.; Mudunuri, P.; Sullivan, M J US Patent 2011/0230519 A1, 2011 130 Van Goor, F.; Alargova, R G.; Alcacio, T E.; Arekar, S G.; Johnston, S C.; Kadiyala, I N.; Keshavarz-Shokri, A.; Krawiec, M.; Lee, E C.; Medek, A WO Patent 2011/133951 A1, 2011 131 Van Goor, F.; Alargova, R G.; Alcacio, T E.; Arekar, S G.; Binch, H M.; Botfield, M C.; Fanning, L T D.; Grootenhuis, P D J.; Hurley, D J.; Johnson, S C.; H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 Kadiyala, I N.; Keshavarz-Shokri, A.; Krawiec, M.; Lee, E C.; Luisi, B.; Medek, A.; Mufunuti, P.; Numa, M.; Sheth, U.; Silina, A.; Sullivan, M J.; Verwijs, M J.; Yang, X.; Young, C R.; Zaman, N T.; Zhang, B.; Zhang, Y.; Zlokarnik, G WO Patent 2011/133953 A1, 2011 Morgan, A J WO Patent 2012/158885 A1, 2012 Van Goor, F F WO Patent 2013/067410 A1, 2013 Xu, Y.; Wang, J.; He, G.; Lu, J CN Patent 103044263 A, 2013 Smith, B M.; Smith, J M.; Tsai, J H.; Schultz, J A.; Gilson, C A.; Estrada, S A.; Chen, R R.; Park, D M.; Prieto, E B.; Gallardo, C S.; Sengupta, D.; Dosa, P I.; Covel, J A.; Ren, A.; Webb, R R.; Beeley, N R A.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H R.; Bjenning, C.; Whelan, K T.; Grottick, A J.; Menzaghi, F.; Thomsen, W J J Med Chem 2008, 51, 305 Fitzgerald, L W.; Burn, T C.; Brown, B S.; Patterson, J P.; Corjay, M H.; Valentine, P A.; Sun, J H.; Link, J R.; Abbaszade, I.; Hollis, J M.; Largent, B L.; Hartig, P R.; Hollis, G F.; Meunier, P C.; Robichaud, A J.; Robertson, D W Mol Pharmacol 2000, 57, 75 Wang, Y.; Serradell, N.; Bolos, J Drugs Future 2007, 32, 766 Smith, B M.; Smith, J M.; Tsai, J H.; Schultz, J A.; Gilson, C A.; Estrada, S A.; Chen, R R.; Park, D M.; Prieto, E B.; Gallardo, C S.; Sengupta, D.; Thomsen, W J.; Saldana, H R.; Whelan, K T.; Menzaghi, F.; Webb, R R.; Beeley, N R A Bioorg Med Chem Lett 2005, 15, 1467 Weigl, U.; Porstmann, F.; Straessler, C.; Ulmer, L.; Koetz, U WO Patent 2007/ 120517 A2, 2007 Kuroda, J.; Kamitsuji, Y.; Kimura, S.; Ashihara, E.; Kawata, E.; Nakagawa, Y.; Takeuichi, M.; Murotani, Y.; Yokota, A.; Tanaka, R.; Andreeff, M.; Taniwaki, M.; Maekawa, T Int J Hematol 2008, 87, 507 Legros, L.; Hayette, S.; Nicolini, F E.; Raynaud, S.; Chabane, K.; Magaud, J P.; Cassuto, J P.; Michallet, M Leukemia 2007, 21, 2204 Chen, Y.; Hu, Y.; Michaels, S.; Segal, D.; Brown, D.; Li, S Leukemia 2009, 23, 1446 Wuilleme-Toumi, S.; Robillard, N.; Gomez, P.; Moreau, P.; Le Gouill, S.; AvetLoiseau, H.; Harousseau, J L.; Amiot, M.; Bataille, R Leukemia 2005, 19, 1248 Paudler, W W.; Kerley, G I.; McKay, J J Org Chem 1963, 28, 2194 Powell, R G.; Rogovin, S P.; Smith, C R., Jr Ind Eng Chem Prod Res Dev 1974, 13, 129 Powell, R G.; Weisleder, D.; Smith, C R., Jr J Pharm Sci 1972, 61, 1227 Powell, R G.; Weisleder, D.; Smith, C R., Jr.; Rohwedder, W K Tetrahedron Lett 1970, 815 Abdelkafi, H.; Nay, B Nat Prod Rep 2012, 29, 845 Li, G P.; Wu, X P CN Patent 1493572 A, 2004 Liu, Y US Patent 2010/0240887 A1, 2010 Robin, J.-P.; Robin, J.; Cavoleau, S.; Chauviat, L.; Charbonnel, S.; Dhal, R.; Dujardin, G.; Fournier, F.; Gilet, C.; Girodier, L.; Mevelec, L.; Poutot, S.; Rouaud, S WO Patent 99/48894 A1, 1999 Robin, J.-P.; Radosevic, N.; Blanchard, J WO Patent 2010/103405 A2, 2010 Robin, J.-P.; Blanchard, J.; Chauviat, L.; Dhal, R.; Marie, J.-P.; Radosevic, N US Patent 2005/0090484 A1, 2005 Kvols, L K.; Oberg, K E.; O’Dorisio, T M.; Mohideen, P.; de Herder, W W.; Arnold, R.; Hu, K.; Zhang, Y.; Hughes, G.; Anthony, L.; Wiedenmann, B Endocr Relat Cancer 2012, 19, 657 Petersenn, S.; Unger, N.; Hu, K.; Weisshaar, B.; Zhang, Y.; Bouillaud, E.; Resendiz, K H.; Wang, Y.; Mann, K J Clin Pharmacol 2012, 52, 1017 Lewis, I.; Bauer, W.; Albert, R.; Chandramouli, N.; Pless, J.; Weckbecker, G.; Bruns, C J Med Chem 2003, 46, 2334 Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P Tetrahedron Lett 1988, 29, 4005 Shvarts, V.; Chung, S Expert Rev Neurother 2013, 13, 131 Rektor, I Expert Opin Pharmacother 2013, 14, 225 McElhinny, C J., Jr.; Carroll, F I.; Lewin, A H Synthesis 2012, 44, 57 Koyakumaru, K.; Matsuo, Y.; Satake, Y WO Patent 2004/009553 A1, 2004 Arimoto, I.; Nagato, S.; Sugaya, Y.; Urawa, Y.; Ito, K.; Naka, H.; Omae, T.; Kayano, A.; Nishiura, K US Patent 2007/0142640 A1, 2007 Pixuvri, 2012, http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/ human/medicines/002055/human_med_001549.jsp&mid=WC0b01ac058001d124, [Access Date: 2012-May-31] Cavalletti, E.; Crippa, L.; Mainardi, P.; Oggioni, N.; Cavagnoli, R.; Bellini, O.; Sala, F Invest New Drugs 2007, 25, 187 Beaven, A W.; Rizzieri, D Clin Invest (London, U K.) 2012, 2, 49 Mukherji, D.; Pettengell, R Expert Opin Pharmacother 2010, 11, 1915 Evison, B J.; Mansour, O C.; Menta, E.; Phillips, D R.; Cutts, S M Nucleic Acids Res 2007, 35, 3581 de Isabella, P.; Palumbo, M.; Sissi, C.; Capranico, G.; Carenini, N.; Menta, E.; Oliva, A.; Spinelli, S.; Krapcho, A P.; Giuliani, F C.; Zunino, F Mol Pharmacol 1995, 48, 30 Krapcho, A P.; Petry, M E.; Getahun, Z.; Landi, J J., Jr.; Stallman, J.; Polsenberg, J F.; Gallagher, C E.; Maresch, M J.; Hacker, M P J Med Chem 1994, 37, 828 Krapcho, A P.; Hacker, M P.; Cavalletti, E.; Giuliani, F C US Patent 5587382 A, 1996 Spinelli, S.; Didomenico, R WO Patent 9526189 A1, 1995 Krapcho, P A EP Patent 503537 A1, 1992 Cortes, J E.; Kantarjian, H.; Shah, N P.; Bixby, D.; Mauro, M J.; Flinn, I.; O’Hare, T.; Hu, S.; Narasimhan, N I.; Rivera, V M.; Clackson, T.; Turner, C D.; Haluska, F G.; Druker, B J.; Deininger, M W N.; Talpaz, M N Eng J Med 2012, 367, 2075 O’Hare, T.; Shakespeare, W C.; Zhu, X.; Eide, C A.; Rivera, V M.; Wang, F.; Adrian, L T.; Zhou, T.; Huang, W.-S.; Xu, Q.; Metcalf, C A., III; Tyner, J W.; 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 2031 Loriaux, M M.; Corbin, A S.; Wardwell, S.; Ning, Y.; Keats, J A.; Wang, Y.; Sundaramoorthi, R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.; Sawyer, T K.; Dalgarno, D C.; Deininger, M W N.; Druker, B J.; Clackson, T Cancer Cell 2009, 16, 401 Zhou, T.; Commodore, L.; Huang, W.-S.; Wang, Y.; Thomas, M.; Keats, J.; Xu, Q.; Rivera, V M.; Shakespeare, W C.; Clackson, T.; Dalgarno, D C.; Zhu, X Chem Biol Drug Des 2010, 77, Gozgit, J M.; Wong, M J.; Wardwell, S.; Tyner, J W.; Loriaux, M M.; Mohemmad, Q K.; Narasimhan, N I.; Shakespeare, W C.; Wang, F.; Druker, B J.; Clackson, T.; Rivera, V M Mol Cancer Ther 2011, 10, 1028 Huang, W.-S.; Metcalf, C A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini, S P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J T.; Broudy, M I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N I.; Mohemmad, Q K.; Iuliucci, J.; Rivera, V M.; Dalgarno, D C.; Sawyer, T K.; Clackson, T.; Shakespeare, W C J Med Chem 2010, 53, 4701 Zou, D.; Huang, W.-S.; Thomas, R M.; Romero, J A C.; Qi, J.; Wang, Y.; Zhu, X.; Shakespeare, W C.; Sundaramoorthi, R.; Metcalf III, C A.; Dalgarno, D C.; Sawyer, T K WO Patent 2007/075869 A2, 2007 Huang, W.-S.; River, V M.; Clackson, T P.; Shakespeare, W C.; Squillace, R M.; Gozgit, J M WO Patent 2011/053938 A1, 2011 Shakespeare, W C.; Haluska, F G WO Patent 2012/139027 A1, 2012 Droppert, P In Biotech Strategy Blog: http://biotechstrategyblog.com/2012/01/ radotinib-approved-in-south-korea-for-cml.html/, 2012 Radotinib hydrochloride http://www.cancer.gov/drugdictionary?cdrid= 723999 Davies, S.; Bolos, J.; Serradell, N.; Bayes, M Drugs Future 2007, 32, 17 Kim, D.-Y.; Cho, D.-J.; Lee, G.-Y.; Kim, H.-Y.; Woo, S.-H.; Kim, Y.-S.; Lee, S.-A.; Han, B.-C WO Patent 2007/018325 A1, 2007 Kim, D Y.; Cho, D J.; Lee, G Y.; Kim, H Y.; Woo, S H WO Patent 2010/018895 A1, 2010 Delorme, D.; Vaisburg, A.; Moradei, O.; Leit, S.; Raeppel, S.; Frechette, S.; Bouchain, G.; Zhou, Z.; Paquin, I.; Gaudette, F.; Isakovic, L WO Patent 2005/ 092899 A1, 2005 Breitenstein, W.; Furet, P.; Jacob, S.; Manley, P W WO Patent 2004/005281 A1, 2004 Mullard, A Nat Rev Drug Disc 2013, 12, 87 Bayer’s StivargaÒ (regorafenib) Tablets Approved by U.S FDA for Treatment of Patients with Locally Advanced, Unresectable or Metastatic GIST, http:// www.onyx.com/view.cfm/662/bayers-stivarga-regorafenib-tablets-approvedby-us-fda-for-treatment-of-patients-with-locally-advanced-unresectable-ormetastatic-gist, [Access Date: 2013-Feb-25] Marrari, A.; George, S Drugs Future 2011, 36, 17 Strumberg, D.; Schultheis, B Expert Opin Invest Drugs 2012, 21, 879 Wilhelm, S.; Dumas, J.; Ladouceur, G.; Lynch, M.; Scott, W J WO Patent 2004/ 113274 A2, 2004 Dumas, J.; Boyer, S.; Riedl, B.; Wilhelm, S WO Patent 2005/009961 A2, 2005 Stiehl, J.; Heilmann, W.; Logers, M.; Rehse, J.; Gottfried, M.; Wichmann, S WO Patent 2011/128261 A1, 2011 Said, G.; Grippon, S.; Kirkpatrick, P Nat Rev Drug Disc 2012, 11, 185 de Lartigue, J Drugs Today (Barc) 2012, 48, 331 Razavi, H.; Palaninathan, S K.; Powers, E T.; Wiseman, R L.; Purkey, H E.; Mohamedmohaideen, N N.; Deechongkit, S.; Chiang, K P.; Dendle, M T A.; Sacchettini, J C.; Kelly, J W Angew Chem., Int Ed 2003, 42, 2758 Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K Chem Eur J 2011, 17, 10113 Wu, G.; Zhou, J.; Zhang, M.; Hu, P.; Su, W Chem Commun 2012, 8964 Labaudiniere, R F.; O’Neill, M H WO Patent 2013/038351 A1, 2013 Kelly, J W.; Sekijima, Y WO Patent 2004/056315 A2, 2004 Bulawa, C E.; Connelly, S.; DeVit, M.; Wang, L.; Weigel, C.; Fleming, J A.; Packman, J.; Powers, E T.; Wiseman, R L.; Foss, T R.; Wilson, I A.; Kelly, J W.; Labaudiniere, R Proc Natl Acad Sci U.S.A 2012, 109, 9629 Yoshida, T.; Akahoshi, F.; Sakashita, H.; Kitajima, H.; Nakamura, M.; Sonda, S.; Takeuchi, M.; Tanaka, Y.; Ueda, N.; Sekiguchi, S.; Ishige, T.; Shima, K.; Nabeno, M.; Abe, Y.; Anabuki, J.; Soejima, A.; Yoshida, C.; Takashina, Y.; Ishii, S.; Kiuchi, S.; Fukudaa, S.; Tsutsumiuchi, R.; Kosaka, K.; Murozono, T.; Nakamaru, Y.; Utsumi, H.; Masutomi, N.; Kishida, H.; Miyaguchi, I.; Hayashi, Y Biorg Med Chem 2012, 5, 69 Abe, Y.; Anabuki, J.; Soejima, A.; Shimamura, K.; Hayashi, Y.; Sakai, K Diabetes, 65th Scientific Sessions (2005), 2005; San Diego, California, Abstract 1493 Sakashit, H.; Akahoshi, F.; Kitajima, H.; Tsutsumiuchi, R.; Hayashi, Y Biorg Med Chem 2006, 14, 3662 Rocklin, R WO Patent 2012018704 A1, 2012 Fox, R I J Rheumatol Suppl 1998, 53, 20 Baumann, P.; Mandl-Weber, S.; Voelkl, A.; Adam, C.; Bumeder, I.; Oduncu, F.; Schmidmaier, R Mol Cancer Ther 2009, 8, 366 Lolli, M L.; Giorgis, M.; Tosco, P.; Foti, A.; Fruttero, R.; Gasco, A Eur J Med Chem 2012, 49, 102 Palmer, A M Curr Opin Invest Drugs 2010, 11, 1313 Williamson, R A.; Yea, C M.; Robson, P A.; Curnock, A P.; Gadher, S.; Hambleton, A B.; Woodward, K.; Bruneau, J.-M.; Hambleton, P.; Moss, D.; Thomson, A.; Spinella-Jaegle, S.; Morand, P.; Courtin, O.; Saute, C.; Westwood, R.; Hercend, T.; Kuo, E A.; Ruuth, E J Biol Chem 1995, 270, 22467 Mulakayala, N.; Rao, P.; Iqbal, J.; Bandichhor, R.; Oruganti, S Eur J Med Chem 2013, 60, 170 2032 H X Ding et al / Bioorg Med Chem 22 (2014) 2005–2032 213 Chen, G.; Sun, L CN Patent 102786437 A, 2012 214 Deo, K.; Patel, S.; Dhol, S.; Sanghani, S.; Ray, V WO Patent 2009/147624 A2, 2009 215 Deo, K.; Patel, S.; Dhol, S.; Sanghani, S.; Ray, V WO Patent 2010/013159 A1, 2010 216 Metro, T.-X.; Bonnamour, J.; Reidon, T.; Sarpoulet, J.; Martinez, J.; Lamaty, F Chem Commun 2012, 11781 217 Shi, J.; Zhang, Q.; Jin, Y.; Li, J Chin Pharm J 2008, 43, 1353 218 Flanagan, M E.; Blumenkopf, T A.; Brissette, W H.; Brown, M F.; Casavant, J M.; Shang-Poa, C.; Doty, J L.; Elliott, E A.; Fisher, M B.; Hines, M.; Kent, C.; Kudlacz, E M.; Lillie, B M.; Magnuson, K S.; McBride, C E.; McCurdy, S P.; Munchhof, M J.; Perry, B D.; Sawyer, P S.; Strelevitz, T J.; Subramanyam, C.; Sun, J.; Whipple, D A.; Changelian, P S J Med Chem 2010, 53, 8468 219 Changelian, P S.; Flanagan, M E.; Ball, D J.; Kent, C R.; Magnuson, K S.; Martin, W H.; Rizzuti, B J.; Sawyer, P S.; Perry, B D.; Brissette, W H.; McCurdy, S P.; Kudlacz, E M.; Conklyn, M J.; Elliott, E A.; Koslov, E R.; Fisher, M B.; Strelevitz, T J.; Yoon, K.; Whipple, D A.; Sun, J.; Munchhof, M J.; Doty, J L.; Casavant, J M.; Blumenkopf, T A.; Hines, M.; Brown, M F.; Lillie, B M.; Subramanyam, C.; Shang-Poa, C.; Milici, A J.; Beckius, G E.; Moyer, J D.; Su, C.; Woodworth, T G.; Gaweco, A S.; Beals, C R.; Littman, B H.; Fisher, D A.; Smith, J F.; Zagouras, P.; Magna, H A.; Saltarelli, M J.; Johnson, K S.; Nelms, L F.; Des Etages, S G.; Hayes, L S.; Kawabata, T T.; Finco-Kent, D.; Baker, D L.; Larson, M.; Si, M.-S.; Paniagua, R.; Higgins, J.; Holm, B.; Reitz, B.; Zhou, Y.-J.; Morris, R E.; O’Shea, J J.; Borie, D C Science (New York, N.Y.) 2003, 302, 875 220 Blumenkopf, T A.; Flanagan, M E.; Munchhof, M J EP Patent 1235830 B1, 2004 221 Flanagan, M E.; Li, Z J WO Patent 2003/048162 A1, 2003 222 Ruggeri, S G.; Hawkins, J M.; Makowski, T M.; Rutherford, J L.; Urban, F J WO Patent 2007/012953 A2, 2007 223 Cai, W.; Colony, J L.; Frost, H.; Hudspeth, J P.; Kendall, P M.; Krishnan, A M.; Makowski, T.; Mazur, D J.; Phillips, J.; Ripin, D H B.; Ruggeri, S G.; Stearns, J F.; White, T D Org Process Res Dev 2005, 9, 51 224 Price, K E.; Larrivee-Aboussafy, C.; Lillie, B M.; McLaughlin, R W.; Mustakis, J.; Hettenbach, K W.; Hawkins, J M.; Vaidyanathan, R Org Lett 2009, 11, 2003 225 FDA approves new treatment for most common type of skin cancer, http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289545.htm, [Access Date: 2012-Jan-30] 226 Sekulic, A.; Migden, M R.; Oro, A E.; Dirix, L.; Lewis, K D.; Hainsworth, J D.; Solomon, J A.; Yoo, S.; Arron, S T.; Friedlander, P A.; Marmur, E.; Rudin, C M.; Chang, A L S.; Low, J A.; Mackey, H M.; Yauch, R L.; Graham, R A.; Reddy, J C.; Hauschild, A N Eng J Med 2012, 366, 2171 227 Gunzner, J L.; Sutherlin, D.; Stanley, M S.; Bao, L.; Castanedo, G M.; Lalonde, R L.; Wang, S.; Reynolds, M E.; Savage, S J.; Malesky, K.; Dina, M S US Patent 2006/0063779 A1, 2006 228 Gunzner, J L.; Sutherlin, D.; Stanley, M S.; Bao, L.; Castanedo, G M.; Lalonde, R L.; Wang, S.; Reynolds, M E.; Savage, S J.; Malesky, K.; Dina, M S WO Patent 2009/126863 A2, 2009 229 Cheng, D.; Han, D.; Zhang, G.; Wan, Y.; Xie, Y F.; Jiang, J.; Gao, W.; Pan, S WO Patent 2010/027746 A2, 2010 230 Zhu, J.; Mao, J.; Yang, M.; Wu, X CN Patent 102731373 A, 2012 231 Neves, J.; Teixeira, L.; Bhatia, S.; Ermrich, M WO Patent 2011/005127 A1, 2011 ... it is widely believed that the knowledge of new chemical entities and their syntheses will greatly enhance the ability to design new drugs in shorter periods of time The pharmaceutical industry... of the amino acids of this pentapeptide were modified to improve the potency of the molecule.70 After licensing the molecule to Proteolix, the introduction of the morpholino group was found to. .. methods.148,152 The most likely process-scale synthetic route features the coupling of the homoharringtonine side chain with the cephalotaxine core, and a subsequent conversion of the a-hydroxy moiety to