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A second route (Method B in Scheme 26) involves the reaction of triphosgene with the de-protected terminal amine, providing chloroformamides that lose HC1 to give isocyanates. A urea derivative is formed by adding an anthranilate or an anthranilic acid derivative. Alter-

natively, an activated carbamate can be produced from 4-nitrophenyl chloroformate as the reactive intermediate (Method C in Scheme 26).

In addition, by treatment of the immobilized isocyanate or carbamate with a heterocyclic anthranilate or a heterocyclic anthranilic acid, a variety of other core structures were synthesized, e.g., pyrimidopyrimidinediones, pyridopyrimidinediones, 2,4-pteridinediones, or azolopyrimidinediones. Again, the cyclization occurs in the presence of DBU. Finally, the compounds are released by the addition of dilute TFA. Ala, Val, lie, Met, Phe, Tyr(tBu), Asp(tBu), Glu(tBu), Arg(Mtr), Lys(Boc),Trp(Boc) -derivatized 2,4 quinazolinediones without N'-alkylation were synthesized in this manner. The following alkylating agents were utilized for the preparation of Phe-derivatized quinazolinediones: Mel, BrCH2CH2OCH2CH2 OMe, ClCH2Ph, ICH2(CH2)4Me, 2-BrCH2-naphthalene, N-(BrCH2CH2CH2)-phthalimide, 4-MeOChH4CH2Br, 2-cyano-C6H4CH2Br, BrCH2C002'Bu, and BrCH2CONH2. The HPLC purity of the 10 alkylated heterocycles was reported to be between 75 % and 99 %.

Procedure: Method A

An appropriate N-Fmoc-protected aminoacid resin (100 mg, 0.06 mmol for the Sasrin support-immobilized amines) was deprotected by treatment with 20 % piperidine in DMF for 30 min.The resin was filtered, washed liberally with DMF, MeOH, and DCM, and dried under vacuum. The amine resin was suspended with an appropriate isocyanate or 4-nitro-phenylcarbamate (0.2-0.5 mmol, 3.3-8.3 equiv.) in 10 % (v:v) pyridine/DMF (1-2 mL), and agitated at room temperature until a negative ninhydrine test indicated the absence of a free amine on the solid phase (typically, 0.5-3 h for reactions with isocyanates, or 1-24 h for reactions with p-nitrophenylcarbamate). The resulting urea resin 97 was filtered, washed with DMF, MeOH, and DCM, and dried under vacuum. Immobilized urea derivatives thus obtained were further cyclized into 2,4-quinazolinediones by agitation at 40-80° C (preferably at 50-65° C) with an organic base (such as 2-10 % DBU or tetramethylguani-dine in DMF) or an inorganic base (such as 1-10 % lithium, sodium or cesium carbonate in DMF or NMP) for 2-24 h.The resin 98 (R2= H) was filtered, washed sequentially with liberal amounts of DMF, MeOH, and DCM, and dried under vacuum.The resulting 2,4-quinazolinediones were cleaved from the support with 1-40 %TFA in DCM for 0.5-2 h.The Sasrin resin-immobilized products were typically released from the support with 1 %TFA in DCM (30 min). When necessary, amino acid side chain functionalities were further deprotected with mixtures ofTFA and additives (scavengers: thiols, phenols, or trialkylsilanes), such as 5 % triethylsilane - 40 %TFA in DCM (0.5-4 h, depending on the nature of the protecting groups).The crude products were lyophilized and analyzed by NMR, MS, and HPLC. Alkylation-procedure. Method (a): An appropriate N1-H quinazolinedione resin 98 (R2 = H), prepared as discussed above (~ 100 mg Sasrin support, 0.06 mmol), was agitated with an appropriate alkylating agent (1.2 mmol, 40 equiv.) and an organic base (such as tetram-ethylguanidine, DBU, 1.2 mmol, 40 equiv.) in NMP (1.75 mL) for 10-48 h at 20-70° C (typically 18 h at rt).The resulting resin 98 (R2 * H) was filtered, washed with liberal amounts of DCM, MeOH, and dried under vacuum (rt, 0.5Torr). Cleavage and isolation of the N1-alkylated quinazolinediones 99 was performed as described above for preparations of N1-H quinazolinediones.

Alkylation-procedure. Method (fa): An appropriate N1-H quinazolinedione resin 98 (R2 = H) (~ 100 mg Sasrin support, 0.06 mmol) together with an appropriate alcohol (2.4 mmol, 80

equiv.), a trisubstituted phosphine (such as triphenylphosphine, 0.472 g, 1.8 mmol, 30 equiv.), and a dialkyl diisopropylazodicarboxylate (0.283 mL, 1.8 mmol, 30 equiv.) in 1,4-dioxane (3.6 mL) was agitated at rt for 4-24 h (typically overnight).The resulting resin 98 (R2 * H) was filtered, washed with liberal amounts of DCM, MeOH, and dried under vacuum (rt, 0.5Torr). Cleavage and isolation of the N1-alkylated quinazolinediones 99 was performed as described above for preparations of N1-H quinazolinediones (see Method A).

Procedure: Method B

An appropriate resin (such as an immobilized amino acid reagent, see above. Method A; ~ ~ 100 mg for Sasrin support, 0.06 mmol) was agitated with triphosgene (0.19 mmol, 3.2 equiv.) and an organic base (such as 2,6-lutidine, 0.3 mL) in DCM (1.5 mL) for 0.5-1.5 h (until a negative ninhydrin test indicated the absence of a free amine on solid phase).The resulting isocyanate resin was washed liberally with DCM.Subsequently an appropriate amine (such as methyl anthranilate, 1 mmol, 16.7 equiv.) together with 2,6 lutidine (0.2 mL) in DCM (2 mL) was added.The mixture was agitated at rt until the reaction was completed (typically, 2-8 h). The resin was filtered, washed liberally with DMF, MeOH, and DCM, and dried under vacuum.The resultant immobilized ureas 97 were further converted into fused 2,4-quinazollnediones as described in Method A.

Procedure: Method C

An appropriate amine resin (such as immobilized amino acid reagents, see above. Method A; ~ 100 mg for Sasrin support, 0.06 mmol) was agitated with p-nitrophenyl chloroformate 202 mg (1.0 mmol, 16.7 equiv.) and an organic base (such as 2,6-lutidine, 0.3 mL) in DCM (1.5 mL) for 1-2 h (until a negative ninhydrin test indicated the absence of a free amine on a solid phase). The resulting p-nitrophenylcarbamate resin was filtered, washed with liberal amounts of DCM, and dried under vacuum (rt, 0.5Torr). An appropriate amine (such as methylanthranilate, 1 mmol, 16.7 equiv.) and a solution of an organic base such as 10 % (v:v) pyridine or 2,6-lutidine in DMF (2 mL) was added, and the mixture was agitated at 20-70° C for 8-24 h (typically, this reaction with methyl anthranilates was essentially complete overnight at rt). The resin was filtered, washed with liberal amounts of DMF, MeOH, and DCM, and dried under vacuum.The resulting immobilized ureas 97 were further converted into fused 2,4-quinazolinediones as described in Method A.

3.4.17 Benzopiperazinones

Although benzopiperazinones (l,2,3,4-tetrahydroquinoxalin-2-ones) are structurally related to benzodiazepines, their use in drug discovery is less established. Examples of biological activity of benzopiperazinones include inhibitors of aldose reductase [123], partial agonists of the y-aminobutyric acid (GABA)/benzodiazepine receptor complex [124, 125], and angiotensin II receptor antagonists [126]. In addition, derivatives with antiviral activity associated with HIV have been reported [127,128],

Two very similar routes for the synthesis of the heterocycle have been reported. The quinoxalinones reported in an earlier publication have two diversity points, (N4 and C3) [129], whereas a later publication described a sequence incorporating four diversity points including the amino acid attachment of the template to the support [130]. Focusing here on the latter publication (Scheme 27), 4-fluoro-3-nitrobenzoic acid was loaded onto Wang resin via an ester linkage employing DCC and a catalytic amount of DMAP in dichloromethane or by coupling to bromomethyl Wang resin [131] using Csl in DMF at room temperature (Scheme 27). The subsequent ipso-fluoride displacement [132-135] with amino acid ester hydrochloride salts in the presence of 5 % DIEA/DMF provided polymer-bound 3-nitro-4-aniline ben-zoates 101 after agitation for 24 h. Complete reduction of the nitro group was achieved by treatment with an aqueous 2 M SnCl2 solution in DMF at 80° C.The reaction was performed in deoxygenated solvents to avoid formation of an oxidized byproduct. The resulting anilines cyclized to afford immobilized benzopiperazinones 102 without any trace of precursor material. Upon cleavage with TFA, a considerable amount of racemization was detected by chiral HPLC analysis. It transpired that a further advantage of derivatizing the aniline site (N4 position) consists of a greatly decreased racemization extent during the acid cleavage. Treatment of the benzopiperazinone resin 102 with chloroformâtes and thiochloroformates in the presence of NaHC03 at 80° C under an argon atmosphere provided the N4-derivatized quinoxalinone resin. Further diversity generation at the anilide site was achieved by alkyla-tion using 4-benzyl-2-oxazolidinone and benzyl bromide in anhydrous THF at 60-65 ° C under argon to produce benzopiperazinones with an ee >99 % upon TFA cleavage. For even more variability, different amino acids can be used as linker between the aromatic carboxylic acid unit of the scaffold and the solid-support (not presented in Scheme 27), In that case, the appropriate Fmoc-protected amino acids were attached to the solid support via an ester linkage, and deprotected with 20 % piperidine solution in DMF. Subsequent coupling of 4-fluo-ro-3-nitrobenzoic acid through an amide linkage gave an amino acid-derivatized resin, suitable for further modification. Unfortunately, no examples were reported where all four variable residues are introduced. The yield of the reported examples including C3 and N4 substitution ranges from 34 % to 69 %. Six examples, including the ipso-fluoride displacement, provided the benzopiperazinones in 17 % to 50 % isolated yield.

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