Synthetic approaches to the 2012 new drugs

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 1. 2. 3. 4. 5. 6. 7.

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: [email protected] (H.X. Ding), carolyn.a.leverett@pfizer.com (C.A. Leverett), robert.kynejr@pfizer.com (R.E. Kyne), [email protected] (K.K.-C. Liu), [email protected] (S.M. Sakya), andrew.flick@pfizer.com (A.C. Flick), christopher.j.odonnell@pfizer.com (C.J. O’Donnell).   Tel.: +86 10 8484 8357. à 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

8. Bosutinib hydrate (BosulifÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. 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. 2. 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 2 to give bis-thiophenoate 3 in 36% yield. Subsequent transesterification with (R)-quinuclidinol (4) gave rise to the quinuclidine-containing ester 5 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. 3. 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 2. 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 9 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 4. 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 1. 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

2

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

2 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. 1 (continued)

H N

2009

H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

S MeO

OH

MgBr 2

O OMe

S

Et2 O, −30 °C 36%

O

OH S

MeO

3

S

S

OPh 6

Br

OH S

O N

NaH, toluene, ↑↓ 50%

O

1

4

N

O

OH

O

CH3 CN : CHCl3 (2:3), RT 89%

N+ O

5

O Br

S

-

I Aclidinium bromide

OPh , Acetophenone, ↑↓

Br

99% Scheme 1. Synthesis of aclidinium bromide (I).

Cl Br

N

Cl OH

N

OH

N K2 CO3 , DMF, 90 °C

+ N N N N

N H

7

90% N CPh3

N

8

9

N

N

CPh3

Cl

O Cl

OH

N

O

N N

1. K2 CO 3, DME, RT 2. 11, 50 °C

O

1% KMnO 4

O

N

O

O

3. 4 N HCl, dioxane, RT 69%

0 °C to 50 °C, 88% N N N

N

N CPh3

Cl

O

O O

10

11

N N

NH

II Allisartan isoproxil

Scheme 2. 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.

5. 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

0 °C to RT, 91%

12

O

H N

CN

4 N HCl/Dioxane

N

0 °C to RT, 96%

14

O O

H N

H 2N

CN

N

1. 16, CDI, THF

N

2. Et 3N, THF, 0 °C to RT 90%

O

H N

N H

CN N

N N III Anagliptin

15

O O O

OH

N NH 2

N H

N N

13

16

Scheme 3. 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

1. Ac 2O, DIPEA, NMP, 60 °C 2. Pd(OAc)2 , 2-vinylpyridine XantPhos, 90 °C

NH H N

S

85-90% f or 2 steps

N

NH S

H N N

3. 1,2-DAP, THF, polishing filter 4. NMP, THF, 62% for 4 steps

I

N

20

IV Axitinib Scheme 4. 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 4 steps. 6. 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 1 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 2

NO2 1. SOCl2, DMF, toluene, ↑↓

CO 2H O

NHBoc

2. NaN 3, H2 O, 0 °C 3. t-BuOH, ↑↓, 57% for 3 steps

O

O

O 22

21 Br

CN

NO2 Boc

N

23 O

K2 CO3, CH 3 CN, ↑↓, 85%

NH2 1. 1 N HCl EtOAc, RT, 77%

O

CN

NH O

2. FeCl3•6 H2 O 0 °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 2 steps

O

O O N

NH

N

2 N LiOH, MeOH, ↑↓

HO

O

O

84%

29

V Azilsartan

Scheme 5. 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 6. 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 2 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. 7. 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

1. LDA, THF, -70 °C 2. 32, THF, -70 °C 3. AcOH, THF, -10 °C

CH3

H3 C

O

4. 34, DMSO, ↑↓ 5. 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 7. Synthesis of bedaquiline fumarate (VI).

H3 CO

Cl Br 37 i-PrOH, 1 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 2 steps O

NO2

40 Cl

Cl

NH

O

NC

O

N H

N

NH 2

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 8. 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 8. 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 2 OH

Cl POCl3 , CH 3 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 2.

49

O

1. SOCl2, Et 3 N, THF, 5 °C

H 2N

, THF, 10 °C

HO

F

O

O

oxalyl chloride N H

DMF, THF, RT

50

70% for two steps Scheme 9. 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 2 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, 0 °C, 93% H2 N

BocHN

CO2 Me 53

CO2 Me

O

CO2H 54

55

O BocHN

1. TFA, DCM, 0 °C

H N

N H

CO2 Me

O

2. Boc-Homophe-OH, BOP HOBT, DMF, DIPEA, 0 °C 85% for 2 steps

56

Cl

H N

O N H

1. TFA, DCM 2. ClCH2C(O)Cl DMF, DIPEA, 0 °C 67% for 2 steps

H N

O

CO2 Me

O

1. KI, THF morpholine

N

2. LiOH, MeOH 0 °C to 5 °C 87% for 2 steps

O

H N

O

H N

N H

O

57

O

58

1. 59, HBTU, HOBT, DMF, DIPEA, 0 °C

N O

2. Recrystallization from MeOH/H 2 O 75% for 2 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, 5 °C, 81%

BocHN

O

O

60

62

1. Ca(OCl)2 , NMP, H2 O −10 °C to −5 °C, 41% 2. TFA, CH 2 Cl2 , 0 °C, 92%

61

O TFA H 2 N O 59

Scheme 11. Synthesis of fragment 59 of carfilzomib (IX).

CO2 H

2015

H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

9. Cabozantinib (S)-malate (CometriqÒ)

10. Carfilzomib (KyprolisÒ)

Cabozantinib (S)-malate (CometriqÒ), which was discovered and developed by Exelixis, gained approval by the U.S. FDA in November 2012. The drug’s indication is for the treatment of medullary thyroid cancer (MTC), and is the second drug for this disease after AstraZeneca’s vandetanib (CaprelsaÒ). The drug was successfully launched on January 24, 2013.60,61 Cabozantinib inhibits multiple receptor tyrosine kinases including RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2.62 It is currently also undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers. Of the three syntheses of cabozantinib reported,63–66 the kilo-gram scale process route65,66 is described in Scheme 9. The preparation began with 6,7-dimethoxy-quinoline-4-ol (46) which upon treatment with POCl3 provided chloride 47 in 70% yield. Exposure of 47 to 4-aminophenol under basic conditions using t-BuONa furnished diaryl ether 48 in 72% yield. This aniline was then coupled with amidoacid chloride 51 (which arose from the activation of commercial diacid 49 to the corresponding monochloride, coupling with p-fluoroaniline, and subsequent exposure to oxalyl chloride to furnish the transient acid chloride) to construct cabozantinib as the free base 52 in 95% yield. Salt formation of cabozantinib 52 was carried out with (S)-malic acid, which ultimately delivered the final product of cabozantinib (S)-malate (VIII) in 75% yield.65,66

Carfilzomib is an irreversible inhibitor of the chymotrypsin-like protease in the proteasome and was approved in the U.S. for the treatment of multiple myeloma.67,68 Carfilzomib was discovered by Proteolix, which was later acquired by Onyx Therapeutics, who completed the development of this drug. Carfilzomib is also undergoing clinical evaluation for additional oncology indications such as relapsed solid tumors, lymphoma, prolymphocytic leukemia, acute myeloid leukemia and acute lymphocytic leukemia. Carfilzomib is an analog of the natural product epoxomicin which was first synthesized in the laboratories of Professor Crews at Yale University.69 Subsequent development of the SAR led to the discovery of YU-101 in which 3 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 improve the solubility of the drug while maintaining efficient interaction with the target. The most scalable route to carfilzomib closely resembles the original route developed toward epoximicin and is described herein.71,72 The synthesis was initiated with the amide coupling of phenyl alanine methyl ester (53) and N-Boc leucine (54) using standard coupling reagents to afford dipeptide 55 in high yield (Scheme 10). Acidic removal of the amine protecting group, followed by a second amide coupling reaction with N-Boc homophenyl alanine, provided tripeptide 56 in 85% yield for the two steps. Acidic removal of the amine protecting group and subsequent acylation with chloroace-

O

HO

O

HO

OH

O

TMSO

TMSCl, NMM, THF

TMSO

0 °C to 35 °C, then -20 °C, 99%

OTMS OTMS

OH 63

O

64 Cl

1. (COCl) 2, DCM, DMF 20 °C, 100%

Cl

Cl O

Br

Et3 SiH, BF3 •OEt2

O

Br

OH

2. phenetole, AlCl3 , DCM 0 °C to 5 °C, 91%

Br

CH 3CN, 10 °C, 75% O

65

O

66

67 Cl

1. n-BuLi, 64, THF, toluene, -78 °C 2. MeOH, CH3 SO3 H, 85%

HO

O OMe OH

HO OH

O 68

1. Et3 SiH, BF3 •OEt2 DCM, CH3 CN -10 °C 2. Ac 2O, pyridine DMAP, DCM 55% f or 2 steps

Cl O

AcO AcO

OAc

2. propanediol H 2O

OAc 69

1. aq. LiOH THF, H2 O MeOH RT, 100%

Cl HO

O

OH OH

HO

OH

H 2O

OH

O

O X Dapagliflozin propanediol hydrate

Scheme 12. Synthesis of dapagliflozin propanediol hydrate (X).

2016

H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

tyl chloride yielded b-chloro amide 57 in 67% yield. Reaction of 57 with morpholine in the presence of catalytic amounts of potassium iodide followed by saponification of the methyl ester with lithium hydroxide led to acid 58 in 87% yield for the two steps. Finally, amide coupling between acid 58 and keto-epoxyamine 59 (whose preparation is described in Scheme 11) using HOBT as the coupling reagent and recrystallization of the resulting product ultimately gave carfilzomib (IX) in 75% yield. Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as described in Scheme 11. Reaction of 54 with isobutyl chloroformate followed by N,O-dimethylhydroxylamine provided Weinreb amide 60 in 94% yield. Grignard addition of isopropenylmagnesium bromide (60) provided enone 62 in 81% yield. Epoxidation of 62 with calcium hypochlorite provided a mixture of epoxides giving 41% yield of the desired isomer (presumably isolated by chromatography), and subsequent treatment with TFA liberated the amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield.

5-bromo-2-chlorobenzoyl acid (65) was converted to the corresponding acid chloride with oxalyl chloride. Subsequently, this acid chloride was subjected to Friedel–Crafts acylation with ethyl phenyl ether (‘phenetole’) in the presence of aluminum trichloride at low temperature to give benzophenone 66 in 91% yield. Next, the carbonyl functionality within 66 was removed upon treatment with triethylsilane and boron trifluoride-etherate, producing 5-bromo-2-chloro-40 -ethoxydiphenylmethane (67) in 75% yield as the aglycon partner. Aryl bromide 67 was subjected to lithium halogen exchange conditions and subsequent exposure to lactone 64, provided a mixture of lactols which were then immediately subjected to methanesulfonic acid, leading to glucol 68 in 85% yield. The anomeric methoxy group of 68 was reduced with triethylsilane and boron trifluoride-etherate followed by peracetylation to deliver a-C-glycoside tetraacetate 69 in 55% (two steps) after recrystalliaztion in ethanol. Hydrolysis of polyacetate 69 with lithium hydroxide gave dapagliflozin in quantitative yield, and upon treatment with propanediol in water, dapagliflozin propanediol hydrate (X) was produced.

11. Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ, EdistrideÒ, AppebbÒ)

12. Enzalutamide (XtandiÒ) Dapagliflozin propanediol hydrate, an orally active sodium glucose cotransporter type 2 (SGLT-2) inhibitor, was developed by Bristol–Myers Squibb (BMS) and AstraZeneca for the once-daily treatment of type 2 diabetes. As opposed to competitor SGLT-2 inhibitors, dapagliflozin was not associated with renal toxicity or long-term deterioration of renal function in phase III clinical trials.73 The drug exhibits excellent SGLT-2 potency with more than 1200-fold selectivity over the SGLT-1 enzyme.74 The most likely process-scale synthesis has been described in a literature publication and patent, and this is summarized in Scheme 12 below.74,75 The synthesis began with global silylation glucolactone 63 to form tetrasiloxide 64. In parallel, commercial

In August 2012, the FDA approved enzalutamide, marketed by Medivation and Astellas Pharma U.S. for the treatment of metastatic castration-resistant prostate cancer (CRPC), specifically for those patients who had previously received docetaxel.76 Enzalutamide is an inhibitor of androgen receptors (AR)—whose increased expression has been closely linked with castration-resistant prostate cancer (CRPC), thus, AR inhibitors have seen increased recent attention from the medicinal chemistry community. Phase I/II trials were particularly promising for enzalutamide, as 43% of patients showed >50% sustained suppression of a key serum biomarker.77 Of the several patents and papers describing

O CO 2H Br

SOCl2, IPAc

Cl

DMF, 60 °C to 72 °C

F

O

Br

CH3 NH2 , IPAc, 2 °C to 35 °C 90% for 2 steps

F

70

NHMe Br

71

72 O

H2 N

CO2 H 73

NHMe

CuCl, K2 CO3, DMF, H 2O, 30 °C then 2-acetylcyclohexanone, 105 °C 76%

HO

N H

F

CF3 NC NHMe

O

K2 CO3 , DMF, H 2 O MeI, 30 °C to 40 °C 95%

74

O

MeO

N H

O

S

76, DMSO N

IPAc, 84 °C 78%

F

O

N

NHMe

O 75

F

XI Enzalutamide

S

CF3

CF3 Cl

Cl

NC NH2 77

F

NC

Heptane, H 2O, 5 °C to 40 °C 84%

Scheme 13. Synthesis of enzalutamide (XI).

NCS 76

2017

H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

synthetic approaches,78–81 a 2011 patent represents the most likely scale production route to enzalutamide, and this is described in Scheme 13.82 Commercially available carboxylic acid 70 was first converted to the corresponding acid chloride 71, followed by amide formation with methylamine to furnish benzamide 72 in 90% yield over two steps. Bromide 72 was then coupled with amine 73 using copper(I) catalysis to afford trisubstituted benzene 74 in 76% isolated yield. Esterification of 74 to 75 with iodomethane furnished one fragment for the key ring-forming event. Isothiocyanate 76, available in one step from the corresponding aniline 77, was then exposed to aminoester 75 in the presence of warm isopropyl acetate, resulting in construction of the lynchpin thiohydantoin and delivering enzalutamide (XI) in an impressive 78% yield. This 5-step process has successfully generated multi-gram quantities of the drug in 50.7% overall yield.

was also independently developed by Simcere Pharmaceutical Group and is marketed as IremodÒ in China. The drug exhibited inhibitory effects on granuloma inflammation, and was shown to be efficacious for the prevention of joint destruction in adjuvant arthritis.84,85 While several synthesis of iguratimod have been published,86 the most likely scale synthesis, which does not require chromatographic purification, is described in Scheme 14.87 The synthesis began with commercially available 3-nitro-4chloro anisole (78) which was reacted with potassium phenoxide (generated from phenol and potassium t-butoxide at 110 °C) to provide the corresponding nitrophenyl ether which was subsequently reduced and sulfonylated to furnish sulfonamide 79. Next, this diphenyl ether was submitted to a Friedel–Crafts reaction with aminoacetonitrile hydrochloride which gave rise to aminomethylacetophenone 80 in 90% yield. This aminoketone was then formylated with formic trimethylacetic anhydride 81 at room temperature to afford formamide 82 in 91% yield, and this material was immediately subjected to O-demethylation conditions with aluminum trichloride and sodium iodide in acetonitrile to give the phenol 83 in 95% yield. Finally, treatment of the aminomethyl acetophenone phenol 83 with N,N-dimethylformamide dimethylacetal in DMF at low temperatures furnished iguratimod (XII) in 87% yield.

13. Iguratimod (CareramÒ, IremodÒ) Iguratimod, which was discovered by Toyama Pharmaceuticals and jointly co-developed with Eisai in Japan, was approved by the PMDA (Pharmaceuticals and Medical Devices Agency) of Japan on June 29, 2012 for the treatment of rheumatoid arthritis.83 This drug

O 2N

O

H N

S

1. PhOH, t-BuOK, DMF, 110 °C, 84% 2. Fe/4 N HCl, EtOH, 65 °C to 70 °C, 72%

O

O

O O

3. MeSO 2Cl•Py, 0 °C to RT, 82%

Cl

78

79

S

1. NCCH2 NH2 •HCl, AlCl3 , 40 °C 2. dry HCl, 25-30 °C, PhNO2

O

H N

O

O

O O

O O

90% for 2 steps

NH 2 HCl

O

S

H

O

81

H N

O

O O

acetone, RT, 91%

O

80

H N

S AlCl3 , NaI

O

O O

S

N O

O

CH3 CN, RT, 95%

O

N H

H

82

OH

O O

O

N H

H

H N

O

O O

DMF, 15 °C, 87%

O

O N H

H

XII Iguratimod

83 Scheme 14. Synthesis of iguratimod (XII).

COOH 85 O

O S

1. 85, Et 3N, CH 3CN, RT

O

84

O S O O

Br 2. Et 3N, CH3 CN, 75 °C 72% for two steps

O

NH 2 , HOAc 50 °C to 120 °C, 85%

86 Scheme 15. Synthesis of imrecoxib (XIII).

O S O N O

XIII Imrecoxib

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 3 DCM, 0 °C to RT

Cl

EtO

O

O

Cl

57%

Et3N, EtOAc 0 °C to RT, 99%

N H 94

O2 N

91

O

92

93 O OH

EtO 1. Pd/C, H 2, MeOH

O

O KOH, MeOH

O

2. 94, Et3N, DCM, RT 53% f or 2 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. 1-amino-2-propanol, 85 °C to 100 °C 2. SOCl2 , DMA, PhCH3 , 65 °C 71% for 2 steps

Cl

96

97

1. AlCl3, 1,2-dichlorobenzene, 128 °C 2. aq. NaOH, cyclohexane

NH • HCl

Cl

Br

PBr 3, 0 °C to 85 °C

3. L-(+)-tartaric acid, acetone /H2 O 4. Recrystallization from acetone/H 2O 27% for 4 steps

Cl

O

OH 2 99

NH • HCl

3. HCl (gas), 0 °C to 5 °C 90% for 3 steps

Cl

• 1/2 H 2O

XVI Lorcaserin hydrochloride hydrate Scheme 18. Synthesis of lorcaserin hydrochloride hydrate (XVI).

OH

HO

Cl

98

1. K2 CO3, H2O, RT 2. EtOAc

OH

NH • O

2019

H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

Br 1. i. Mg, THF ii. diethyl oxalate, ↑↓, 70%

HO

CH 2CO2 Me

2. 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*

+

2. 105 , RT, 84% (2 diastereomers, 1:1)

MeO2 C

3. BF3, MeOH, RT, 69%

102

1. 104 , Et3N, DMAP, toluene, RT

CO2 H

1. p-TsOH, toluene, 65 °C, 69% 2. 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 1. 104 , Et N, toluene , 30 °C 3

O

2. 108 , RT, 43%

O

OMe

O O

MeO2C

CO2Me 107

109 O N O H

O

N

O

1. HBr/HOAc, DCM, -10 °C, 87%

OMe

O

2. 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

1. Fmoc-OSu, aq. Na2CO3 , THF, RT 2. triphosgene, N-Boc-diaminoethane THF, RT 3. 0.1 N HCl in THF 49% f or 3 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 ± 4 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

1. 20% piperidine in DMF, 0 ºC to RT, 0.25 h

O

2. Fmoc-DTrp(Boc)-OH DIC/HOBt, DMF, RT, 16 h

O O

O O

O HN

R

20% piperidine, DMF, 0 ºC to rt, 0.25 h

( )4 BocHN

NH NH Fmoc

112; R = Fmoc 113; R = H

OBn

114

O O O

OBn

1. 20% piperidine in DMF, 0 ºC to RT, 0.25 h

O O

2. 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 7 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

1. 20% piperidine in DMF, 0 ºC to RT, 0.25 h

O

2. Fmoc-Phe-OH, DIC/HOBt, DMF, RT, 16 h

O 1. 20% piperidine in DMF, 0 ºC to RT, 0.25 h

3. 20% piperidine in DMF, 0 ºC to RT, 0.25 h

O O

2. 111, DIC/HOBt DMF, RT, 16 h 116

NH

( )4 N H BocHN Boc N

O

Ph

H N O

N H

O

4. 2% TFA in CH2 Cl2 RT, 1 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 2

O

Ph N

N H

1. DPPA, DIEA, DMF, 0 ºC, 16 h 2. aq. TFA, RT, 40 mins

H2 N

( ) 3 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

1. 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

1. 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

2. Recrystallization from acetone /H2 O 86% for 3 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

2. 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 5 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

1.

CO2 H

20% H 2SO4 N

140 °C, 81%

O

O

NH2 134

HN

133b

NH2

O OH OH

•2

N

2. AcOH, H 2O 3. 3 M aq. maleic acid 40 °C to 50 °C 92% for 3 steps

F

CO2 H

F

132a

H2N THF, 55 °C

HN

O

133

O

NH 2

XX Pixantrone dimaleate Scheme 25. Synthesis of pixantrone dimaleate (XX).

N Si(CH 3) 3 136

N N

N

N

N

TBAF, THF

N

RT, 94%

Pd(PPh3) 4, CuI, DIPEA CH 3 CN RT, 71%

Br

N

N

Si(CH 3) 3 135

137

138

N N

N HCl

1. 139, Pd(PPh3 )4 , CuI EtOAc, Et3 N, RT

N H N

2. EtOH, HCl, RT 53% for 2 steps

N

O CF3 XXI Ponatinib hydrochloride

I

I 1. SOCl2, DCM, RT OH

2. H 2N

O 140

O CF 3 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 0 °C in aqueous TFA, and the mixture was stirred at this temperature for 30 min. 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 3 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 2 HCl

CF3

XXII Radotinib dihydrochloride

N NH H 2N

H2N

N

O

N H HNO 3 144

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

2. methylamine toluene, H 2O, 20 °C 3. acetyl chloride EtOH, toluene, RT, quant.

N

22. Ponatinib hydrochloride (IclusigÒ)

O

1. 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 3 steps.171

N

1. toluene, NaOH

N H HCl

2. 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

1. LiOH, THF, H2 O, 40 °C 2. 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 2

1.

O

MsOH, RT

2. 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 1. HOBt, EDC, DMF, RT, 62%

HN +

S

1,2-DCE, RT, 50% O N

N

S

2. DMSO, SO3 Py, RT, 55%

HO

O 165

164

163

Boc N O N

NH N

N

N

O N

N S

N N

1. TFA, DCM, RT, 93% 2. 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

1. 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

2. PhCHO, NaHB(OAc) 3 toluene, 73%

NBn

N H

O

172

173

O 1. 2 N NaOH, i-PrOH, MeOH

1. LAH, THF, RT 2. HCl, i-PrOH, 87%

NBn

N H

2. di-p-toluoyl-L-tartaric acid 42% for 2 steps

2HCl

HO2 C

O

HO2 C

O

NBn

N H

2

O

175 98.6% ee

174

Cl N Cl

176 N

N H

NBn

N N

K2 CO 3, H 2 O, 95 °C to 105 °C quant. Cl

N H

N

1. H2 , Pd(OH)2 /C H 2 O, 70 °C to 75 °C N

2. DBU, MeOCCH 2CN 1-butanol, 40 °C 3. 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) 2 , Pd(dppf)Cl 2

B

N 2-bromopyridine, Pd(PPh 3 )4

N H 182

Cl

NaHCO3 , H 2O, DME ↑↓, quant.

O

185 , Et 3N, DCM

Cl

183

Cl

O

0°C to 5 °C, 99%

Cl

N H

NH2

SO 2Me 184

XXVIII Vismodegib

O

Cl HO 2C

O N H

Ot-Bu

N N TFA, DCM, 0 °C

Ot-Bu

181

O

Cl

KOAc, DMSO, 110 °C, 91%

98%

O

Et 3 N, ↓↑, 84%

73%

CO2 H

Cl

10% NaOH, toluene, Et3 N

Cl

Cl

DMF, SOCl2 , 0 °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 1. 2. 3. 4. 5. 6. 7. 8. 9. 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, 7. 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, 1. 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, 1. 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.