(Bio)isosteres of ortho- and meta-substituted benzenes

Abstract

Saturated bioisosteres of substituted benzenes offer opportunities to fine-tune the properties of drug candidates in development. Bioisosteres of para-benzenes, such as those based on bicyclo[1.1.1]pentane, are now very common and can be used to increase aqueous solubility and improve metabolic stability, among other benefits. Bioisosteres of ortho- and meta-benzenes were for a long time severely underdeveloped by comparison. This has begun to change in recent years, with a number of potential systems being reported that can act as bioisosteres for these important fragments. In this review, we will discuss these recent developments, summarizing the synthetic approaches to the different bioisosteres as well as the impact they have on the physiochemical and biological properties of pharmaceuticals and agrochemicals.

Keywords: bioisosteres; drug discovery; meta-benzene; ortho-benzene.

Figure 1

Scaffolds commonly reported as bioisosteric replacements of para-substituted benzene and examples patented by Merck [19], AbbVie [20] and Bristol-Myers Squibb [16].

Figure 2

1,2-BCPs as isosteres for ortho-and meta-substituted benzenes: comparison of reported exit vector parameters [–27].

Scheme 1

1,2-Disubstituted bicyclo[1.1.1]pentanes as isosteres of ortho-substituted benzenes. A: Baran, Collins and co-workers’ synthesis of [1.1.1]propellane 3a and transformation to BCP (±)-4 [26]. B: Reactions of BCP (±)-4 to differently-substituted BCPs [26]. C: Synthesis of 1-dialkylamino-1,2-BCPs by Bennett and co-workers [29]. D: Lebold, Sarpong and co-workers’ synthesis of 1,2-disubstituted BCPs [32]. DB = Dibenzo, TTMSS = tris(trimethylsilyl)silane, NHPI = N-hydroxyphthalimide, DPPA = diphenylphosphoryl azide, Levin’s reagent = N-(benzyloxy)-1-[4-(trifluoromethyl)phenyl]formamido 2,2-dimethylpropanoate.

Scheme 2

Synthesis of 1,2-BCPs from BCP 15 by bridge C–H bromination as reported by MacMillan and co-workers [33]. DBN = 1,5-Diazabicyclo[4.3.0]non-5-ene.

Figure 3

Comparative physicochemical data of telmisartan, lomitapide and their BCP isosteres [26,33]. Shake flask distribution coefficient (SF logD), kinetic aqueous solubility (KS), Ralph Russ canine kidney (RRCK), human hepatocyte stability (HHEP). ^aReported by Baran, Collins and co-workers, ^bReported by MacMillan and co-workers.

Figure 4

1,2-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes: Exit vector parameters of telmisartan and 1,2-BCH (+)-23 obtained through X-ray crystallography reported by Walker and co-workers [34].

Scheme 3

Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via alkene insertion into bicyclo[1.1.0]butanes. A: Brown and co-workers’ synthesis and representative substrate scope of 1,2-disubstituted BCHs [38]. B: Brown and co-workers’ synthesis of bifunctional 1,2-BCHs [38]. C: Procter and co-workers’ synthesis of 1,2-disubstituted BCHs [35]. D: Procter and co-workers’ derivatization of BCHs [35]. 2,2’-OMeTX = 2,7-dimethoxythioxanthone, cat = catechol, pin = pinacol, NHPI = N-hydroxyphthalimide, DPPA = diphenylphosphoryl azide, mCPBA = meta-chloroperbenzoic acid, TFA = trifluoroacetic acid.

Scheme 4

Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via intramolecular crossed [2 + 2] cycloaddition. A: Fessard, Salomé and co-workers’ synthesis of 1,2-BCHs as precursors for ortho-substituted benzene isosteres [40]. B: Fessard, Salomé and co-workers’ derivatization of 1,2-BCHs [40]. C: Mykhailiuk and co-workers’ synthesis of 1,2-BCHs as ortho-substituted benzene isosteres [36]. TBS = tert-Butyldimethylsilyl, ITX = 2-isopropylthioxanthone, DMP = Dess–Martin periodinane, DPPA = diphenylphosphoryl azide.

Figure 5

Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,2-BCH bioisosteres [36]. Shake flask distribution coefficient (SF logD), calculated partition coefficient (clogP), kinetic solubility in saline (KS), intrinsic clearance in human liver microsomes (CL_int), metabolic decomposition half-time (t_1/2).

Figure 6

Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-55, boscalid and its bioisostere 1,5-BCH (±)-56 against Aspergillus niger in dependence on the concentration of the fungicide [36].

Figure 7

1,5-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-substituted benzenes. Comparison of exit vector parameters for ortho-benzene (valsartan) and 1,5-BCH isosteres (57a, 57b) obtained from X-ray structures as reported by Mykhailiuk and co-workers [42].

Scheme 5

Synthesis of 1,5-disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes via intramolecular [2 + 2] cycloaddition A: Reaction sequence developed by Mykhailiuk and co-workers for the synthesis of 1,5-BCHs and selected examples of the reported substrate scope [42]. B: Transformations of 1,5-BCHs to bifunctional scaffolds reported by Mykhailiuk and co-workers [42]. C: Application of the Mykhailiuk and co-workers’ synthesis for the synthesis of a fluxapyroxad bioisostere [42]. D: Yoo and co-workers’ synthesis of 1,5-BCHs [43].

Figure 8

Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,5-BCH bioisosteres [45]. Shake flask distribution coefficient (SF logD), calculated partition coefficient (clogP), kinetic solubility in saline (KS), intrinsic clearance in human liver microsomes (CL_int).

Figure 9

Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-64, boscalid and its bioisostere 1,5-BCH (±)-71 against Fusarium oxysporum in dependence on the concentration of the fungicide [45].

Figure 10

1,5-Disubstituted 3-oxabicylco[2.1.1]hexanes as isosteres for ortho-benzenes: Comparison of exit vector parameters for valsartan and 3-oxa-1,5-BCH (±)-72a and 1,5-BCH (±)-57a obtained from X-ray crystallography as reported by Mykhailiuk and co-workers [42,45].

Scheme 6

Synthesis of 1,5-disubstituted 3-oxabicyclo[2.1.1]hexanes as isosteres for ortho-benzenes via intramolecular crossed cycloaddition. A: Mykhailiuk and co-workers’ synthesis and representative substrate scope of 3-oxa-1,5-BCHs [45]. B: Mykhailiuk and co-workers’ synthesis of fluxapyroxad and boscalid bioisosteres as exemplary 3-oxa-1,5-BCH derivatizations [45].

Figure 11

Comparison of physicochemical data of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisosteres (±)-75 and (±)-76 as reported by Mykhailiuk and co-workers [45]. Shake flask distribution coefficient (SF logD), calculated partition coefficient (clogP), kinetic aqueous solubility (KS), intrinsic clearance rate in human liver microsomes (CL_int).

Figure 12

Antifungal activity of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisosteres (±)-75 and (±)-76 against Fusarium oxysporum [45].

Figure 13

1,2-Disubstituted bicyclo[3.1.1]heptanes as isosteres of ortho-benzenes. Schematic representation of isosteric replacement of ortho-benzene with 1,2-BCHeps.

Scheme 7

Synthesis of 1,2-disubstituted bicyclo[3.1.1]heptanes as isosteres for ortho-benzenes via alkene insertion. A: Stephenson and co-workers’ synthesis of 1,2-BCHeps as isosteres for ortho-substituted benzene and selected examples of the reported substrate scope [46]. B: Stephenson and co-workers’ synthesis of drug isosteres as exemplary derivatization reactions of 1,2-BCHeps [46].

Figure 14

1,2-Disubstituted stellanes as ortho-benzene isosteres: Comparison of selected exit vector parameters in ortho-benzene phthalic acid [49] and 1,2-stellane 82 [48].

Scheme 8

Synthesis of 1,2-disubstituted stellanes as isosteres for ortho-benzenes reported by Ryabukhin, Volochnyuk and co-workers [48].

Figure 15

1,2-Disubstituted cubanes as ortho-benzene isosteres: Comparison of substituent distances and angles in ortho-benzene and 1,2-cubane as representative exit vector parameters. ^aReported by Mykhailiuk [14]. ^bReported by MacMillan and co-workers [51].

Scheme 9

Synthesis of 1,2-disubsituted cubanes as isosteres for ortho-benzenes. A: Synthesis of 1,2-cubane developed by MacMillan and co-workers [51]. B: MacMillan and co-workers’ newly developed Cu-catalysed cross coupling reactions of 1,2-cubane [51]. NHPI = N-Hydroxyphthalimide, TCNHPI = N-hydroxytetrachlorophthalimide.

Figure 16

1,3-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector parameters obtained from crystal structures reported by Walker and co-workers [34].

Scheme 10

Synthesis of 1,3-disubstituted bicyclo[2.1.1]hexanes as isosteres for meta-benzenes reported by Walker and co-workers [34].

Figure 17

1,4-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector parameters obtained from crystal structures reported by Walker and co-workers [34].

Scheme 11

Synthesis of 1,4-disubstituted bicyclo[2.1.1}hexanes as isosteres for ortho-benzenes via intramolecular crossed cycloaddition. A: Rigotti and Bach’s synthesis of 1,4-BCHs [55]. B: Rigotti and Bach’s derivatizations of 1,4-BCHs [55]. DPPA = Diphenylphosphoryl azide.

Figure 18

1,4-Disubstituted-2-oxabicyclo[2.1.1]hexanes as meta-benzene isosteres: comparison of selected exit vector parameters [58].

Scheme 12

Synthesis of 1,4-disubstituted 2-oxabicyclo[2.1.1]hexanes as isosteres for meta-benzenes. A: Mykhailiuk and co-workers’ synthesis and representative substrate scope of 2-oxa-1,4-BCHs [–59]. B: Synthesis of multifunctional 2-oxa-1,4-BCHs reported by Mykhailiuk and co-workers [58]. C: Hartwig and co-workers’ synthesis and substrate scope of 2-oxa-1,4-BCHs through C–H functionalisation [57]. ^aAs reported by Grygorenko and co-workers. ^bThe synthesised iodide was unstable and therefore treated with KOAc. ^cTreated with KHF₂ after completion of the reaction. ^dIn situ protection of the alcohol functionality with HBpin. NHPI = N-Hydroxyphthalimide, DPPA = diphenylphosphoryl azide, 2-mphen = 2-methylphenantroline.

Figure 19

Comparative physicochemical data for 2- and 3-oxa-1,4-BCHs and para-substituted benzene equivalents as reported by Mykhailiuk and co-workers [58]. Experimental distribution coefficient (logD), kinetic aqueous solubility (KS) and intrinsic clearance in mouse liver microsomes (CL_int). ^aMeasured at pH 7.4.

Figure 20

1,5-Disubstituted bicyclo[3.1.1]heptanes as isosteres of meta-benzenes: comparison of exit vector parameters [14,27]. ^aReported by Mykhailiuk and co-workers ^bObtained from single-crystal X-ray structures, reported by Anderson and co-workers ^cCalculated on CPCM(THF)-B2PLYP-D3BJ/def2-TZVP level of theory, reported by Anderson and co-workers.

Scheme 13

Synthesis of [3.1.1]propellane as a precursor for 1,5-disubsituted bicyclo[3.1.1]heptanes. A: ^aGassman’s original synthesis of [3.1.1]propellane [61] and ^bUchiyama’s modification thereof [47]. B: Anderson and co-workers’ synthesis of [3.1.1]propellane [27]. DB = Dibenzo.

Scheme 14

Synthesis of iodine-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as isosteres for meta-benzenes. A: Anderson’s and Uchiyama’s access of iodine-substituted 1,5-BCHeps [27,47]. B: Anderson’s and Uchiyama’s derivatization of iodine-substituted BCHeps [27,47]. ^aReported by Anderson and co-workers. ^bReported by Uchiyama and co-workers. ^cEt₃B can also be used as an initiator.

Scheme 15

Synthesis of nitrogen-, chalcogen- and tin-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as isosteres for meta-benzenes. A: Anderson and co-workers’ synthesis of nitrogen-substituted 1,5-BCHeps [27]. B: Anderson and co-workers’ and Uchiyama and co-workers’ synthesis of chalcogen- and tin-substituted 1,5-BCHeps [27,47,60]. ^aReported by Anderson and co-workers. ^bReported by Uchiyama and co-workers. ^cReported by Anderson, Mykhailiuk and co-workers. BTMG = 2-tert-Butyl-1,1,3,3-tetramethylguanidine, TMHD = 2,2,6,6-tetramethyl-3,5-heptanedione.

Figure 21

Comparative physicochemical data of URB597 and 1,5-BCHep isostere 146 [27]. Kinetic aqueous solubility (KS), intrinsic clearance in human liver microsomes (CL_int), half-life in human liver microsomes (t_1/2) and 50% inhibition concentration of CYP2C9 (IC₅₀).

Figure 22

[2]-Ladderanes as isosteres of meta-benzenes: comparison of reported exit vector parameters [63].

Scheme 16

Synthesis of cis-2,6-disubstituted bicyclo[2.2.0]hexanes as isosteres for meta-benzenes. A: Brown and co-workers’ synthesis of trans-[2]-ladderanes 150a and 150b [63]. B: Transformation of trans-[2]-ladderanes into bifunctional cis-[2]-ladderanes 151 and 152 [63]. C: Selected derivatization reactions of cis-[2]-ladderanes [63]. ITX = Isopropylthioxanthone, p-ABSA = 4-acetamidobenzenesulfonyl azide, TCNHPI = N-hydroxytetrachlorophthalimide, DPPA = diphenylphosphoryl azide, DMP = Dess–Martin periodinane.

Figure 23

Comparative physicochemical data of meta-benzene 158 and [2]-ladderane isostere 159 [63]. Partition coefficient (logP), apparent permeability (Papp), equilibrium solubility and intrinsic clearance in rat liver microsomes (CL_int).

Figure 24

1,3-Disubstituted cubanes as isosteres of meta-benzenes: comparison of selected exit vector parameters [14,51]. ^aReported by Mykhailiuk. ^bReported by MacMillan and co-workers.

Scheme 17

Synthesis of 1,3-disubsituted cubanes as isosteres for meta-benzenes. A: MacMillan and co-workers’ de novo synthesis of 1,3-cubanes [51]. B: Cross coupling reactions for derivatisations of 1,3-cubanes [51]. C: Coote and co-workers’ de novo synthesis of 1,3-cubanes [64]. D: Coote and co-workers’ derivatization of 1,3-cubanes [64]. ^aDowex 50W X8 resin was used as the proton source. NHPI = N-Hydroxyphthalimide, TCNHPI = N-hydroxytetrachlorophthalimide, DMP = Dess–Martin periodinane, CDI = carbonyldiimidazole, DPPA = diphenylphosphoryl azide.

Figure 25

Comparative physicochemical data of lumacaftor and its 1,3-cubane bioisostere 183 [51]. Distribution coefficient (logD), intrinsic clearance in human liver microsomes (CL_int), half-maximal rescue concentration (RC50 CFTR).

Figure 26

1,3-Disubstituted cuneanes as isosteres of meta-benzenes: comparison of selected exit vector parameters [–72]. ^aReported by Lam and co-workers. ^bReported by Iwabuchi and co-workers. ^cReported by Stephenson and co-workers. ^dObtained from the crystal structures reported by Lam and co-workers and Stephenson and co-workers.

Scheme 18

Synthesis of 1,3-cuneanes as isosteres of meta-benzene. A: Synthesis of 1,3-cuneanes reported by Lam and co-workers, Stephenson and co-workers and Iwabuchi and co-workers [–72]. B: Synthesis of ketoprofen bioisostere 189 reported by Iwabuchi and co-workers [72]. ^aReported by Lam and co-workers. ^bReported by Stephenson and co-workers. ^cReported by Iwabuchi and co-workers. ^dYield corresponds to the isolated 3:1 mixture of 1,3-cuneane and 2,6-cuneane. HFIP = 1,1,1,3,3,3-Hexafluoro-2-propanol, AZADO⁺ = 2-azaadamantane N-oxyl.

Figure 27

Comparative physicochemical data of sonidegib and its 1,3-cuneane isostere 190 [71]. ^aSolubility was too low to be measured. Partition coefficient (logP), intrinsic clearance in human liver microsomes (CL_int), half-life in human liver microsomes (t_1/2).

Figure 28

Exemplary polysubstituted scaffolds related to disubstituted scaffolds suggested as isosteres of ortho- or meta-benzene.