Synthetic Entries to and Biological Activity of Pyrrolopyrimidines

Dec 23, 2015 - sympathetic nervous system, which is responsible for the fight-or-flight response. Antagonists of adrenergic receptors are typically us...
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Synthetic Entries to and Biological Activity of Pyrrolopyrimidines Laurens M. De Coen, Thomas S. A. Heugebaert, Daniel García, and Christian V. Stevens* Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure links 653, B-9000 Ghent, Belgium ABSTRACT: This review summarizes recent literature (2000−2015) on the synthesis and pharmaceutical properties of pyrrolopyrimidines. These modified pyrimidine bases, fused to a pyrrole ring, and their corresponding nucleosides display a broad applicability in medicinal chemistry. This overview is divided into three main sections, according to the respective isomers: pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, and pyrrolo[3,4-d]pyrimidines. Each section contains a description of common retrosynthetic strategies, with particular attention for newly reported synthetic entries to the scaffold. Next, the synthetic strategies and the ways in which the scaffolds can be further modified are exemplified according to the biological properties of the obtained products.

CONTENTS 1. Introduction 2. Pyrrolo[2,3-d]pyrimidine 2.1. Methodology for the Synthesis of the Scaffold 2.2. Methodology for Functionalization of the Scaffold 2.3. Biocides 2.3.1. Bactericides 2.3.2. Protozoicides 2.4. Receptor Antagonists 2.4.1. CRF Receptor 2.4.2. Adrenergic Receptor 2.4.3. Adenosine Receptor 2.4.4. Histamine H4 Receptor 2.5. Enzyme Inhibitors 2.5.1. Cholinesterase 2.5.2. Tubulin 2.5.3. Nav1.7 2.5.4. HSP90 2.5.5. NAE 2.5.6. Antifolates 2.5.7. Anticancer Compounds with Unidentified Target 2.5.8. Kinase Inhibitors 2.6. Nucleosides 2.7. Natural Products and Derivatives 2.8. Others 3. Pyrrolo[3,2-d]pyrimidine 3.1. Synthetic Entries to the Scaffold 3.1.1. Pyrimidine Condensation 3.1.2. Alkyne Hydroamination 3.1.3. Alkyne Cycloisomerization 3.1.4. Reductive Alkene Hydroamination 3.1.5. Reductive Pyrrole Condensation 3.1.6. Radical Cyclization 3.1.7. Madelung Cyclization 3.2. Methods for Derivatization of the Scaffold 3.2.1. VEGRF2 Kinase Inhibitors © 2015 American Chemical Society

3.2.2. Immucillins 4. Pyrrolo[3,4-d]pyrimidine 4.1. Pyrimidine Condensation 4.2. Van Leusen Pyrrole Synthesis 4.3. Pyrrole Condensation 5. Conclusion Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments Abbreviations References

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126 128 128 128 129 130 132 132 132 132 132 132 132 134

1. INTRODUCTION Pyrimidines and purines are among the most important naturally occurring heteroaromatic compounds. They are a class of compounds with widespread biological activity and are present in nucleosides (pyrimidines uracil, thymine, and cytosine and purines adenine and guanine) and their respective polymers, DNA and RNA (where uracil occurs instead of thymine and ∼100 modified RNA nucleosides1 may be incorporated), which are fundamental in genetic information transmission and the normal functioning of a living cell. The high importance of these biomacromolecules has inspired a wide array of synthetic work, and the conception of new modified bases has stimulated an extensive amount of effort and attention.2 One interesting variation is the synthesis of fluorescent bases that could be used as molecular signaling devices in genetic analysis. These devices allow for an easy and straightforward DNA and RNA analysis. As the canonical bases do not have any fluorescence, several groups have been attached or the base itself has been modified.3,4 As a second example, DNA is also used as a template for bottom-up

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toyocamycin (7), the modified RNA base nucleoside Q (8), batzelladine A from a Bahamian sponge (9, anti-HIV), luotonin A (10, topoisomerase I cytotoxicity) isolated from Peganum nigellastrum Bunge, etc. (Scheme 2). There is, therefore, no doubt that these scaffolds have interesting biological properties, and although these heterocyclic compounds have been known since the middle of the twentieth century,7,8 they were not extensively studied until the last few decades. From then on, the interest of the chemical and pharmaceutical industry in heterocyclic fused pyrimidines, also named deazapurines, has increased notably, resulting in a large increase of the number of patents, research papers, and reviews, all of which led to the introduction of several drugs in the market (Pemetrexed by Eli Lilly, 11) or late clinical stages (Immucillin H by BioCryst Pharmaceuticals, 12). Despite several recent reviews in which modified pyrimidine and purine nucleosides are discussed, there are no overviews of the heterocyclic fused analogues and their medicinal chemistry.9−14 This Review focuses on recent aspects (2000−2015) of pyrimidines and pyrimidinones that are fused to a pyrrole core. The synthesis, reactivity, and potential pharmacological properties of these interesting molecules will be discussed. Patents were excluded from this Review. The present overview is divided into three main sections, according to the respective isomers. Each section will start with a brief description of common retro-synthetic strategies, with particular attention for newly reported synthetic entries to the scaffold. The synthetic strategies, along with the ways in which the scaffolds can be further modified, will then be exemplified according to the biological properties of the obtained pyrimidine bases.

construction of functional nanostructures with a well-defined size and shape, taking advantage of the highly organized double helix of DNA.5 DNA-templated organic synthesis (DTS) in its turn consists of two reaction partners that are attached to complementary strands of oligomeric DNA or RNA that is synthesized specifically. The union of both oligomers results in a confinement of molecules and a dramatic increase of their effective concentration. In this way, the strategy of nature using enzymes or RNA can be mimicked.6 Pyrimidine bases play an important role in medicinal chemistry as well. Among the pyrimidine-based drugs, several examples can be selected including the anticancer agents 5fluorouracil (1), troxacitabine (2), and Ara-C (3) or the antiretroviral AZT (4, Scheme 1). Scheme 1. Selected Medicinally Important Pyrimidines (Including Nucleosides)

Heterocyclic fused-pyrimidine bases are present in natural alkaloids with a multitude of biological activities. For instance, the antibiotics cadeguomycin (5), tubercidin (6), and

Scheme 2. Selected Medicinally Relevant Fused Pyrimidines (Including Nucleosides)

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Scheme 3. Classical Approaches to Pyrrolo[2,3-d]pyrimidines

Scheme 4. Pyrrole Condensation through 5-endo-dig-Alkyne Hydroamination

performed by reaction of 4-aminopyrimidines with αhalogenated ketones or aldehydes and is combined with the subsequent pyrrole condensation in a one-pot procedure. Apart from these two traditional approaches, which will be exemplified in sections 2.3−2.8, a range of new entries to the scaffold have been reported. Knochel and co-workers developed a general base-mediated protocol for the synthesis of indoles via 5-endo-dig cyclization. Bromo- (or iodo-) aniline 27 was coupled with an alkyne by Sonogashira reaction, giving a satisfactory yield of 28 (Scheme 4). This precursor was treated with a strong base in NMP at room temperature, giving good yields of pyrrolo[2,3-d]pyrimidine 29 through 5-endo-dig cyclization.15 In a similar fashion, cyclization of 6-chloropyrimidines 31 using cesium carbonate under microwave conditions resulted in pyrrolopyrimidines 30 in excellent yields. A one-pot procedure with alkylamines, hydrazine, or anilines and potassium tert-butoxide resulted in the corresponding 6substituted pyrrolopyrimidines 32 or 33 in moderate (for hydrazine and anilines) to good (for alkylamines) yields.16,17 An Ugi−Smiles four-component reaction with pyrimidinols 34 afforded intermediates 35 in low to moderate yields. The subsequent Sonogashira coupling and treatment with a suitable base produced the desired pyrrolo[2,3-d]pyrimidines 36 or 37 in good yields (Scheme 5). The Ugi adducts and Sonogashira

2. PYRROLO[2,3-D]PYRIMIDINE Pyrrolo[2,3-d]pyrimidines are commonly called 7-deazapurines, and literature reports a variety of biological applications such as antibacterial, antiviral, anticancer, anti-inflammatory, and antihyperglycemic activities. As the shape of the 7-deazapurine scaffold closely resembles that of purines, they are used as substitutes for the canonical constituents of DNA and RNA and are employed in nucleic acid sequencing. 2.1. Methodology for the Synthesis of the Scaffold

Traditionally, two approaches toward the synthesis of pyrrolo[2,3-d]pyrimidines prevail. One approach is that the pyrimidine ring is constructed onto an aptly substituted pyrrole, via two consecutive amide bonds using urea derivatives, esters, and formamides or their retro-synthetic analogues, e.g., isocyanates or ortho-esters as C1-building blocks (Scheme 3, route A). A second very common approach is the synthesis of 4aminopyrimidines, containing a 2-oxo-ethyl (or alkyl) substituent at the 5-position. These two substituents can then be condensed to form the desired fused pyrrole (Scheme 3, route B). Many variations have been published depending on the starting materials, e.g., in which the carbonyl functionality is masked as an acetal, oxime, or vinyl ether. In a common variation, the introduction of the 2-oxo-alkyl substituent is 82

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Scheme 5. Pyrrole Synthesis through 5-enolexo-exo-dig Cyclization

products could be isolated or the whole process could be performed in a one-pot setup when aromatic aldehydes were employed. When formaldehyde was used (R1 = H), the vicinal proton is less acidic and a strong base, NaH, at room temperature was necessary. When using aliphatic aldehydes other than formaldehyde (R1 = alkyl), the final cyclization of intermediates 38 was particularly sensitive to the substitution pattern of the starting benzylamines (R2). Cyclization was observed for phenyl, o/p-chloro, or p-fluorophenyl groups but not for electron-rich aryl rings (p-MePh, p-OMePh). Quite surprisingly, in some cases the cyclization mechanism also followed a different course and pyrrolopyrimidines 39 were formed, implying activation of the benzylic residue.18,19 Various 1,3,5-triazines 40 underwent a nonconcerted inverse electron-demand Diels−Alder reaction with N-alkylated 2aminopyrroles 41. The cycloadduct 43 first eliminates a nitrile through retro-Diels−Alder. This nitrile subsequently reacts with the free amino group of the pyrrole, forming an amidinium ion 44, which by final elimination produces the aromatic pyrrolo[2,3-d]pyrimidines 42 in good yields (Scheme 6). Several alkyl, benzyl, and thioether chains were allowed. The presence of electron-withdrawing substituents such as esters

and trifluoromethyl groups enhances the reactivity of the triazine, allowing the reaction to occur at room temperature, while heating was necessary in their absence.20−24 New MCR-based synthetic chemistry was developed to access the marine alkaloid rigidins and analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Condensation of methanesulfonamides 45, aldehydes 46, and cyanoacetamide 47 resulted in the formation of highly functionalized pyrroles 48 (Scheme 7). Ring closure with oxalyl chloride afforded 7-deazaxanthines 49 in good overall yields. Debenzylation of selected deazaxanthines resulted in rigidins A−D (50) in excellent yields.25 When oxalyl chloride was replaced by aryl or alkyl esters, C2aryl- and C2-alkyl-7-deazahypoxanthines 51 were obtained in variable yields. Using triethyl orthoformate, 7-deazahypoxanthines 52 were obtained in low to very good yields (Scheme 8). By replacing cyanoacetamide 47 by malononitrile 53 or cyanomethylketones 55 and adding formamide to the reagent mix, a one-pot reaction could be established affording 7deazaadenines 54 or 7-deazapurines 56, respectively, in varying yields.25,26 Some further examples of MCRs that afford pyrrolo[2,3d]pyrimidines are presented in Scheme 9. First, a Biginelli-type reaction between five-membered tertiary amides 57, acetophenones 58, and urea or guanidine using KF/alumina as solid support furnished bi- or tricyclic heterocycles 59 in good yields. The condensation of 2,4,6-triaminopyrimidine 60 with dimedone 61 and arylglyoxal 62 in ethanol with acetic acid as catalyst produced an unexpected cyclization affording heterocycles 63 in moderate yields.27,28 Pyrrolo[2,3-d]pyrimidine-2,4diones 67 bearing an aryl group on C-6 and a 2-oxoindolin-3-yl substituent on C-5 were constructed in very good to excellent yields by a three-component sequential tandem reaction of 6aminouracil 64 with isatins 65 and acetophenones 66.29 A new method for the synthesis of 5-arylpyrrolo[2,3d]pyrimidine-2,4-diones 69 was established by reacting 6aminouracil 64 with nitroalkenes 68 using PEG−SO3H as polymer-supported catalyst (Scheme 10). The pyrrolopyrimidinones were obtained in good yields, and the highest yields were obtained with nitroolefins bearing an electron-donating group on the aromatic ring. The nitroolefins could also be

Scheme 6. Tandem Diels−Alder, Retro-Diels−Alder Approach

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Scheme 7. Synthesis of Rigidins A−D

Scheme 8

synthesized in situ by reacting uracils 64 with aromatic aldehydes in the presence of nitromethane, using CuFe2O4 as catalyst. This catalyst could easily be recovered with an external magnet.30,31

Suzuki coupling, Boc-deprotection, and copper(I)-catalyzed N-arylation at position 7, a nickel(0)-catalyzed Kumada-type cross-coupling reaction was carried out allowing substitution of the sulfur-containing groups with aryl moieties (Scheme 11).33 A number of C−H activation reactions have been developed to access functionalized pyrrolo[2,3-d]pyrimidines. Palladiumcatalyzed C−H arylation of pyrimidines 76 gave C-6 arylated compounds 77 in good yields (Scheme 12a). Palladium− copper-catalyzed C−H chloroamination and amination of 78 resulted in compounds 80 and 81, respectively, in moderate yields. The 2-nitrophenylsulfonyl (oNs) group was easily deprotected with thiophenol under basic conditions to give 6aminopyrrolopyrimidine 82 in good yield (Scheme 12b).

2.2. Methodology for Functionalization of the Scaffold

The 2-, 4-, 5-, and 6-positions of the pyrrolo[2,3-d]pyrimidine scaffold can be functionalized by palladium-catalyzed crosscoupling reactions (Heck, Sonogashira, Stille, and Suzuki).32 Copper(I)- and nickel(0)-catalyzed reactions are also employed, as illustrated by the site-selective synthesis of 2,4,7triarylpyrrolo[2,3-d]pyrimidines 75 using a combination of orthogonal cross-coupling reactions. After Boc-protection, 84

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Scheme 9

Scheme 10

Scheme 11

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Scheme 12. C−H Functionalization Strategies

excellent yield. Similar treatment of the oxo-analogue and subsequent activation with POCl3 afforded the second key intermediate 90. Modification of these intermediates allowed the establishment of a structure−activity relationship (SAR) for R2, R4, and R5. The SAR studies were aided by crystal structure data of GyrB/ParE after complexation with compounds 91. Furthermore, these studies were based not only on Ki values but also on minimal inhibitory concentrations (MIC values); in this way, also the penetration of the cell envelopes and the susceptibility to bacterial efflux pumps was taken into account. After laborious optimization, low-nanomolar dual-targeting inhibitors with single-digit MIC values (μg/mL) against robust Gram-negative pathogens were obtained (Scheme 13).37,38 Rajanarendar and co-workers have reported new pyrrolo[2,3d]pyrimidines with antibacterial activity. Reaction of isoxazole 92 with phenacyl bromide 93 afforded 94 in good yields (Scheme 14). Pyrroles 95 were then obtained by treatment with malononitrile, and condensation with thiourea gave the final pyrrolo[2,3-d]pyrimidine-2-thiones 96 in good yields. These compounds exhibited MIC values of 8−26 μg/mL for both Gram-positive (B. subtilis, B. sphaericus, and S. aureus) and Gram-negative (P. aeruginosa, K. aerogenes, and C. violaceum), comparable to Ciprofloxacin (22−28 μg/mL). These pyrrolopyrimidines also possessed antifungal activity, with MIC values ranging from 6 to 18 μg/mL, comparable to Fluconazole (14− 20 μg/mL).39 A series of similarly substituted pyrrolo[2,3-d]pyrimidines 97−100 (Scheme 15) was evaluated by Mohamed and co-

Copper-catalyzed C−H sulfenylation gave 5-thiopyrrolopyrimidines 84 in low (R1 = Bn) or moderate to excellent (R1 = H) yields (Scheme 12c).34−36 Given the much frequented classical approaches (Scheme 3) and the versatility of the newly reported entries to the pyrrolo[2,3-d]pyrimidine scaffold, a wide array of derivatives with divergent substitution patterns is currently available. This has allowed the application of these 7-deazapurines in several biological systems, as will be exemplified in the following sections. To avoid repetition, the following syntheses were grouped according to the biological activity of the end products. 2.3. Biocides

2.3.1. Bactericides. During bacterial replication, the topological state of DNA is controlled by topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE). The adenosine 5'-triphosphate (ATP)-binding pockets of these enzymes are highly conserved, making these enzymes interesting targets for broad-spectrum inhibitor development. A pharmacophore-based fragment screen has identified pyrrolo[2,3-d]pyrimidines 91 as lead scaffolds for optimization. Two key intermediates 89 and 90 for substrate screening were synthesized through the dehydration of masked 2-oxo-alkylsubstituted aminopyrimidines 88 (Scheme 13). Reaction of methyl cyanoacetate 85 with bromobutanone 86 and subsequent acetal formation afforded compound 87 in good yield. Treatment with either urea or thiourea led to pyrimidinones 88 in good yields. Acid-catalyzed ring-closure of the thio-analogue 88 gave a first key intermediate 89 in 86

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Scheme 13

Scheme 14

workers as antibiotics against different pathogens such as C. albicans, S. aureus, or B. subtilis. Although these compounds were not more potent than the currently marketed drugs, in some cases they were bifunctional, having anti-inflammatory activity as well.40−45 2.3.2. Protozoicides. The increasing resistance of Plasmodium falciparum to marketed drugs drives the search for new classes of antimalarial agents. The first-line antimalarial drug, artemisinin, acts on intracellular forms of the parasite. Therefore, one of the strategies to deal with current drug resistance is to engage the parasite in other stages of its life cycle. The invasion of red blood cells by Plasmodium merozoites requires interaction between two parasite proteins, AMA1 (apical membrane antigen 1) and RON2 (rhoptry neck

protein 2). Therefore, these proteins are potential drug targets against malaria. Recently, the screening of a library of 21 000 compounds identified three pyrrolo[2,3-d]pyrimidines as the first small-molecule inhibitors of the AMA1−RON2 interaction, with IC50 values ranging from 6 to 30 μM (101−103, Scheme 16).46 In an attempt to find analogues with improved aqueous solubility and higher activity, compounds 107a−k were synthesized following typical procedures. Alkylation and subsequent bromination of 4-chloropyrimidine 104 afforded 5bromo-4-chloropyrimidines 105 in good yields (Scheme 16). Nucleophilic aromatic substitution of the 4-chloro substituent followed by Suzuki coupling resulted in pyrrolopyrimidines 107 in low to moderate yields. Although these compounds possessed better c log P values and substantially reduced 87

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Scheme 15

Scheme 16

Scheme 17

88

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Scheme 18

Scheme 19

pyrimidines were found to inhibit PTR1 from Trypanosoma brucei (TbPTR1). After a series of optimizations, directed by SAR and crystallographic studies, pyrrolo[2,3-d]pyrimidines 110 and 111 were synthesized in low yields from pyrimidines 60 and 108, respectively (Scheme 17). An amino or keto substituent at C-4 and aryl groups on both C-5 and C-6 were crucial for activity. The compounds exhibited Ki values in the low micromolar range (0.135−10 μM) against TbPTR1 and IC50 values in the same order of magnitude (0.08−100 μM) against Trypanosoma brucei. Eight compounds were sufficiently active in both screens for evaluation in murine tests. Although there was evidence of trypanocidal activity, the compounds were too toxic to mice and were not further developed.48,49 A series of 4-amino-6-aryl-pyrrolo[2,3-d]pyrimidines 115 and 116 (Scheme 18) was synthesized and tested for protozoicidal properties using a Tetrahymena strain as model organism. The

aggregation behavior, they failed to achieve better inhibitory activity. This study further revealed that the inhibition of the AMA1−RON2 interaction is not mediated by direct stoichiometric interaction with AMA1. Inhibition may be due to their activity as kinase inhibitors and/or due to off-target mechanisms.47 Another pathogenic protozoic species is Trypanosoma, causing several diseases such as sleeping sickness (by Trypanosoma brucei) and Chagas disease (by Trypanosoma cruzi). Treatment of human African trypanosomiasis (HAT, sleeping sickness) in sub-Saharan Africa is still problematic due to side effects and toxicity issues of current drugs, as well as increasing resistance against these drugs. One of the new potential approaches to tackle this parasite is targeting pteridine reductase (PTR1), an essential enzyme that reduces dihydrobiopterin in Trypanosoma spp. Pyrrolo[2,3-d]89

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Scheme 20

blood−brain barrier (BBB) penetration of 119b was shown to be acceptable in mice.52 2.4.2. Adrenergic Receptor. The adrenergic receptors (ARs) are a class of G protein-coupled receptors (GPCRs). Typical agonists of these receptors are the catecholamines, especially epinephrine (adrenaline) and norepinephrine (noradrenaline). Binding of these agonists will stimulate the sympathetic nervous system, which is responsible for the fight-or-flight response. Antagonists of adrenergic receptors are typically used to treat various medical conditions related to the sympathetic nervous system. The synthesis of studied compounds 128 started from trisubstituted pyrroles 126, which were easily condensed with 2-chloroethyl isocyanate affording ureas 127 in excellent yields (Scheme 20). Treatment with 1-(2-R2-phenyl)piperazines (PPz’s) elongated the chain prior to final pyrimidine cyclization by KOH in MeOH, which afforded target compounds 128 in good yields. All of the compounds 128 displayed affinity for α1ARs in the low nanomolar range. New and selective α1 adrenergic receptor antagonists are necessary for treatment of benign prostatic hypertrophy. It was observed that 2-chloro substitution of these PPz’s (128aa−ga) is crucial to obtain α1 selectivity. Further decoration of the pyrrole phenyl substituent with methyl or methoxy groups afforded interesting compounds in terms of affinity and selectivity (128ba and 128fa); however, these same modifications at position 4 were detrimental (128ca and 128ga). Chlorine atoms have an opposite effect and show better behavior at the 4-position. In fact, compound 128ea was one of the most potent and selective examples. The subtype selectivity was determined only for selected compounds. 128ca was not selective, 128ga showed some selectivity for α1B, whereas 128ea was a highly selective antagonist for α1D.53 2.4.3. Adenosine Receptor. The adenosine receptors are a class of GPCRs with adenosine as endogenous agonist, and they play a role in heart function, neurotransmitter release, inflammation and immune responses, and other processes. Antagonists of the adenosine A2A receptor may be useful in the treatment of Parkinson’s disease (PD). 2-Amino-4-furylthieno[3,2-d]pyrimidines were identified as active ligands of A2A and reversed haloperidol-induced hypolocomotion in mice. The corresponding pyrrole analogues 131 and 133 were prepared by Stille coupling of dichlorinated compound 129. The introduction of a 2-amino group was performed by nucleophilic displacement of the remaining chloride using veratrylamine and subsequent deprotection (Scheme 21). As compared to the

synthesis followed classical pyrrolopyrimidine chemistry: condensation of pyrroles 112 with formamide resulted in pyrrolopyrimidines 113 in good yields. Activation with POCl3 and subsequent reaction with amines gave amino compounds 115 in moderate yields. For methoxyphenyl-substituted pyrrolopyrimidines, demethylation using boron tribromide afforded the 4-hydroxyphenyl-substituted products 116 in low to moderate yields. The highest activities were found for phenylethyl-substituted phenolic compounds (116, R1 = CH3, Scheme 18). Minimum protozoicidal concentrations (MPC) in the order of 8−16 μg/mL could be obtained.50 2.4. Receptor Antagonists

2.4.1. CRF Receptor. Corticotropin-releasing factor (CRF) is a short neuropeptide hormone that plays a central role as neurotransmitter in stress-related situations. The CRF receptor has four subtypes, and CRF1 inhibition might be a target for disorders such as depression and anxiety, although clinical efficacy is not clear.51 The majority of the known inhibitors have a sp2 hybridized nitrogen that can act as a hydrogen-bond acceptor. In a successful attempt to discover new active analogues, the introduction of a carbonyl function as a hydrogen-bond acceptor in the scaffold was proposed, while maintaining a bulky aryl group with an orthogonal conformation. Thus, 2,6-diaminopyrimidin-4-ol was treated with methylamine, obtaining the 2-methylamino derivative 117. This was condensed with the appropriate α-halo-carbonyl under basic conditions to afford cyclized pyrrolo[2,3-d]pyrimidinones 118, 120, and 123 in moderate yields (Scheme 19). Iterative alkylation of 118 at the pyrimidine and 2-amino group using NaH in DMF yielded the active compounds 119. The alkylation and subsequent bromination of 120 yields 121. To reach the corresponding iodinated derivative 124, a longer pathway was needed including amine protection, di-iodination with NIS, and selective deiodination of position 6 using zinc. Finally, halogenated compounds 121 and 124 were coupled with aryl boronic acids in low yields, affording compounds 122 and 125. Testing showed IC50 values in the single-digit μM range for all compounds. The most active compounds contain two npropyl groups at N-2, e.g., 119b (Scheme 19) with an IC50 of 0.12 μM, which is equipotent to one of the reference drugs. Further modification introducing a methyl at position 5 resulted in a 10-fold drop in activity. Furthermore, aryl group modification introducing electron-withdrawing or -donating substituents did not improve the binding affinity, suggesting independence to electronic effects in the aryl group. The 90

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Scheme 21

Scheme 22

Scheme 23

hH4R binding and selectivity over other histamine receptors. The pyrrolo[2,3-d]pyrimidine scaffold was constructed from 2,6-diamino-4-hydroxypyrimidine 134 by reaction with a range of α-halocarbonyl derivatives (Scheme 22). The reaction proceeded regiospecifically, yielding the 6-substituted products 135. According to the authors, the prototypical subsequent approach of 4-chlorination using POCl3 resulted in complex reaction mixtures. To substitute the 4-position with the appropriate amines, POCl3 was successfully replaced by BOP, resulting in 4-N-substituted pyrrolo[2,3-d]pyrimidines 136 in low to moderate yields. SAR indicated that the pyrrole nitrogen, and more importantly the 2-amino group, should be left unsubstituted. The best Ki value (0.39 μM) was obtained

thieno-analogues, the low nanomolar activity (Ki = 16 nM) was maintained in the case of 133. However, in vivo it was inactive. The affinity of compound 131 was low (Ki = 242 nM).54 2.4.4. Histamine H4 Receptor. The human histamine 4 receptor (hH4R) is a member of the histamine receptor family. This receptor is found predominantly on cells of the immune system and modulates the release of various inflammatory mediators. Therefore, this receptor is a potential drug target for various chronic inflammatory and allergic diseases such as inflammatory bowel disease, asthma, rheumatoid arthritis, and pruritus. When 2-aminopyrimidines were found to be hH4R antagonists (e.g., compound 137), 2-aminopyrrolo[2,3-d]pyrimidine analogues were synthesized and evaluated for 91

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Scheme 24

7 cell lines. 7-Deazaxanthines 49 and rigidins 50 were inactive or weakly active (double-digit μM GI50 values or higher). 7Deazahypoxanthines 52 and 7-deazaadenines 54 showed better activity (single- or double-digit μM values), but significantly better values were obtained for 7-deazahypoxanthines 51 and 7deazapurines 56. Double-digit nanomolar antiproliferative activities were observed for the most active compounds (down to 29 nM). SAR data indicated that the favored substitution pattern consisted of an unsubstituted or parasubstituted benzene ring at C-8 (Ar2) and either the unsubstituted or meta-halogen-substituted benzene ring at C7 (Ar1). For C-2 substitution in compounds 56, only the compound with a methyl substituent gave good results. Further testing of the most active compounds 51 confirmed in vitro inhibition of tubulin assembly and colchicine binding. Importantly, these 7-deazahypoxanthines still exhibited nanomolar GI50 values in vitro against multidrug-resistant (MDR) MES-SA/Dx5 cells, while taxol and vinblastine displayed more than a thousand-fold drop in potency. In addition, the compounds were able to fight cancer cell lines representing cancers with dismal prognoses or derived from tumor metastases in vitro, displaying nanomolar GI50 values. Altogether, this new chemical class of antitubulin agents has significant potential as new anticancer agents.25,26 2.5.3. Nav1.7. The treatment of chronic pain is still a major challenge in healthcare, with current pain treatments suffering from poor efficacy and dose-limiting toxicity. Recent studies indicated the voltage-gated sodium ion channel Nav1.7 as an important regulator of human pain, and selective blocking agents of this channel may thus represent a new class of pain relief therapeutics.58 During an electrophysiology-based screening campaign (automated by PatchXpress (PX)), pyrrolopyrimidine 143 was identified as a highly potent and statedependent inhibitor of hNav1.7 (Scheme 24). However, compound 143 suffered from poor intrinsic instability in liver microsomes, and despite modest selectivity versus hERG (20×) it lacked selectivity over cardiac hNav1.5 channels. By modulating LipE (PX IC50 − cLogP), a compound with improved metabolic stability and selectivity over hERG and hNav1.5 was obtained. A large number of compounds was synthesized, and SAR was established. Eventually, the best compound was obtained when C-2, C-3, and C-6 were left unsubstituted, an alkoxy piperidine was the linker on C-4, the

for compound 136cc. Compared to 2-aminopyrimidine 137, this pyrrolo[2,3-d]pyrimidine has a much better selectivity profile versus the human histamine 3 receptor and thus forms an excellent lead for further development.55 2.5. Enzyme Inhibitors

2.5.1. Cholinesterase. The cholinesterases acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze the neurotransmitter acetylcholine into acetate and choline. They have been associated with Alzheimer’s disease (AD) after patients were found to possess increased levels of AChE/ BuChE and low levels of acetylcholine in the brain. Tacrine was the first cholinesterase inhibitor to get Food and Drug Administration (FDA) approval for treatment of AD. However, due to safety concerns, it has been discontinued in the United States in 2013. Other FDA-approved drugs such as Donepezil have appeared on the market, but because of adverse effects and contraindications, the search continues for better drugs to treat AD. A series of 4-arylamino-6-arylpyrrolo[2,3-d]pyrimidines 138 (Scheme 23) was synthesized following essentially the same methodology as seen before (ref 50, Scheme 18) with the only difference being that, for compounds 138, anilines were used instead of benzylamines to substitute the chlorine on C-4. Micromolar inhibition values were obtained, but a clear SAR could not be established.56 2.5.2. Tubulin. Tubulins are globular proteins. The most common tubulins are α- and β-tubulin, which can form the heterodimer αβ-tubulin, the structural building block of microtubules. Microtubules are one of the major cytoskeletal components in eukaryotic cells and play a critical role in the segregation of chromosomes during mitosis, turning them into a validated target for cancer therapy. Microtubule-targeting agents disrupt the microtubule assembly/disassembly dynamics by either stabilizing (e.g., taxanes) or destabilizing (e.g., vinca alkaloids) microtubules. Four major binding sites have been identified, one of them being the colchicine site. Agents directed at the colchicine site might be able to circumvent βIIItubulin overexpression, which compromises the clinical use of taxanes and vinca alkaloids.57 The synthesis of compounds 49−52, 54, and 56 was already discussed in section 2.1 (Schemes 7 and 8). These compounds were tested for antiproliferative activity against HeLa and MCF92

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headgroup was N-benzyl, and the tail group was pyridin-2-yl. This compound (142, R1 = pyridin-2-yl) showed a hNav1.7 PX IC50 value of 0.11 μM, hNav1.5 PX IC50 of 0.16 μM, human liver microsome (HLM) clearance of 130 μL/min/mg, and >100× selectivity against hERG. Unfortunately, no significant gains in selectivity over Nav1.5 could be realized. The synthesis of this lead compound, as depicted in Scheme 24, followed typical pyrrolo[2,3-d]pyrimidine chemistry. Starting from 4chloropyrrolo[2,3-d]pyrimidine 104, N-benzylation proceeded in excellent yield and nucleophilic aromatic substitution of chlorine by Boc-protected 4-hydroxypiperidine afforded 140 in moderate yield. After Boc removal, reductive amination resulted in N-substituted piperidine compounds 142.58 2.5.4. HSP90. Heat shock protein 90 (HSP90) is an abundant chaperone protein that regulates folding of so-called “client proteins” and stabilizes these proteins during stressful conditions such as heat, cold, radiation, wound healing, and tissue remodeling. The over 200 reported client proteins include well-known oncogens and established cancer targets, which explains why this protein is an attractive target in oncology. Inhibition of HSP90 causes client proteins to adopt aberrant conformations, eventually resulting in proteosomemediated degradation. HSP90 inhibitors have shown promising anticancer activity in vitro and in vivo, and various HSP90 inhibitors are currently undergoing clinical trials.59 On the basis of a first-generation purine-based HSP90 inhibitor 144 (Scheme 25), a second-generation deazapurine

which regioselectively reacted with NIS to give 150 in good yield. The introduction of the pivaloyl protecting group was essential for smooth deoxychlorination and iodination. Alkylation toward 151 proceeded well under typical conditions, and subsequent deprotection of the pivaloyl group using zinc chloride resulted in the isolation of 152 in very good yield. This key intermediate was further modified toward different C-5substituted analogues. Sonogashira coupling eventually resulted in compound 145, which possessed the best combination of pharmacokinetic properties and efficacy in murine cancer models.59 In a fragment-based screening campaign for HSP90 inhibitors, several other purine compounds were identified as hit fragments. Interestingly, crystallographic data revealed that these fragments were bound to HSP90 in a different orientation than 2-aminopurine inhibitor 144 (Scheme 25). This suggested that they could be exploited for the design of novel HSP90 inhibitors. By combining the fragment hit data and information from earlier research, purines 153 (Scheme 27) were synthesized and were found to possess only moderate affinity to HSP90. X-ray data revealed that one of the imidazole nitrogens donated a key hydrogen bond to a carboxylate residue from HSP90. Tautomerism of the imidazole moiety could weaken this interaction, and therefore, deazapurines 154 were synthesized. However, this modification was detrimental for binding affinity. This loss of affinity was attributed to a steric clash between the newly introduced hydrogen atom on C-5 and a conserved water molecule. By introducing a cyano group in compounds 155, the water molecule was displaced, while the cyano group could reestablish the interaction with the protein previously maintained by the bridging water molecule. This successful design was reflected in improved binding affinities, resulting in (sub)-single-digit micromolar Ki values. Reaction of ethyl 2-cyano-4,4-diethoxybutanoate 156 with thiourea under basic conditions gave pyrimidine 157 in 50% yield (Scheme 28). After methylation of the thiol, acidmediated ring closure afforded the pyrrolo[2,3-d]pyrimidine scaffold in excellent yield. Deoxychlorination with phosphorus oxychloride and SEM protection of the pyrrole nitrogen proceeded in very good yields. To introduce a cyano group at C-5, this position was first brominated using NBS. Then, lithium−halogen exchange with butyllithium and quenching with carbon dioxide resulted in the carboxylic acid 161 in excellent yield. Further conversion of the acid to the acid chloride with oxalyl chloride, and subsequent reaction with aqueous ammonia afforded amide 162 in good yield. Dehydratation with trifluoroacetic anhydride eventually resulted in compound 163 with the cyano group at C-5. After Suzuki coupling, the sulfide was converted into a sulfone by oxidation with m-chloroperbenzoic acid. The sulfone could then be substituted with ethyl thioglycolate under basic conditions in excellent yield, and subsequent saponification with sodium hydroxide afforded carboxylic acid 167 quantitatively. This acid was then transformed to the amide 168 in an HBTU-mediated reaction. The acetal function on the aryl substituent was cleaved by pyridinium p-toluenesulfonate (PPTS) as mild acid catalyst. The deprotected hydroxy group was then alkylated with iodomethane or ethyl iodide, and eventually the SEM group was removed by tetrabutylammonium floride (TBAF) and ethylenediamine to give compounds 155 in moderate yields. These compounds showed (sub)single-digit nanomolar binding affinities with HSP90 and

Scheme 25

inhibitor 145 was developed by the Biamonte group with substantially improved in vitro and in vivo potency, showing a 20-fold higher efficacy in murine antitumor experiments. Crystallographic data and SAR already indicated that N-7 of structure 144 faced a solvent-exposed area. Modification of other positions only resulted in loss of potency, and thus, N-7 was replaced by a carbon atom and further modified. Despite the fact that the authors describe a two-step route toward key intermediate 152, they preferred the route that is shown in Scheme 26. This entire sequence (134 → 152) could be performed without any chromatographic purification on a kilogram scale and as such was more convenient. The pyrrolo[2,3-d]pyrimidine scaffold was synthesized from 2,6diaminopyrimidin-4-ol 134 in a similar fashion as shown earlier (ref 55, Scheme 22), with the only difference being that here dimethylacetamide (DMA) is used as a cosolvent and scaffold 146 precipitates as a 1:1 DMA complex. Subsequent recrystallization from methanol removes the DMA. Protection of the amino group with pivaloyl chloride afforded amide 148 in excellent yield. Deoxychlorination with POCl3 yielded 149, 93

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Scheme 26

doses by disrupting CRL-mediated protein turnover. This disruption resulted in apoptotic tumor cell death by deregulation of S-phase DNA synthesis. MLN4924 has also been found to inhibit tumor angiogenesis in in vivo models and has shown potential to overcome resistance of cancer cells against DNA interstrand cross-linking anticancer agents such as cisplatin. This compound is currently undergoing clinical trials and holds promise for the treatment of various types of cancer.63−66 The first step in the synthesis of MLN4924 is the reaction of (1R,2R,3S,5S)-3-(hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2ol 170 with anisaldehyde dimethyl acetal under mild acidic catalysis by pyridinium p-toluenesulfonate to obtain the hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine 171 in good yield. Compound 171 was then coupled to pyrrolo[2,3d]pyrimidine 172, which opened the oxirane ring regioselectively. The newly formed hydroxyl group was removed by Barton−McCombie deoxygenation. Acidic cleavage of the acetal function by acetic acid afforded diol 175 in excellent yield. The primary alcohol of 175 was then transformed to the sulfamate by reaction with diphenylcarbamoyl-protected sulfamoyl chloride and subsequent cleavage of the carbamoyl protective group by aqueous hydrochloric acid to obtain MLN4924 in good yield.63 2.5.6. Antifolates. Antifolates are antagonists of folic acid, inhibiting one or more of the enzymes that take part in the folic acid metabolism, for example, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Folic acid is a cofactor of various methyltransferases that are involved in serine, methionine, thymidine, and purine biosynthesis. Thus, antifolates inhibit cell division, synthesis and repair of DNA and RNA, and synthesis of proteins. Well-known antifolates are the anticancer and immunosuppressant agent methotrexate (178, MTX) and the anticancer agent pemetrexed (11, Scheme 30). The latter was approved by the FDA for treatment of malignant pleural mesothelioma in 2004 and as a first-line

Scheme 27

nanomolar GI50 values against three human cancer cell lines in vitro, and they will be further developed.60 2.5.5. NAE. NEDD8-activating enzyme (NAE) adenylates a small ubiquitin-like protein, NEDD8, which is then transferred via a NEDD8-conjugating enzyme (UBC12) to Cullin-RING ligases (CRLs). CRLs are ubiquitin ligases that attach ubiquitin to target proteins. These ubiquitinated proteins are then recognized by the proteosome for destruction. Thus, NAE regulates the degradation of proteins that are substrates of the CRLs. Inhibition of NAE has emerged as a new antitumor target, because the substrates of CRLs play important roles in cellular processes associated with cancer cell growth and survival pathways. This approach should be more selective and less toxic than agents that inhibit protein degradation at the proteosome level, such as the FDA-approved anticancer agent Bortezimib.61,62 High-throughput screening initially identified N6-benzyl adenosine as an inhibitor of NAE. The fact that this adenosine derivative was found to inhibit NAE is not illogical, because ATP is used and converted to adenosine monophosphate (AMP) by NAE during the NEDD8 activation reaction. An iterative medicinal chemistry campaign followed and eventually resulted in the discovery of MLN4924 (176, Scheme 29), a small-molecule inhibitor of NAE, structurally related to AMP and displaying an IC50 value of 4 nM and good selectivity relative to closely related enzymes. MLN4924 suppressed the growth of human tumor xenografts in mice at well-tolerated 94

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Scheme 28

treatment in combination with cisplatin for the treatment of nonsmall cell lung cancer (NSCLC) in 2008. Besides treatment of cancer and autoimmune diseases, another interesting application of antifolates is the use as antiprotozoal, antimicrobial, or antifungal agents. Obviously, this requires selectivity of the antifolates for protozoa, microbes, or fungi, respectively. Examples of such approved drugs are the antiprotozoal pyrimethamine 179 and the broad-spectrum antimicrobial trimethoprim 180 (Scheme 30). These molecules are examples of so-called nonclassical antifolates, because they lack the glutamate tail that is typical for classical antifolates. To date, the clinical importance of antifolates is well-established, and research efforts continue in order to find agents with improved activity and/or selectivity and less adverse effects. Classical antifolates do not cross membranes by diffusion. The major membrane transporters known to date include the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the high-affinity folate receptors (FRs) α and β. While RFC is ubiquitously expressed in tumors and normal tissues, FRs are expressed abundantly in certain malignancies and only in a limited number of normal epithelial tissues. PCFT is highly expressed in different solid tumors and in the upper small intestine, the liver, and the kidney. PCFT exhibits an acidic pH optimum, in accordance with the low pH microenvironments of the small intestine and many solid tumors. PCFT is modestly expressed in most other normal

tissues, but the presence of low-pH conditions is unlikely there. Thus, one way to obtain more selective antitumor agents would be the synthesis of antifolates, which are selectively transported by FRs and/or PCFT.67 Lometrexol 181 (Scheme 30) is a tetrahydropyrido[2,3d]pyrimidine that inhibits GARFTase. Its potency was improved and its toxicity was lowered by isosteric replacement of the phenyl by a thienyl ring. To increase their GARFtase inhibitory potency, this same thienyl ring was introduced in pemetrexed 11. The shorter-chain analogues 183a−c were synthesized by condensation of thienyl α-bromoketones 182 with aminopyrimidine 134. To achieve the longer-chain isosteres 183d−f, alkynyl heterocycles 185 were synthesized by condensation of α-bromoketones 184 (Scheme 31). Sonogashira coupling afforded intermediates 186 in good yields, which were finally hydrogenated and saponified. Both 183d and 183e were active toward KB (nasopharyngeal) tumors (IC50 of 0.55 and 3.2 nM, respectively) and cells that overexpress FRs and RFCs. The activity of 183f (231 nM) is substantially lower. The observed inhibitory effect was reversed when an excess of folic acid was added; thus, FRs were the main target of these compounds. In Chinese hamster ovary (CHO) sublines, 183d and 183e showed two-digit nM activity (43 and 101), inhibiting growth of cells expressing hPCFT (human proton-coupled folate transporter), whereas 183f was inert. Compound 183d was able to inhibit colony formation of 95

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Scheme 29

Scheme 30

and/or PCFT. Several experiments identified GARFTase as the likely intracellular target, resulting in the inhibition of de novo purine biosynthesis. In one study, mice were grafted subcutaneously with human KB tumors or IGROV1 ovarian tumors. Compounds 183c and 183d were administered

KB cells for 99% at 1 nM. 183a and 183b were mainly inactive, showing that a longer chain is necessary for activity. The threecarbon linked compound 183c, on the other hand, is the most potent of the series, more potent than four-carbon linked 183d and even the reference marketed drugs for cells expressing FRs 96

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Scheme 31

Scheme 32

intravenously and were shown to be effective in vivo. The only adverse dose-limiting symptom observed was body weight loss, which was reversible after treatment. A folate-deficient diet increased the effectiveness of the treatment.68,69 2.5.7. Anticancer Compounds with Unidentified Target. The N-benzylpyrrolo[2,3-d]pyrimidines 189 (Scheme 32) were originally designed as RTKs inhibitors (see below). Although they were inactive against these kinases, they were potent inhibitors of 56 cancer cell lines in the submicromolar range. Benzyl-protected heterocycles 187 were coupled using the Sonogashira reaction to afford intermediates 188 in moderate-to-good yields. Subsequent hydrogenation of the alkyne and deprotection of the pivaloyl group afforded compounds 189 in good yields. Final removal of the benzyl protective group furnished compounds 190 (Scheme 32). This final removal of the benzyl group, forming compounds 190, led to significant (100 to 10 000-fold) loss of activity as compared to compounds 189. Methoxy substitution increased the activity,

especially at positions 3 and 5; thus, trimethoxy derivative 189b was found to be the most active. Binding to microtubuli was observed, bestowing the compounds with antimitotic activity. The resulting cells displayed a depletion of the microtubuli. Moreover, structures 189 were efficient inhibitors of resistant tumor cells with overexpressed P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1). These proteins are ATP-mediated transmembrane efflux pumps that release drugs to the extracellular space. Some compounds 189 were able to reverse Pgp and/or MRP drug resistance, with the 2-OMe motif as the most appropriate substitution pattern for this effect.70,71 The HCl salt of compound 192a also showed microtubulidisrupting effects in cells, similar to colchicine. Its synthesis proceeded by treatment of ethyl butanoate 156 with acetamidine hydrochloride in basic media, followed by sulfuric acid treatment to afford 2-methylpyrrolo[2,3-d]pyrimidin-4-one 191 in 64% yield. Chlorination with POCl3 and addition of 97

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Scheme 33

Scheme 34

194. Further Stille coupling afforded vinyl ether 195. Dissolution in refluxing HCl, as previously reported by Cheung and co-workers,74 in the presence or absence of trimethoxyaniline, furnished the key cyclized intermediates 196 and 198 in excellent yields. Amination of the 2-position of 196 was carried out with 30 different amines, using KOtBu as a base. Arylation of N-7 was performed by Ullman-type75 couplings, typically in good yields, and delivered compounds 199−200.76 Pyridinecontaining analogues (201, R3 = pyridine) were prepared through Mitsunobu reaction in moderate yields (Scheme 34). Modification of the 2-position showed that several secondary aromatic amines 197 were active with an IC50 of 0.1−1 μM. A methoxy group was beneficial for the activity in ortho and meta. Also the 3,4,5-trimethoxyphenyl moiety performed well and was used for further investigation. Next, changes were made at N-7, affording compounds 199−201. Pyridine-containing analogues performed well, optimally linked at the 2- or 3position. Substituents on the pyridine ring led to loss of activity, especially for electron-withdrawing groups. The replacement of pyridine by other heterocycles containing a basic nitrogen (e.g., thiazole or pyrimidine) retained the activity when the

aniline gave 4-anilino derivatives 192 (Scheme 33). The EC50 (loss of half of the microtubuli) of 192a was 5.8 μM. Polymerization of purified tubulin was inhibited as well. Data suggest that 192a is a poor substrate of Pgp, avoiding this drugresistance mechanism. Demethylated 192b was less active in the tubulin-inhibition tests, and the position of the methoxy substituent was found to be of importance as well. Molecular modeling suggests that the pyrrole NH was not involved in hydrogen bond formation. Moreover, 192a·HCl had a potent GI50 in the larger part of 60 tested cancer cell lines.72 2.5.8. Kinase Inhibitors. 2.5.8.1. Focal Adhesion Kinase. Focal adhesion kinase (FAK) is a tyrosine kinase found at the cell membrane, mediates focal adhesion, regulates processes such as anchorage-dependent proliferation and cell migration, and is thus related to metastasis. FAK is highly active in melanoma, myeloma, and lymphoma cells. Pyrrolo[2,3-d]pyrimidines were used by both the Combs and the Lackey groups as cyclic equivalents of 2,4-diarylaminopyrimidines, which were the only FAK inhibitors described at that time.73 The synthesis started from trihalogenated pyrimidine 193, which was treated with ammonia to quantitatively afford amine 98

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Scheme 35

Scheme 36

To avoid these effects, carboxylic acid 206 was synthesized, resulting in an excellent IC50 of 4 nM (Scheme 35).76 2.5.8.2. Aurora Kinase. Inhibition of Aurora kinase is a new molecular target for cancer that occurs in three isoforms. Isoform A is involved in the early S phase of the cell. Isoform B is a chromosome passenger protein, and isoform C complements B. Notably, Aurora A and B are overexpressed in many cancers and are linked to the development of chemoresistance. By using 2-chloropyrrolo[2,3-d]pyrimidine (196, Scheme 34), several selective Aurora A kinase inhibitors were obtained by introducing different decoration patterns. Chan−Lam77 or Buchwald78 coupling conditions were applied to attach the aryl groups to the N-7 atom. The 2-anilino groups were introduced directly by aromatic nucleophilic substitution of the chloride when the aniline was nucleophilic enough, or using palladium cross-coupling if necessary. The initially identified hit 207 (Scheme 36) gave an IC50 of 47 nM against Aurora A, but with poor selectivity at cyclin-dependent kinase 4 (CDK4). Better selectivity was accomplished by the introduction of polar groups such as phenyl 3-acetic acid and phenylthiomorpholine dioxide. There may be charge−charge repulsion with Glu residues in CDK4, whereas in Aurora A an Arg residue resides at the corresponding position. Similar improvements were observed in compounds 208 upon arylation of N-7 with pyridyl

corresponding nitrogen atom was located at the correct position. Also, compounds with variable linker chain lengths between the pyridine and the pyrrolopyrimidine (e.g., 201) showed weak or no activity. Further modifications were made to these molecules in an attempt to generate interactions with basic lysine and arginine or acidic aspartic and glutamic polar residues. A first derivative (202) aims to make a salt bridge with Lys454, which led to the loss of activity (Scheme 35). Similar results were obtained with sulfonamide 203. The ground-state conformation of these molecules is not suitable for binding, as the aryl group is nearly perpendicular to the pyrrolopyrimidine ring. Compounds 204 (Scheme 35) were synthesized using the same pathway as for heterocycles 199 (Scheme 34). Ortho substituents led to weak inhibitors, except for ester and cyano groups. Para substitution neither improved nor deteriorated activity. In contrast, most of the meta-substituted compounds exhibited enhanced activity, down to the submicromolar range. Therefore, new 3′substituted compounds were produced such as tetrazoles 205 (Scheme 35) and amides 200 (Scheme 34). The activity did not improve for tetrazoles 205, while amides 200 showed reduced inhibitory activity, probably because a lone-pair interaction between the pyridyl nitrogen and the adjacent carbonyl oxygen caused an unfavorable conformation. 99

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Scheme 37

However, further modified compounds 214 resulted in a decrease or abolition of potency, which was shown by determining A431 cytotoxicity. Derivatives 214a, 214b, and 214f were as potent as cisplatin but slightly less potent than 213f. The correlation between inhibition of EGFR and A431 cytotoxicity was not always clear. (2) VEGFR-2: Compounds 213b (2-Me, 0.25 μM) and 213e (2,5-diOMe, 0.62 μM) were the most potent of the series and were fourfold and eightfold more potent than the standard semaxanib (SU5416), respectively. Derivatives containing 1naphthyl, 2-Cl, and 4-biphenyl groups were equipotent to SU5416, indicating that 2-substitution increased inhibition of VEGFR-2. In contrast with the above-described EGFR inhibitors, electron-donating groups are preferred over electron-withdrawing ones. Changing the C-4 aniline further improved inhibition of this receptor. Dihalogenated 214a and 214c and 4-i-propyl-substituted 214g showed submicromolar activity and were over 40-fold more active than semaxanib. (3) VEGFR-1: Bulky naphthyl substituted 213h and 213i were equipotent to the standard reference (CB676475), 213e was about half as potent, and biphenyl and tri-OMe analogues were inactive. Heterocycles 214 showed poor inhibition as well. The best result was obtained with 214b, being fivefold less potent than CB676475. (4) PDGFR-β: Compounds 213e (8.92 μM), 213f (17.0 μM), and 213k (14.7 μM) were the only analogues active against PDGFR-β (platelet-derived growth factor receptor β), being equipotent or twofold to threefold less potent than AG1295. This suggests that polysubstitution is necessary for activity. The series of 214 was mainly inactive. (5) CAM angiogenesis inhibition: Phenyl-substituted compounds 213b and 213e were potent single-digit μM inhibitors in the chick chorioallantoic membrane (CAM) assay, but the most potent examples were 1-naphthyl-substituted (213h) and 4-biphenyl-substituted (213j) compounds. It should be noted that the corresponding 2-deaminated compounds were synthesized and were significantly less potent against RTKs than their 2-amino counterparts, proving that the amino-group at C-2 is necessary for activity and forms an

or 3-methylsulfonylphenyl groups (Scheme 36). Meta substitution of the piperazinyl phenyl moiety (209) resulted in similar activities. It was also observed that 2-pyridyl was the best choice for R3. Thus, by combining both moieties, 210 was obtained as a selective and potent in vitro Aurora A kinase inhibitor (0.8 nM). It was active against cell proliferation ( n-Pr > Me), thus suggesting a hydrophobic pocket in the Y5 receptor. Phenethyl, sulfide, and 119

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Scheme 75

Scheme 76

Scheme 77

commonly cyclized using reductive methods. Cikotiene’s group reported the addition of a secondary amine to alkyne 394, delivering enamine 395 (Scheme 77). Subsequent in situ reduction of the nitro group by hydrogenation induced the expulsion of diethylamine and cyclization toward 396 (a variation of the Leimgruber−Batcho indole synthesis) in excellent yields.151

This reductive cyclization strategy was employed in the search for dopamine D4 ligands. This subtype is associated with schizophrenia and was found to be overexpressed in brain tissue of schizophrenic patients. The antipsychotic agent L-745.870 (402, Scheme 78) is a strong azaindole-based dopamine D4 ligand. As such, several pyrrolo[3,2-d]pyrimidine analogues were synthesized in order to explore the effects of further nitrogen incorporation. A range of 2-amino-6-methylpyrimidi120

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Scheme 78

Scheme 79

sodium dithionite or neat triethyl phosphite were low and depended strongly on the substituents. In a few cases, a SnCl2mediated reduction was employed, affording the heterocycles with excellent yields.153 There is a large body of evidence that adenosine A2B receptors in the smooth muscle tissue of human airways are linked to asthma. Antagonists of this receptor have potential as antiasthma drugs and also play a pivotal role in the control of a variety of physiological functions. The first generation of ligands (404, Scheme 79) is relatively potent, but poorly selective between A2A and A2B. Decoration of the phenyl ring generally improved the affinity for the receptors, with the exception of a fluorine substitution. The 3-thienyl analogue was very active, and electron-donating groups resulted in the best activities. Furthermore, the presence of hydrogen-bond donors, e.g., NH2, gave the best activity levels at the A2B subtype. On

nones were obtained by condensation of guanidinium sulfates 398 and ethyl acetoacetate 397. The formed pyrimidinone was nitrated, and the subsequent treatment with dimethylformamide dimethyl acetal (DMFDMA) yielded compound 399. Annulation was performed by catalytic hydrogenation. Aminomethylation followed by treatment with different arylsubstituted piperazines afforded compounds 401 (Scheme 78). The additional nitrogen of these pyrrolo[3,2-d]pyrimidines was accepted by the receptor, and thus, further substitution of the phenyl ring was pursued to increase D4 affinity. Expansion of the cyclic amines at position 2 was only tolerated up to fivemembered rings. In other words, morpholine gave low binding affinity, whereas excellent values were obtained with a pyrrolidine at position 2.152 Also 1,3-dialkyl-5-nitro-6-styryl uracils 403 were cyclized by treatment with reductive agents, affording fused heterocyles 404−407 (Scheme 79). The yields of the reactions using 121

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Scheme 80

Scheme 81

the other hand, N-methyl derivatives 406 were inactive, thus proving the importance of N7−H hydrogen bonding. Following the reductive cyclization step, regioselective parachlorosulfonylation could be performed and subsequent treatment with different amines led to the formation of sulfonamides 407 in moderate yields (Scheme 79). The benzenesulfonamide group of 407 has several advantages: i.e., metabolic stability, increased water solubility, and bioavailability. Although N-picolinylpiperazines (X = N, R = H) were interesting, the most potent and selective compounds in this series were N-benzylpiperazines (X = CH). Further substitution of the benzyl ring with halogens and cyano groups increased potency for the A2B receptor to nanomolar concentrations. The sulfonamides 407 (X = N, CH, R = H) were dosed orally to rats, showing that the improved physicochemical properties resulted in an increased oral bioavailability.154 Simultaneously, the results of Jacobson et al. on xanthenes,7 introducing an oxyacetamido group in para position of the

aromatic ring, were validated for these compounds (Scheme 80). Several modifications in the phenyl bridge were also made, and halogens were introduced at position 9, using conventional methodologies. The combination of these modifications resulted in more than 400 compounds 408−410 that were tested as adenosine receptor ligands. The data were not easily interpreted, but the general remarks are that amides (Z = NRR′) are more active than esters and acids 409 (Z = OR, OH); halogenation (Hal) of the heterocyclic core is counterproductive; and EWG substitution of the aniline increased potency and/or selectivity (fluoro, bromo, acetyl, cyano). The combination of these features afforded the compounds with formula 410 (Scheme 80), which showed promising activity, good affinity (nanomolar concentrations), and good in vitro selectivity for A2A and A3 as compared to A1.155 Further efforts were made in the synthesis of more specific competitive antagonists for the A2B receptor, and a large series 122

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Scheme 82

Scheme 83

Scheme 84

of piperazin- and piperidinamides 411 (Scheme 81) were tested in vitro.156 The SAR suggested that binding potency may be increased by lipophilic substituents on the piperazinamides. Furthermore, an alkyl chain at N-1 (R1), larger than that at N-3 (R2), could enhance selectivity. Compounds 411a−c were highly potent and selective. However, their lack of water solubility is still a major issue. Therefore, it was necessary to increase the hydrophilicity of these molecules.157

By serendipity, the authors discovered that at higher temperatures the intermediate 412 cyclized in the absence of a reducing agent, affording compound 413 in a one-pot procedure. This scaffold was derivatized with the side-chains used in 408−411 (Schemes 80 and 81). This resulted in the synthesis of derivatives 414a and b (Scheme 82), both being highly potent and selective antagonists (Ki = 1.0 and 2.6 nM, respectively). They show a fivefold higher water solubility than 123

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Scheme 85

Scheme 86

chloro substitution was 10:1 (418, Scheme 84), but these intermediate isomers were not isolated. Treatment of the crude mixture with iron in acetic acid led to the reduction of the nitro group, followed by cyclization, which yielded compounds 419 in moderate yields. These can in turn be further functionalized at the chlorine atom or ester group.159 A similar cyclization strategy was reported using nitriles as the electrophile. Nitropyrimidine 421a is commercially available, whereas 421b was synthesized from 420 by treatment with benzylamine under basic conditions (Scheme 85).160 Compounds 421 were gem-dibrominated (422) in high yield. Monobrominated compounds were difficult to obtain. Surprisingly, however, treatment of the dibromide with an excess of KCN introduced only one cyano group, while both bromines were cleaved. Subsequent treatment with benzyl bromide and tributylamine afforded monoalkylated compounds 423. Additional alkylation could be done using potassium hydroxide, yielding dialkylated compounds 424. When these 5-nitro pyrimidines were catalytically reduced with molecular hydrogen, the in situ-formed amine attacked the cyano group,

their nonhydroxylated counterparts, which makes them good candidates for the development of antiasthmatic agents.155,157 Carotti and co-workers have shown the reductive cyclization strategy to be highly tunable and have achieved the synthesis of N5-hydroxylated pyrrolopyrimidines 415. The typical starting point of the synthesis of these aryl pyrrolopyrimidines is a Henry reaction of 5-nitro-6-methyl uracil 412 with different functionalized aldehydes, affording 6-styryluracils 403 after dehydration in moderate-to-good yields. Reduction of the nitro group to an amine afforded the pyrrolo[3,2-d]pyrimidinones 404 in near quantitative yields as expected. However, when using SnCl2 at room temperature in DMF, N-hydroxy derivatives 415 were obtained. Upon further heating the reduction is completed and 404 is obtained (Scheme 83).158 3.1.5. Reductive Pyrrole Condensation. A one-pot reductive cyclization sequence from readily available starting materials 416 and 417 was reported by Zhang and co-workers (Scheme 84). Weak bases were not suitable for this reaction, and consequently, NaH was employed to achieve a good conversion within hours. The regioselectivity of 2- over 6124

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Scheme 87

Scheme 88

residues in its hinge area, a new series of inhibitors of angiogenesis-related kinases was synthesized based on the pyrrolo[3,2-d]pyrimidine core. As a first synthetic step, 4chloropyrrolo[3,2-d]pyrimidine 436 was methylated using methylmesylate in 80% yield. Next, nucleophilic substitution with aminophenols afforded compounds 437 in ∼60% yield (Scheme 88). Acylation of the introduced anilines with isocyanates, isothiocyanate, or acyl chlorides afforded compounds 438 and 439. In addition, 2-chlorobenzimidazole was used as a urea surrogate, thus obtaining arylated 438e in low yield (9%). Following this general procedure, a large series of compounds 438a−w was synthesized to achieve a complete SAR study. Ureide groups in para position (438 vs 439) significantly improved activity. A 100-fold drop in potency was observed when introducing amides or thioureas to replace the ureas. Using imidazole as an isosteric replacement (438e) also induced a loss of potency. In addition, phenyl groups filled the lipophilic pocket better than methyl (438f) or propyl (438g) groups. Therefore, several phenyl derivatives 438h−w were evaluated. Regarding the phenyl substitution, the meta position was optimal. Small fluorine groups slightly improved affinity, while Me-, Br-, or CF3-containing compounds were 10-fold more potent than the nonsubstituted phenyl derivative. The introduction of CF3 had the additional advantage of inhibiting human umbilical vein endothelial cells (HUVEC) with similar affinity values as for VEGFR2 kinase. Oxygen was preferred as the linker atom (X). Also substitution of the central aromatic

affording compounds 425−429. Nitrogen debenzylation was not observed. In 1964, Imai reported antibacterial and antiprotozoic activity of 2,4-diaminopyrrolo[3,2-d]pyrimidine 425a (R = H).8 Compounds 425b, 426, and 428 also showed interesting in vitro cytostatic activity against different carcinogenic cells at 10 μM. For example, growth of human T-lymphoblastoids CCRFCEM, promyelocytic leukemia, and cervix carcinoma was inhibited by these heterocycles.160 3.1.6. Radical Cyclization. A new, high-yielding route for the synthesis of pyrrolo[3,2-d]pyrimidines proceeded via azaClaisen rearrangement followed by radical cyclization. Starting compound 430 was obtained by N-allylation, and its Claisen rearrangement was catalyzed by boron trifluoride etherate in xylene. Radical cyclization in refluxing DMF using benzoyl peroxide as initiator afforded product 432 in almost quantitative yield (Scheme 86). No reaction took place in the presence of radical scavengers such as hydroquinone.161 3.1.7. Madelung Cyclization. Madelung cyclization was useful for the preparation of several analogues 435 from Nacylaminopyrimidines 434 (Scheme 87). It provided fast access to modified pyrrolo[3,2-d]pyrimidines, although R1 and R2 were very limited and poor yields were obtained due to the high temperatures required (360 °C) for cyclization.145 3.2. Methods for Derivatization of the Scaffold

3.2.1. VEGRF2 Kinase Inhibitors. To take advantage of the previously known lipophilic pocket of VEGRF2 kinase and the potential hydrogen bonding by the Glu, Cys, and Asp 125

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ring was evaluated, affording compounds 438q−t. Halogenation at position 3 was harmful for the potency, while chlorination at position 2 increased the potency twofold in cellular inhibition assays. The 2-F derivative obtained the best inhibition with an IC50 value of 4.4 nM in the HUVEC test, while the 2-methoxy derivative showed less activity. In vivo studies showed good bioavailability in mice; moreover, using the compound in the xenograft mouse model with human prostatic cancer proved to be effective. However, improving solubility and adding fibroblast growth factor receptor (FGFR) kinase inhibition (to avoid development of resistance during long-term treatment) are necessary. X-ray analysis of 438t (R = 2-F) bonded to the enzyme confirmed that the N-1 of the pyrimidine forms a hydrogen bond with the main chain NH of Cys. The urea moiety binds through two pseudo-hydrogen-bonding interactions with Glu (NH) and Asp (CO). The external phenyl occupies the hydrophobic pocket in the DFG-out conformation of the enzyme. This cocrystal also suggested sufficient space for new substituents at both the terminal phenyl and the pyrrole. Also, replacing the phenyl group with polar heterocycles could introduce interactions with different residues of the kinases. A first modification of R5 in 438u−w was performed using different alkylating agents, such as halides or tosylates. The synthesis of 6-substituted analogues required a different approach, as discussed in section 3.1.2 (see Schemes 75 and 89).

Scheme 90

3.2.2. Immucillins. The most successful pyrrolo[3,2d]pyrimidine derivatives nowadays are the modified nucleosides called immucillins. Immucillin-H (12, Scheme 91) is an extremely potent inhibitor (picoM) of purine nucleoside phosphorylase (PNP) and was developed as an inosine isostere by Schramm. It is currently in phase II of clinical trials. Immucillin-H is an analogue of the ribooxacarbenium ion-like transition state of PNP (Scheme 91).164 PNP catalyzes the degradation of deoxyguanosine (dGuo) to the free base. When dGuo is not cleaved, it is converted to 2'-deoxyguanosine 5'triphosphate (dGTP) by deoxycytidine kinase (dCK), causing intracellular dGTP accumulation that provokes allosteric inhibition of the ribonucleotide diphosphate reductase (RDR) enzyme. As a result, deoxynucleosides are not produced, DNA synthesis is stopped, and apoptosis is selectively activated in malignant and activated selective T-cells. Aberrant T lymphocyte activity is involved in graft-versus-host diseases, organ allograft rejection, autoimmune diseases, leukemia, etc.165 X-ray crystallography revealed a network of many hydrogen bonds (at least six) between the inhibitor and the enzyme. Most of the modifications were unsuccessful. Modified immucillins showed that 3′- and 5′-hydroxy groups are important for activity and that NH methylation or sulfur substitution in the deazapurine moiety resulted in a >100-fold loss of activity. The N-linked methylene-bridge-containing analogue (similar to DADMe-Imm H) was found to be equipotent to Imm-H.166 Designed for the bovine PNP enzyme, Imm-H binds less tightly to human PNP, around ninefold less. Human PNP has a more dissociated transition state, with a fully developed ion, typical of SN1 reactions, and a longer distance between base, sugar, and phosphate (Scheme 91). Thus, DADMe-ImmucillinH 443 was synthesized, affording a second generation of immucillins. Although the hydrogen bonds of the 2′-hydroxyl are missing, the methylene bridge permits a closer ion pair with the phosphate leaving group, compensating for the lost binding energy. Currently, DADMe-Imm-H is in Phase I of the clinical trials. On a side note, it showed similar activity against Plasmodium falciparum, the protozoan parasite that causes malaria.167 From the wide variety of known Imm-H derivatives, DADMe-Imm-G 444 (Scheme 92) is eight times more active than Imm-H. However, the synthesis of the pyrrolidine starting from D-xylose takes 13 steps. Simpler, more readily available analogues would increase the potential for drug development. A straightforward synthesis starting from nucleobases 445 and 448 using intermolecular Pictet−Spengler reactions, or Vilsmeier−Haeck formylation followed by reductive amination,

Scheme 89

The introduction of large substituents at the 5- and 6positions was tolerated but did not improve the compounds’ performance. Those bearing a terminal OH at position 5 (438u,w) were single-digit nM inhibitors of VEGFR2, approximately equipotent to 438t, but only a modest improvement in FGFR1 binding was measured. Compounds 389, substituted at position 6, were twofold to fourfold less potent than 438t against VEGFR2 and inactive against FGFR1. Later, the ureum-linked benzene ring was replaced by different heterocycles, as shown in Scheme 90. Trifluoromethylpyridines 440 were potent inhibitors of VEGFR2, comparable to the phenyl derivative. tert-Butylpyrazole and isoxazole substitution gave a slight loss in VEGFR2 activity, while FGFR1 was boosted to values of 200−900 nM. Also 438q was further expanded upon by the introduction of substituents at positions 4 (R6) and 5 (R7, 441, Scheme 90). Methoxy, morpholine, piperazine, and piperidine substitution was accepted by VEGFR2 at both positions. More importantly, it was found that the N-methyl piperazinylmethyl moiety as R6 (441d) delivered a potent dual inhibitor of these kinases (IC50 = 9.3 and 14 nM). A cell assay with HUVEC showed strong inhibitory activity, and the piperazine group led to a great improvement of water solubility.147,162,163 126

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Scheme 91

Scheme 92

was reported in low-to-moderate yields (Scheme 92). Some of the simplified cyclic analogues, 446a and 446c, were equipotent to Imm-H, and the acyclic 447c [R3 = (CH2)2OH] was twofold more potent in vitro. Analogue 446c was 1 order of magnitude less active than Imm-H in T cell lines.168 Another simplification was done by introducing easily prepared hydroxyl azetidines instead of the N-ribosyl core, but the inhibitory potencies of these compounds were in the nM concentration range, which is >200-fold less potent than DADME-Imm-H.169

DADMe-Imm-H was also subjected to azacarbohydrate ring opening, leading to a third generation of immucillins. Small changes in the chain gave large differences in binding affinity. Several derivatives displayed only nanomolar activities. Nonetheless, DATMe-Imm-H 449 (Scheme 93), which has an opened equivalent of the azaribose present in Imm-H, showed a picomolar activity level in human PNP. It was suggested that flexibility of the chain allows for better positioning of the hydroxyl groups in the catalytic site. As an added advantage, 127

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Alkaline hydrolysis of the ester of 461 furnished acids 462 in good yields (Scheme 96). Compounds 462 were transformed to either compounds 463 by decarboxylation in concentrated HCl or amides 464 in the presence of BtOH, HBTU, and an amine. Yields were variable. Esters 461 were also converted to the corresponding aldehydes, followed by Wittig reaction and reduction of the obtained α,β-unsaturated ester toward 465. Reduction of the ester functionality of 461 followed by alkylation with propanol delivers ethers 466 in low yields (Scheme 96). Most of the final compounds were tested for Hsp90 inhibition. Only amides 464 showed interesting activity on the condition that they were substituted with alkyl- (R2) and 3,4-methylenedioxybenzyl (R) groups (IC50 between 8 and 41 μM).175 Heat shock protein 90 (Hsp90) is an ATPase and belongs to the family of molecular chaperones that regulates noncovalent folding or unfolding and degradation of proteins. Chaperones are key regulators in cellular growth, and their pharmacological blockage may have an effect in the treatment of malignancy. Adding to the druggability, the ATP-binding domain of Hsp90 is unique when compared to other kinases. Flat (hetero)polycondensed aromatics intercalate with DNA, bonding through stacking, charge-transfer interactions, electrostatic forces, and hydrogen bonding. They have antiproliferative properties and can be used as anticancer drugs. Glycine esters 467 and their derivatives were condensed with carbon disulfide and were alkylated to reach the N-[bis(methylthio)methylene]amino moiety (BMMA) 468 with excellent yields. These BMMAs were treated with pyrrole 469 in hot acetic acid, producing the imidazo[1,2-c]pyrrolo[3,4-e]pyrimidinones 470 in one step, albeit in low yields (Scheme 97). Some of these compounds gave moderate antiproliferative activity (IC50 ≈ 30 μM) in LoVo cell lines.176,177

Scheme 93

Imm-H has four asymmetric carbons whereas the second and third generations have only two. A final simplification was obtained in the fourth generation, represented by achiral SerMe-Imm-H 450 (Scheme 93). By attaching serinol the synthetic complexity of the molecule was reduced and a small increase in activity was obtained.170−173

4. PYRROLO[3,4-D]PYRIMIDINE The final isomer has been investigated to a lesser extent. Again, condensation of a pyrimidine ring onto an aptly substituted pyrrole 452 is one of the main approaches. However, only dithiocarbonimidates 453 and formamidine 454 have been used as the one-carbon synthons. Also the condensation of a pyrrole ring onto an existing pyrimidine has only limited examples using the Van Leusen pyrrole synthesis (455 and 456) or the condensation of halomethyl pyrimidine carbaldehydes 457 with primary amines (Scheme 94). This is remarkable, given the numerous possibilities for the synthesis of these iso-condensed systems.174

4.2. Van Leusen Pyrrole Synthesis

Construction of the pyrrole ring through the Van Leusen reaction allowed the straightforward synthesis of pyrrolo[3,4d]pyrimidine-2,4-diones. The starting material was uracil 471, which was dibenzylated to afford 472 as the major compound. Treatment of 472 with 3 equiv of NaH and 1.5 equiv of tosylmethylisocyanide (TosMIC) generated the target heterocycle 473 in excellent yield. Catalytic hydrogenation using Pd on carbon and ammonium formate afforded core structure 474 in moderate yield (Scheme 98).178 Modification of the N-alkyl groups led to a potent thymidine phosphorylase (TP, involved in tumor-dependent angiogenesis) inhibitor 476 (Scheme 98). Its isomer 480 was obtained in an analogous manner, using BOM-diprotected uracil 477, for which TosMIC-induced ring

4.1. Pyrimidine Condensation

Substituted pyrrole 460 was obtained in good yields by mixing ethoxymethylidenemalononitrile 368 and diethyl 2-aminomalonate 459 in basic medium, followed by N-alkylation with benzyl chlorides (Scheme 95). Pyrrole 460 was efficiently converted to deazapurines 461 by condensation with formamidine.175 Scheme 94

128

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Scheme 95

Scheme 96

Scheme 97

closure was achieved in good yields. Subsequent pyrrole Nalkylation provided heterocycle 478 in moderate yield along with dimer 479 as a byproduct. The dimer was hydrogenated to form 481, while bromide 478 underwent Arbuzov reaction and deprotection, providing the acyclic nucleotide 480 (Scheme 99). In the inhibition tests using E. coli TP, compounds 476 and 480 were comparable to the reference compounds (IC50 ≈ 10−20 μM). In human TP assays they are less potent, and only compound 476 was active in both TP from placenta and TP from cell line V79. Unfortunately, no antitumor activity was found in the cancer cell lines evaluated.179

keto-6-bromomethyluracils 483 reacted with substituted anilines and yielded functionalized pyrrolo[3,4-d]pyrimidines 484, 488, and 490, which were further annulated. Treatment of 483 with ortho-diaminobenzene afforded compounds 484 in excellent yields. Heating these amines in POCl3 in the presence of carboxylic acids gave pyrazine tetracycles 485. Diazotation with NaNO2 in AcOH led to the formation of triazine 486 in excellent yields, while a treatment with a furaldehyde under acidic conditions resulted in the isolation of dihydropyrazine 487. The oxo-analogue 489 of this last compound could be obtained through an analogous sequence, by the use of a hydroxylated aniline in the pyrrolopyrimidine synthesis. Finally, reaction of the bromomethyluracil 482 with anthranilic acid or its esters afforded compounds 490. Intramolecular acylation in POCl3 of the acids afforded pyrrolinones 491 in moderate yields (Scheme 100).180

4.3. Pyrrole Condensation

An alternate approach to the pyrrole synthesis is the condensation of primary amines with alpha halomethyl pyrimidine carbaldehydes. Available from methyluracil 482, 5129

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Scheme 98

Scheme 99

Compound 487 was originally the most active cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor of the series 485−487. CFTR inhibition is desirable in the treatment of secretory diarrheas and polycystic kidney disease.181 Kidney organ culture models of polycystic kidney disease (PKD) showed a prevention of expansion and a reduction of the size of cysts upon administration of 487.182 SAR analysis showed that 5-methylfuran is more active than furan, thiophene, or phenyl and that N-heterocycles were inactive. It was shown that the NH of the dihydropyrazine core is also necessary, because a total loss of activity was observed when the compound was aromatized with KMnO4. To avoid in vivo aromatization and consequently loss of activity, different N-alkylations and the use of nitrosamines were evaluated, but the potency decreased significantly. Therefore, it was decided to move to the oxygen analogues, which are unable to undergo oxidation but are still able to form hydrogen bonds (Scheme 100). Here, the authors observed that a bromine substituent on the furan ring performs better than a methyl group. To increase water solubility, a carboxylic acid group was introduced, which is deprotonated at physiological pH. All these variations resulted in compound 489, the most active and stable in vitro and ex vivo hit, a potential candidate for PKD.183

5. CONCLUSION In conclusion, it can be stated that the different isomers of pyrrolopyrimidines have been investigated in a broad range of medicinal applications. As a result, a remarkable number of patents, research papers, and reviews were published in this field. Two important features account for the pharmacological importance of this scaffold. Its resemblance to natural nucleosides allows it to interact with different enzymes involved in biological nucleoside processes such as de novo nucleotide synthesis and DNA/RNA replication. This has resulted in many antiviral, anticancer, antibacterial, and antiprotozoal analogues. Next to that, fluorescent nucleosides have found application in fluorescent DNA labeling. Second, the presence and relative position of the different heteroatoms in the rigid pyrrolopyrimidine scaffold allows for an efficient interaction with polar amino acid residues in receptors and enzymes. A wide variety of receptors and enzymes have been discussed in this work, and the affinity and selectivity for the biological targets is mainly determined by the substitution pattern of the scaffold. In general, kinases, folate receptors, and G-coupled protein receptors have been extensively targeted in a continuous effort to fight cancer and mental diseases more efficiently. Pyrrolo[2,3-d]pyrimidines have a broad range of biological applications and display antibacterial, antiviral, anticancer, anti-inflammatory, and antihyperglycemic activities. As the shape of the 7-deazapurine resembles that of purines 130

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Scheme 100

very closely, they are used as substitutes for the canonical constituents of DNA and RNA and are also employed in nucleic acid sequencing. Pyrrolo[3,2-d]pyrimidines are isoelectronic to purine and have structure−activity relationships similar to xanthines, although their diminished hydrogen bonding induces altered pharmacokinetic properties. Their main applications are related to adenosine receptors. Pyrrolo[3,4-d]pyrimidine is an emergent isomer that has been discovered as an angiogenesis inhibitor and cystic fibrosis transmembrane conductance regulator. The pharmacological importance of the pyrrolopyrimidine scaffold has been demonstrated by several new pyrrolopyrimidine-based FDAapproved drugs that have appeared on the market, such as pemetrexed, ruxolitinib, and tofacitinib. Others have reached late clinical stages (Immucillin H). It should be noted that, due to the large variety of biological activities within this product class, the possibility of off-target interactions is likely. These off-target effects have not been

investigated or reported in all instances, and an increased awareness thereof will be crucial for the successful development of new pyrrolopyrimidine-based drugs. Although the basic synthetic strategies toward the pyrrolopyrimidine isomers and subsequent decoration of these scaffolds have been described since the early 1960s, new synthetic entries have appeared recently. These new entries have improved the access to these interesting molecules, improving yield, atom economy, and substrate scope; they have helped to develop new decoration patterns. While these new synthetic methodologies can be very important to fully exploit the potential of this scaffold in medicinal chemistry campaigns, the traditional approaches remain very popular. Condensing an aptly substituted pyrrole with one-carbon pyrimidine building blocks is by far the most used method, and while it does not always provide the best yields, the method is robust and reliable. 131

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AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Author Contributions

L.D.C. and T.S.A.H. have contributed equally. Notes

The authors declare no competing financial interest. Biographies

Dr. Daniel Garcia obtained his degree in chemistry from the University of Alicante, where he also obtained his Ph.D. degree working with Prof. M. Yus. He then did postdoctoral work with Prof. Stevens at Ghent University in the period 2010−2012 on the synthesis of new heterocyclic scaffolds for medicinal applications. He later joined Villapharma Research S.L. and is currently working at Medalchemy in Spain.

Ir. Laurens M. De Coen was born in Ghent, Belgium (1987), and studied Chemistry and Biotechnology at Ghent University (Belgium). He carried out his Master’s thesis research on zingerone derivatives and related chalcones as anticancer compounds under the supervision of Prof. Dr. Ir. Christian Stevens in 2011. Subsequently, he joined a Ph.D. project on medicinal scaffolds with Prof. Stevens as promoter. His research interests include heterocyclic chemistrymainly furans, thiophenes, pyrroles, and oxazoleswith medicinal relevance.

Prof. Dr. Ir. Christian V. Stevens (1965) is full professor at the Department of Sustainable Organic Chemistry and Technology at the Faculty of Bioscience Engineering (Ghent University, Belgium). He graduated in 1988 and obtained a Ph.D. in 1992 working with Prof. N. De Kimpe at Ghent University. He then performed post doctoral work at the University of Florida guided by Prof. Alan Katritzky in 1992− 1993 as a NATO research fellow. In 2000, he became associate professor, and he became full professor in 2008. C. Stevens has published over 220 international peer reviewed papers and 14 patents and received several prizes. His research interest focuses on synthetic heterocyclic chemistry for agrochemical and medicinal applications, on chemical modification of renewable resources, and on the use of flow chemistry to scale up organic reactions that are difficult to scale up in batch.

Dr. Ir. Thomas Heugebaert (born 1984) obtained his degree in Bioscience Engineering in 2007 from Ghent University, Ghent, Belgium. There, he joined the Department of Sustainable Organic Chemistry and Technology, research group SynBioc, under the guidance of Prof. Christian Stevens. He obtained his Ph.D. in 2012, studying gold catalysis and its application in the synthesis of biologically active organic molecules, including plant hormones, azaheterocyclic analgesics, and five-membered heteroaromatic compounds. His current postdoctoral research focuses on the development of microreactor technology, improving its efficiency for gas/liquid interface photochemistry. During his postdoctoral stay at Graz University, Austria, in 2014, under the guidance of Prof. Oliver Kappe, he studied the efficient application of continuous flow photochemistry, in the field of clean oxidation technology and renewable chemicals.

ACKNOWLEDGMENTS Financial support for this research from the Research Foundation Flanders (FWO Vlaanderen, T.S.A.H.), the UGent Special Research Fund (UGent BOF, L.D.C), and the Agency for Innovation by Science and Technology (IWT/ 100014/SBO, D.G.) is gratefully acknowledged. ABBREVIATIONS Acac acetylacetonate AChE acetylcholinesterase AD Alzheimer’s disease 132

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JAK2 JNK l mCPBA MCR MDR Mes MIC MPC MRP1 MS Ms MTX MW NAE NBS NIS NMM NMP NPY5 Ns NSCLC o.n PCC PCFT PD PEG PG Pgp Piv PKD PMP PNP PPTS PPz PTR1 pTSA Py RDR RFC RON2 r.t RTK SEM TBAF TbPTR1 TDA-1 TEA Tf TFE TFA Th2 TMS TosMIC TP TPSA Tr Ts TS VZV

AIBN AK AKI AMA1 AR ATase aq BINAP BMMA Boc BOM BOP

azobis(isobutyronitrile) adenosine kinase AK inhibitor apical membrane antigen 1 adrenergic receptors O6-alkylguanine-DNA alkyltransferase aqueous 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl N-[bis(methylthio)methylene]amino t-butoxycarbonyl benzyloxymethyl (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate bpy bipyridyl BuChE butyrylcholinesterase BSA bis(trimethylsilyl)acetamide cat catalytic CFTR cystic fibrosis transmembrane conductance regulator CHO Chinese hamster ovary CNS central nervous system CRF corticotropin-releasing factor CRLs Cullin-RING ligases Cy cyclohexyl DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane dCK deoxycytidine kinase DCM dichloromethane DEAD diethyl azodicarboxylate DENV Dengue virus dGUO deoxyguanosine DHFR dihydrofolate reductase DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMA dimethyl acetamide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMFDMA dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DPP-4 dipeptidyl peptidase IV DTS DNA-templated organic synthesis EDC 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide EDG electron-donating group equiv molar equivalents EWG electron-withdrawing group FAK focal adhesion kinase FGFR fibroblast growth factor receptor FRs folate receptors g gaseous GARFT glycinamide ribonucleotide formyltransferase GPCRs G protein-coupled receptors HAT human African trypanosomiasis, sleeping sickness HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBV hepatitis B virus HCV hepatitis C virus hH4R human histamine 4 receptor HIV human immunodeficiency virus hPCFT human proton-coupled folate transporter HSP90 heat shock protein 90 HSV herpes simplex virus HUVEC human umbilical vein endothelial cells 133

Janus kinase 2 Jun N-terminal kinase liquid meta-chloroperbenzoic acid multicomponent reaction multidrug-resistant mesityl minimal inhibitory concentration minimum protozoicidal concentration multidrug resistance protein 1 molecular sieves methanesulfonyl methotrexate microwave NEDD8-activating enzyme N-bromosuccinimide N-iodosuccinimide N-methylmorpholine N-methylpyrrolidinone neuropeptide Y5 nosyl non-small cell lung cancer overnight pyridinium chlorochromate proton-coupled folate transporter Parkinson’s disease polyethylene glycol protective group P-glycoprotein pivaloyl polycystic kidney disease para-methoxyphenyl purine nucleoside phosphorylase pyridinium p-toluenesulfonate phenylpiperazine pteridine reductase 1 p-toluenesulfonic acid pyridine ribonucleotide diphosphate reductase reduced folate carrier rhoptry neck protein 2 room temperature related tyrosine kinase [2-(rrimethylsilyl)ethoxy]methyl tetrabutyl ammonium fluoride PTR1 from Trypanosoma brucei tris[2-(2-methoxyethoxy)ethyl]amine triethylamine trifluoromethanesulfonyl trifluoroethanol trifluoroacetic acid T helper cells type 2 trimethylsilyl toluenesulfonylmethyl isocyanide thymidine phosphorylase total polar surface area trityl p-toluenesulfonyl thymidylate synthase varicella zoster virus)

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Chemical Reviews

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