3-(acylamidomethyl)phenylboronic acid derivatives as malarial serine protease inhibitors

Abstract

Representatives of 3-(acetylamidomethyl)phenylboronic acid derivatives with general Formula I show potency to inhibit malarial subtilisin-like serine protease (SUB) in low micromolar to nanomolar concentrations. As such they can be applied as compounds for prevention or treatment of malaria. (I)

Description

[0001] 3-(ACYLAMID0METHYL)PHENYLB0R0NIC ACID DERIVATIVES AS MALARIAL

[0002] SERINE PROTEASE INHIBITORS

[0003] Field of invention

[0004] The present invention relates to medicine, and in particular to the treatment of malarial infections, more particularly to inhibitors of malarial serine proteases. Even more particularly, the invention relates to novel 3-(acetylamidomethyl)phenylboronic acid derivatives and pharmaceutical compositions thereof and their use as inhibitors for subtilisin-like serine proteases (SUB).

[0005] Background of invention

[0006] Widespread resistance to practically all currently used drugs has stimulated the search for antimalarials with novel mechanisms of action (Hyde, J. E. Drug-resistant malaria - an insight. FEBS J. 2007, 274, 4688-4698; Choi, S. R.; Mukherjee, P.; Avery, M. A. The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr. Med. Chem. 2008, 15, 161-171; Wells, T. N.; Alonso, P. L.; Gutteridge, W. E. New medicines to improve control and contribute to the eradication of malaria. Nat. Rev. Drug Discov. 2009, 8, 879-891). Resistance to current anti-malarial agents in malaria-endemic regions continues to spread, indicating that current therapeutic agents will be practically ineffective in the near future.

[0007] A precondition for the development of antimalarial agents is inhibition of the malaria parasite life cycle through a mechanism that differs from the mode of action of currently used therapeutic agents (N. K. Sahu, S. Sahu and D. V. Kohli, Novel Molecular Targets for Antimalarial Drug. Chem. Biol. Drug. Des., 2008, 71, 287-297) This could be achieved by targeting functional malarial proteins involved in the blood stage of the parasite life cycle. Malarial enzymes such as subtilisin-like serine proteases (SUB) have been recognized as promising molecular targets for new drug development (Withers-Martinez, C.; Suarez, C.; Fulle, S ; Kher, S ; Penzo, M ; Ebejer, J -P ; Koussis, K ; Hackett, F ; Jirgensons, A ; Finn, P.; Blackman, M. J. Plasmodium subtilisin-like protease 1 (SUB1): Insights into the activesite structure, specificity and function of a pan-malaria drug target. International Journal for Parasitology 2012, 42, 597-612. Thomas, J. A.; Tan, M.S.Y; Bisson, C ; Borg, A.; Umrekar T. R; Hackett F, Hale V.L., Vizcay-Barrena G, Fleck R.A., Snijders A.P., Saibil H.R., Blackman M.J. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nat. Microbiol. 2018, 3(4), 447-455; SUB1 Lidumniece, E.; Withers-Martinez, C.; Hackett, F.; Collins, C. R.; Perrin, A. J.; Koussis, K.; Bisson, C.; Blackman, M. J.; Jirgensons, A. Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease Proc. Natl. Acad. Sci. U.S.A., 2021, 118, e2022696118).

[0008] Several inhibitors for SUB subtype PfSUBl have been developed (Lidumniece, E.; Withers- Martinez, C.; Hackett, F.; Blackman, M. J.; Jirgensons, A. J. Subtilisin-like Serine Protease 1 (SUB1) as an Emerging Antimalarial Drug Target: Current Achievements in Inhibitor Discovery Med. Chem., 2022, 65, 12535-12545) however, so far, none of them have been advanced to clinical trial.

[0009] Summary of the invention

[0010] In a first aspect, the invention features a method of treating malarial infections in humans or animals, comprising administering to a human or animal in need of a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine protease (SUB).

[0011] In another aspect, the invention features a pharmaceutical composition for treatment of malaria infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).

[0012] In another aspect, the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB), in the manufacture of a medicament for treatment or prevention of malaria infections.

[0013] In another aspect, the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug for use in treating or preventing malaria infections, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).

[0014] In one embodiment the inhibitor of subtilisin-like serine proteases (SUB) is a compound of Formula I, generally referred herein as 3-(acetylamidomethyl)phenylboronic acid derivatives: General formula I wherein:

[0015] R, R1R2, R3are independently is H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-Ci -ealkyl, C2- ealkenyl, Cb-ealkynyl, aryl, biaryl, arylCi -ealkyl, arylC2-ealkenyl, arylC2-ealkynyl, heteroaryl, heteroarylCi -ealkyl, heteroarylC2-ealkenyl, R4O(CH2)n, R4S(CH2)n, R4OC(=O)(CH2)n, R4N(R5)C(=O)(CH2)n,R4N(R5)(CH2)n,

[0016] -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR4,

[0017] -O-L-NH2, -O-L-NHR4, -O-L-N(R4)R5, -L-OR4,-O-L-OR4,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR4,-O-L-OR4,-OCF3, -OCH2CF3, -OCF2CF2H, SR4, SCF3, - wherein: n is an integer selected from 1 to 6;

[0018] L represents -WA-XA-YA-ZA-; or -WA-XA-YA-, or -WA-XA- or -WA- wherein:

[0019] WA- represents a single bond, oxygen, sulfur, -NR3or -CR3R4,

[0020] XArepresents oxygen, sulfur, -NR4or -C(R4)R5,

[0021] YArepresents oxygen, sulfur, -NR4or -C(R4)R5,

[0022] ZArepresents oxygen, sulfur, -NR4or -C(R4)R5; wherein:

[0023] R4and R5are independently H, Ci^alkyl, cycloC3-i2alkyl, cycloC3-i2alkyl-Ci-6alkyl, C2- ealkenyl, C2-ealkynyl, aryl, biaryl, arylCi. ealkyl, arylC2-ealkenyl, arylC2-ealkynyl, heteroaryl, heteroarylCi .galkyl, heteroarylCi-ealkenyl, heteroarylthio, 2,3-dihydro-lH-indenyl, Ci. ealkoxyCi-ealkyl, aryloxyarylCi-salkoxy, Ci-ealkylthio, C4-6alkenylthio, cycloCs-nalkylthio, cycloCs-nalkyl-Ci-ealkylthio, cycloCs-ualkyl-Cs-ealkenylthio, Ci-ealkoxyCi -ealkylthio, Ci- ealkoxyCs -ealkenylthio, arylCs -ealkenylthio, heteroarylCi -ealkylthio, Ci-ealkylsulfonyl, cycloCs-nalkyl-Ci-ealkylsulfonyl, arylCi-ealkylsulfonyl, Ci-ealkylamino, di-Ci-ealkylamino, cycloCs-nalkylamino, Ci-Cealkoxy-cycloCs-Cnalkylamino, cycloCs-nalkyl-Ci -ealkylamino, di-Ci-ealkylaminoCi-ealkyl, Ci-ealkoxy-Cr-ealkylamino, arylamino, arylCi. ealkylamino, N- cycloCs-nalkyl-N-C i -ealkylamino, N-aryl-N-Ci-ealkylamino, N-arylCi-ealkyl-N-Ci- ealkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidine, 4-arylpiperidino, 4- heteroarylpiperidino, morpholino, piperazino, 4-Ci-ealkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, l,3-dihydro-2H-isoindol-2-yl, heteroarylCi -ealkoxy, heteroarylamino, or heteroarylCi-ealkylamino. and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0024] Definitions

[0025] The term “alkyl” refers to a straight or branched hydrocarbon chain, containing the indicated number of carbon atoms. For example, Cl -Cl 2 alkyl indicates that the alkyl group may have from 1 to 12 (inclusive) carbon atoms.

[0026] The term “alkenyl” refers to a straight or branched hydrocarbon chain having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2- butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.

[0027] The term “alkenylene” refers to a divalent alkenyl, e.g., — CH=CH — , — CH=CH2CH2 — or — CH=C=CH — . An alkenyl or alkenylene may be optionally substituted.

[0028] The term “alkynyl” refers to a straight or branched hydrocarbon chain having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3 -hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent. The term “alkynylene” refers to a divalent alkynyl, e g., — C=C — or — C=C — CH2 — . An alkynyl or alkynylene may be optionally substituted.

[0029] The term “aryl” refers to refers to phenyl and naphthyl.

[0030] The term “biaryl” refers to two arylgroups linked with a single bond The term “heteroaryl” refers to an aromatic ring having 1-6 heteroatoms The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of the preferred embodiments and, which are not biologically or otherwise undesirable.

[0031] The term “optical isomers” refers to any stereoisomeric representation of a compound

[0032] The term “hydrates” refers to a crystal of a compound containing any stoichiometry of water The term “solvates” refers to refers to a crystal of a compound containing any stoichiometry of any solvent

[0033] The term “polymorphs” refers any type of crystal formed by a compound

[0034] The term “prodrug” refers to any derivative of a compound that, after intake, is metabolized into a pharmacologically active drug.

[0035] The term “therapeutically effective amount” or “pharmaceutically effective amount refers to amount of a compound provided herein which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease conditions, and the potency of the compound

[0036] Stereochemistry

[0037] Many of the chemical structures shown herein indicate one or more specific stereoisomeric configurations. Similarly, many of the chemical structures shown herein are silent in this respect, and do not indicate any stereoisomeric configuration. Similarly, many of the chemical structures shown herein indicate the specific stereoisomeric configurations at one or more positions, but are silent with respect to one or more other positions. Where a chemical structure herein is silent with respect to the stereoisomeric configuration at a position, that structure is intended to depict all possible stereoisomeric configurations at that position, both individually, as if each possible stereoisomeric configuration was individually recited, and also as a mixture (e.g., a racemic mixture) of stereoisomers.

[0038] Combinations

[0039] Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.

[0040] Description of invention

[0041] When testing the 3-(acetylamidomethyl)phenylboronic acid derivatives for their ability to inhibit SUB we have unexpectedly discovered, that said derivatives exhibit pronounced inhibitory properties toward said serine proteases thus are useful in treatment of malaria. According to this invention, the results from SUB inhibition studies demonstrate that 3- (acetylamidomethyl)phenylboronic acid derivatives are novel class inhibitors of serine proteases. Several example compounds from the present invention display nanomolar inhibitory potency.

[0042] Examples of Specific Embodiments

[0043] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

[0044] The following 3-(acetylamidomethyl)phenylboronic acid 9.1-9.16 were prepared as examples of the current invention:

[0045] General formula I

[0046]

[0047] General Synthesis

[0048] Boronic acid derivatives 9.1-9.16 were synthesized according to the Scheme 1. Coupling of amino acids 1 and 2 gave peptide 3. This was V-deprotected and submitted to / V-modification with carboxylic acid derivatives 4. O-Deprotection gave acid 6 which was coupled with benzylamines 7. The resulting intermediate 8 was subjected to the cleavage of boronic ester and / or side chain modification leading to the products 9.

[0049]

[0050] General scheme 1

[0051] Synthesis of intermediates 3. general method A

[0052] Exemplified by the synthesis of 3.1

[0053] A mixture of H-Ile-OMe HC1 (1) (373 mg, 2.05 mmol, 1.0 equiv.), Boc-Cyclopentyl-Gly-OH (2.1) (500 mg, 2.05 mmol, 1.0 equiv.), HOBt (306 mg, 2.26 mmol, 1.1 equiv.), EDC HC1 (473 mg, 2.47 mmol, 1.2 equiv.) and DIPEA (1.1 mL, 6.36 mmol, 3.0 equiv.) were dissolved in CHCh (30 mL) and stirred overnight at room temperature. The reaction mixture was washed with IM HC1 and brine. Organic phase was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:EtOAc mixture (4: 1-2: 1) to provide the desired product 3.1 as a white solid.

[0054] By a method analogous to method A, the following compounds were obtained: Physiochemical characterization of compounds 3.1. -3.2.

[0055] Synthesis of intermediates 5, general method B

[0056] Exemplified by the synthesis of 5.1

[0057] Starting material 3.1 (500 mg, 1.35 mmol, 1.0 equiv.) was dissolved in CHCh (10 mL) and treated with 4 M HCI in dioxane (1.4 mL, 5.6 mmol, 4 equiv .). After a full conversion of the starting material (UPLC-MS control), the solvent was evaporated and the residue (based on a theoretical yield of a 100 %) was utilized in the coupling reaction. A mixture of residue, quinaldic acid (4.1) (234 mg, 1.35 mmol, 1.0 equiv.), HOBt (200 mg, 1.62 mmol, 1.1 equiv.), EDC HCI (311 mg, 1.62 mmol, 1.2 equiv.) and DIPEA (0.7 mL, 4.05 mmol, 3.0 equiv.) were dissolved in CHCT, (30 mL) and stirred overnight at room temperature. The reaction mixture was washed with 5% KHSO4 and brine. Organic phase was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:EtOAc mixture (2: 1-1 : 1) to provide the desired product 5.1 as a white solid.

[0058] Synthesis of intermediate 5.4., method C

[0059] Starting material 3.2 (792 mg, 2.22 mmol, 1 equiv.) was dissolved in dry CH2CI2 (10 mL) and treated with 4 M HCI in dioxane (2.2 mL, 8.9 mmol, 4 equiv ). After a full conversion of the starting material (UPLC-MS control), the solvent was evaporated and the residue (based on a theoretical yield of a 100 %) was utilized in the acylation reaction. Crude residue was dissolved in dry CH2CI2 (10 mL). To the solution was added DIPEA (0.77 mL, 4.44 mmol, 2 equiv.) and AC2O (0.31 mL, 3.33 mmol, 1.5 equiv.). The reaction mixture was left to stir at room temperature for 4h. Then the mixture was poured into water. The phases were separated and the organic phase was washed with sat. NaHCCh (10 mL) and water (10 mL). The organic phase was dried over anhydrous JSfeSCU, filtered and concentrated under reduced pressure. The product 5.4 was purified via silica gel column chromatography (n- hexane:EtOAc 1:1 to 1 :2).

[0060] By a method analogous to method B or C, the following compounds were obtained:

[0061] Physiochemical characterization of compounds 5.1-5.4.

[0062] Synthesis of intermediates 6. general method D

[0063] Exemplified by the synthesis of 6.1

[0064] Starting material 5.1 (545mg, 1.28 mmol, 1.0 equiv.) was dissolved in THF:H2O (20:1, 21 mL) mixture, then LiOH (307 mg, 12.8 mmol, 10 equiv.) was added and the reaction was stirred at room temperature. When full conversion of starting material was observed, water was added and the reaction mixture was acidified by the addition of 5% KHSO4 solution and the product was extracted with chloroform (3 x). Organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to provide the desired product 6.1. By a method analogous to method D, the following compounds were obtained:

[0065] Physiochemical characterization of compounds 6.1 -6.4

[0066] Synthesis of intermediates 8. general method E Exemplified by the synthesis of 8.1

[0067] A mixture of benzylamine 7.1 (64 mg, 0.18 mmol, 1.0 equiv.), acid 6.1 (75 mg, 0.18 mmol, 1.0 equiv.), HOBt (27 mg, 0.20 mmol, 1.1 equiv.), EDC HC1 (42 mg, 0.22 mmol, 1.2 equiv.) and DIPEA (94 pL, 0.54 mmol, 3.0 equiv.) were dissolved in CHCF (7 mL) and stirred overnight at room temperature. The reaction mixture was washed with or 5% KHSO4 and brine. Organic phase was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-5% MeOH in EtOAc mixture to provide the desired product 8.1.

[0068] Synthesis of intermediates 8, general method F Exemplified by the synthesis of 8.9 Under argon atmosphere, an acid 6.1. (80 mg, 0.19 mmol, 1 equiv.) was mixed with benzylamine 7.9 (110 mg, 0.30 mmol, 1.5 equiv.) in dry CHCh at room temperature. The white suspension was cooled to -15°C and then A-methylmorpholine (70 pl, 0.64 mmol, 3.4 equiv.) was added while the internal temperature was kept below -10 °C. T3P reagent (240 pl, 0.40 mmol, 2 equiv.) was added at the same temperature. The reaction mixture was stirred allowed to warm up from -10 to -15°C to 0 °C and stirred for 6h at 0 °C. It was then diluted with CHCh and equal amount of 5% KHSO4 and extracted. Organic phase was extracted once more with 5% KHSO4. Combined water phase was back-extracted with CHCh. Organic phase was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. Crude mixture was purified by flash chromatography on silica gel eluting with 0 - 5% MeOH in EtOAc to provide the desired compound.

[0069] Synthesis of intermediates 8, general method G Exemplified by the synthesis of 8.14

[0070] HATU, DIPEA

[0071] DMF, -20 °C to 0 °C

[0072] 6.1. 7.14 8.14

[0073] Under argon atmosphere an acid 6.1. (254 mg, 0.62 mmol, 1 equiv.) was mixed with benzylamine 7.14 (224 mg, 0.61 mmol, 1 equiv.) were dissolved in dry DMF. The mixture was cooled to -20 °C (ice / salt / water) and DIPEA (427 pl, 1.23 mmol, 4 equiv.) were added. Finally, HATU (470 mg, 1.23 mmol, 2 equiv.) were added in one portion and the mixture was stirred at the same temperature for 30 min - 1 h. After completion (monitored via UPLC) the reaction mixture was washed with IM KHSO4 and the phases were separated. The aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (eluent 10: 1 to 2: 1).

[0074] By a method analogous to method E, F or Gthe following compounds were obtained:

[0075]

[0076] Physiochemical characterization of compounds 8.1-8.14

[0077] Synthesis of intermediate 8.15

[0078] Sulfonamide 8.14 (98 mg, 0.12 mmol, 1 equiv.) was dissolved in dry CHaCh Q mL). To the solution was added DIPEA (0.056 mL, 0.32 mmol, 2.5 equiv.) and AC2O (0.024 mL, 0.26 mmol, 2 equiv ) and the mixture was left to stir overnight Afterwards the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (PE:EtOAc 4: 1 to 1 :1). Yield of 8.15: 46 mg, 45%.

[0079] 1HNMR (400 MHz, Methanol-^) 5 8.46 (d, J= 8.6 Hz, 1H), 8.24 - 8.22 (m, 1H), 8.18 - 8.13 (m, 2H), 8.07 - 8.05 (m, 1H), 8.02 - 7.97 (m, 2H), 7.86 - 7.80 (m, 1H), 7.72 - 7.65 (m, 1H), 4.59 - 4.56 (m, 2H), 4.52 (dd, J= 8.7, 1.7 Hz, 1H), 4.48 (d, J= 6.4 Hz, 1H), 4.27 (d, J= 8.4 Hz, 1H), 2.50 - 2.36 (m, 2H), 2.29 - 2.20 (m, 1H), 2.16 - 2.09 (m, 1H), 1.98 - 1.85 (m, 2H), 1.95 (s, 3H), 1.89 - 1.73 (m, 2H), 1.70 - 1.52 (m, 6H), 1.49 (s, 3H), 1.46 - 1.34 (m, 2H), 1.32 (s, 3H), 1.25 - 1.17 (m, 1H),1.14 (d, J= 11.1 Hz, 1H), 0.92 (d, J= 7.3 Hz, 3H), 0.91 (s, 3H), 0.87 (t, J= 7.4 Hz, 3H).13C NMR (101 MHZ, Methanol-^) 8 172.5, 172.1, 164.9, 149.0, 146.5, 140.3, 139.3, 138 2,

[0080] 137.8, 132.2, 130.2, 129.5, 129.4, 129.3, 128.1, 127.7, 118.2, 86.7, 78.5, 58.1, 57.2, 51.3,

[0081] 42.8, 42.2, 39.5, 37.9, 36.4, 35.0, 28.9, 27.7, 26.1, 26.0, 25.0, 24.7, 24.6, 22.9, 22.7, 14.6, 9.9. HR-MS (ESI / TOF) calcd. for C42H54N5O8BS [M+H]+800.3864, found 800.3875.

[0082] Synthesis of products 9, general method H

[0083] Exemplified by the synthesis of 9.1

[0084] A solution of boronic acid ester 8.1 (59 mg, 0.079 mmol,l equiv.) in MeOH and / / -hexane (1: 1, 3.0 mL) was treated with isobutylboronic acid (32 mg, 0.32 mmol, 4 equiv.) and IM HC1 (200 pL). After 18 h at room temperature, the methanolic phase was washed with n- hexane (2x) and the combined / / -hexane layers were washed with MeOH (2x). The combined methanol phase was evaporated in vacuo. Crude mixture was purified by flash chromatography on reversed phase silica gel eluting with 10-100% MeCN in H2O to provide desired compound.

[0085] Synthesis of products 9. general method I

[0086] Exemplified by the synthesis of 9.3

[0087] 8.3. 9.3

[0088] Starting material 8.3 (109 mg, 0.16 mmol, 1 equiv.) was dissolved in THF / H2O 10:1 (5 mL) and Li OH (31 mg, 1.30 mmol, 8 equiv.) were added. The mixture was stirred overnight at room temperature. Afterwards IM HC1 was added to the mixture and aqueous phase was extracted with EtOAc (3><5 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude acid was dissolved in MeOI [ / / / -hexane (1 :1, 1.5 mL). To the biphasic solution was added isobutylboronic acid (50 mg, 0.49 mmol, 3 equiv.) and aq. IM HC1 (0.24 mL, 0.24 mmol, 1.5 equiv.) and the mixture was left to stir for 24h. Afterwards the phases were separated and the hexane layer was extracted with MeOH (2x5 mL). The combined methanolic phase was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on reversed phase silica gel eluting with 0-100% MeCN in H2O to provide desired compound product 9.3,

[0089] Synthesis of products 9. general method J Exemplified by the synthesis of 9.6

[0090] Starting material 8.6. (50 mg, 0.07 mmol, 1 equiv.) was dissolved in l,4-dioxane / H2O (1 :1, 1 mL). To the solution was added 1 M tetrabutylammonium hydroxide (0.10 mL, 0.10 mmol, 1.5 equiv.) and the mixture was stirred at room temperature for 24 h. Afterwards the solvent was evaporated under reduced pressure and the crude was suspended in EtOAc (5 mL). The suspension was filtered through a short silica plug and the silica washed with additional EtOAc (5 mL). The filtrate was concentrated under reduced pressure. The crude alcohol was dissolved in MeOH / n-hexane (1: 1, 1.5 mL). To the biphasic solution was added isobutylboronic acid (21 mg, 0.20 mmol, 3 equiv.) and aq. IM HCI (0.10 mL, 0.10 mmol, 1.5 equiv.) and the mixture was left to stir for 24 h. Afterwards the phases were separated and the hexane layer was extracted with MeOH (2x5 mL). The combined methanolic phase was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on reversed phase silica gel eluting with 0-100% MeCN in H2O to provide desired compound product 9.6.

[0091] Synthesis of products 9, general method K Exemplified by the synthesis of 9.12

[0092] Starting material 8.12 (45 mg, 0 05 mmol, 1 equiv.) was dissolved in TFA (1.2 mL). To the solution was added anisole (0.02 mL, 0.181 mmol, 3.5 equiv.) and the mixture was left to stir at room temperature for 3 h. Afterwards the TFA was removed under reduced pressure (without heating) and the crude boronate was dissolved in MeOH / w-hexane hexane (1 :1, 1.5 mL).. To the biphasic solution was added isobutylboronic acid (16 mg, 0.16 mmol, 3 equiv.) and aq. IM HCI (0.13 mL, 0.16 mmol, 2.5 equiv.) and the mixture was left to stir for 24h. The combined methanolic phase was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on reversed phase silica gel eluting with 0- 100% MeCN in H2O to provide desired product 9.12.

[0093] Synthesis of products 9, general method L Exemplified by the synthesis of 9.14

[0094] 8.14 9.14 Starting material 8.14. (67 mg, 0.09 mmol, 1 equiv.) was dissolved in TFA (0.4 mL). The solution was cooled to -10 °C and NaNCh (12 mg, 0.18 mmol, 2 equiv.) were added in a single portion. The mixture was stirred at the same temperature for 30 min. Then was added water and CH2Q2 (1 :1, 1 mL) and the mixture was allowed to warm to room temperature. The CH2O2 phase was separated and the aqueous phase was extracted with additional CH2O2 (2x1 mL). The combined CH2Q2 phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude sulfonic acid was dissolved in MeOH / n- hexane (1 : 1, 1.5 mL). To the biphasic solution was added isobutylboronic acid (27 mg, 0.27 mmol, 3 equiv.) and aq. 1 M HC1 (0.22 mL, 0.22 mmol, 2.5 equiv.) and the mixture was left to stir for 24h. The solvent was removed under reduced pressure and the product was purified by flash chromatography on reversed phase silica gel eluting with 0-100% MeCN in H2O to provide desired compound product.

[0095] By a method analogous to method H-L the following compounds 9 were obtained:

[0096] Physiochemical characterization of compounds 9.1-9.16

[0097] The synthesis of building blocks 7.

[0098] To obtain benzyl amine building blocks 7, several synthetic strategies were used (General scheme 2). First, after the side chain transformation reactions, aryl bromides 11, 12 were subjected to Miyaura borylation / transesterification reaction (route A). Side chain transformations, such as, Appel or modified Appel reaction gave substrates 14 which afterwards was submitted to substitution with potassium phthalimide to obtain products 15. Deprotection of phthalimide gave abovementioned building blocks 7. Other route (B) involved introduction of phthalimide group earlier in the synthesis through Appel or Mitsunobu reaction. Substrates 18 then underwent borylation reaction yielding 15 which were deprotected according to the method R. Route C was slightly different. After side chain transformation reactions, substrate 17.3 was transformed to Boc-protected benzyl amine 19. Additional transformation gave the necessary substituent at the meta- position, 20 was borylated according to previously used method and deprotected to yield benzyl amine 7.

[0099] General scheme 2

[0100] Route A

[0101] Side chain transformation reactions toward intermediate 11 :

[0102] To a solution of aniline 10.1 (460 mg, 2 mmol) in acetic acid (2 mL) was added triethyl orthoformate (500 pL, 3 mmol, 1.5 equiv.) and sodium azide (195 mg, 3 mmol, 1.5 equiv.). The reaction solution was heated to 80 °C. After the reaction was completed, it was quenched with 5% Na2CO3 aqueous solution (20 mL), and extracted with EtOAc (2x20 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexane:EtOAc 4: 1-1 : 1). Desired compound 11 was isolated as an off-white solid (536 mg, 95%).

[0103] ’H NMR (400 MHz, Chloroform -d) δ 9 13 (s, 1H), 8.31 (dd, J = 1.8, 1.3 Hz, 1H), 8.29 (dd, J = 2.1, 1.3 Hz, 1H), 8.17 (t, J= 1.9 Hz, 1H), 3.99 (s, 3H).

[0104] 13C NMR (101 MHZ, Chloroform-^ 5 164.2, 140.6, 134.9, 134.0, 133.9, 128.3, 124.1, 120.5, 53.2.

[0105] HR-MS (ESI / TOF) calcd. for CftlxBrNqCb [M+H]+282.9831, found 282.9835

[0106] Side chain transformation reactions toward intermediate 12.1: Compound 10.2 (700 mg, 2 05 mmol, 1 equiv ), 4-phenylboronic acid (275 mg, 2.25 mmol, 1 equiv.), Pd(dppf)C12 CH2Q2 (84 mg, 0.103 mmol, 5 mol%), and K3PO4 (872 mg, 4.11 mmol, 2 equiv.), 1,4-dioxane (28 mL), and water (7 mL) were added to a round-bottom flask. This flask was purged with N2. After stirring for 16 h at room temperature, the mixture was extracted with EtOAc, and the organic layer was washed with water. After drying with MgSOi, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc 20:1) to obtain SI (356 mg, 60%) as a white solid.

[0107] ‘HNMR (400 MHz, Chloroform-t / ) 5 8.20 (t, J= 1.6 Hz, 1H), 8.14 (dd, J= 1.9, 1.5 Hz, 1H), 7.91 (t, J = 1.8 Hz, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.49 - 7.44 (m, 2H), 7.45 - 7.36 (m, 1H), 3.95 (s, 3H).

[0108] 13C NMR (101 MHZ, Chloroform-^ / ) 8 165.9, 143.6, 138.8, 134.5, 132.5, 131.2, 129.2, 128.5, 127.3, 127.1, 123.0, 52.6.

[0109] HR-MS (ESI / TOF) calcd. for Ci4Hi2BrO2[M+H]+291.0021, found 291.0023

[0110] Starting material SI (356 mg, 1.22 mmol, 1 equiv.) was dissolved in THF (20 mL, dry), cooled in ice-water bath, then LAH (620 pL, 1.49 mmol, 1.2 equiv.) was added dropwise. Reaction mixture was left for stirring until full conversion. Reaction mixture was then quenched with sodium potassium tartrate, then extracted with Et20. After evaporation of solvents, crude mixture was submitted to the next reaction without purification.

[0111] Crude alcohol (322 mg, 1.22 mmol, based on the theoretical amount) was dissolved in dry CHCh (15 mL), then 2,6-lutidine (220 pL, 1.90 mmol, 1.5 equiv.) and TBSOTf (320 pL, 1.39 mmol, 1.1 equiv.) was added. Reaction mixture was stirred for 3 h, then extracted with potassium sodium tartrate solution, organic phase was dried over NaiSCh, evaporated and purified by column chromatography on silica gel (hexane: EtOAc) to obtain 12.1 (460 mg, 99%) as a colorless oil.

[0112] ’H NMR (400 MHz, Chloroform-t / ) 8 7.62 - 7.60 (m, 1H), 7.58 - 7.54 (m, 2H), 7.47 - 7.42 (m, 4H), 7.40 - 7.34 (m, 1H), 4.77 (q, J= 0.8 Hz, 2H), 0.97 (s, 9H), 0.13 (s, 6H).

[0113] 13C NMR (101 MHZ, Chloroform-d) 8 144.3, 143.3, 140.0, 129.0, 128.8, 128.0, 127.9, 127.3, 123.5, 122.9, 64.4, 26.1, 18.6, -5.1.

[0114] Side chain transformation reactions toward intermediate 12.2:

[0115] Compound 10.2 (500 mg, 1.47 mmol, 1 equiv.), 4-pyridine boronic acid hydrochloride

[0116] (280 mg, 1.76 mmol, 1.2 equiv.), Pd(dppf)C12 CH2Q2 (60 mg, 0.074 mmol, 5 mol%), and K3PO4 (934 mg, 4.40 mmol, 3 equiv.), 1,4-dioxane (20 mL), and water (5 mL) were added to a round-bottom flask. This flask was purged with N2. After stirring for 16 h at room temperature, the mixture was extracted with EtOAc, and the organic layer was washed with water. After drying with MgSOq, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc 2:1— 1:1— EtOAc) to obtain S2 (369 mg, 86%) as a white solid.

[0117] ‘H NMR (400 MHz, Chloroform-c / ) 8 8.75 - 8.68 (m, 2H), 8.23 (d, J= 1.8 Hz, 2H), 7.95 (t, J = 1.8 Hz, 1H), 7.54 - 7.48 (m, 2H), 3.96 (s, 3H).

[0118] 13C NMR (101 MHZ, Chloroform-c / ) 5 165.5, 150.7, 146.0, 140.6, 134.3, 133.0, 132.9, 127.0, 123.4, 121.7, 52.8.

[0119] HR-MS (ESI / TOF) calcd for CnHnBrNCh [M+H]+291.9973, found 291.9980

[0120] Starting material S2 (358 mg, 1.22 mmol, 1 equiv.) was dissolved in THF (20 mL, dry), cooled in ice-water bath, then LAH (610 pL, 1.46 mmol, 1.2 equiv.) was added dropwise. Reaction mixture was left for stirring until full conversion. Reaction mixture was then quenched with sodium potassium tartrate, then extracted with Et2O. After evaporation of solvents, crude mixture was submitted to the next reaction without purification.

[0121] Crude alcohol (1 equiv. based on the theoretical amount) was dissolved in dry CHCh (15 mL), then 2,6-lutidine (200 pL, 1.76 mmol, 1.5 equiv.) and TBSOTf (300 pL, 1.29 mmol, 1.1 equiv.) was added. Reaction mixture was stirred overnight, then extracted with 5% KHSO4, organic phase was dried over NaiSCL, evaporated and purified by column chromatography on silica gel (hexane :EtOAc) to obtain 12.2 (360 mg, 81%) as a colorless oil. ’l l NMR (400 MHz, Chloroform- ) S 8.71 - 8.65 (m, 2H), 7.66 - 7.62 (m, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.44 (m, 2H), 4.78 (q, J= 0.8 Hz, 2H), 0.96 (s, 9H), 0.13 (s, 6H).

[0122] 13C NMR (101 MHz, Chloroform-^ 5 150.6, 147.1, 144.8, 140.2, 129.6, 128.7, 123.29, 123.27, 121.7, 64.2, 26.1, 18.6, -5.1.

[0123] HR-MS (ESI / TOF) calcd for Ci8H25BrNOSi [M+H]+378.0889, found 378.0895

[0124] Side chain transformation reactions toward intermediate 12.3:

[0125] 5-Bromoisophthalaldehyde 10.3 (800 mg, 3.75 mmol, 1 equiv.) was dissolved in THF / EtOH mixture (20 mL, 3 / 1), then sodium borohydride (40 mg, 1.06 mmol, 0.3 equiv.) was added and reaction mixture was allowed to react until full completion (TLC control). Solvent was evaporated and crude mixture was used in the following reaction without purification.

[0126] Crude alcohol (1 equiv. based on the theoretical amount) was dissolved in dry CHCL (20 mL), then 2,6-lutidine (650 pL, 5.61 mmol, 1.5 equiv.) and TBSOTf (950 pL, 4.13 mmol, 1.1 equiv.) was added. Reaction mixture was stirred overnight, then extracted with 5% KHSO4, organic phase was dried over Na2SO4, evaporated and purified by column chromatography on silica gel (hexane :EtOAc) to obtain S3 (392 mg, 32%) as a colorless oil.

[0127] ’l l NMR (400 MHz, Chloroform-c / ) 5 9.95 (s, 1H), 7.89 - 7.87 (m, 1H), 7.75 - 7.73 (m, 2H), 4.78 (q, J= 0.8 Hz, 2H), 0.96 (s, 9H), 0.13 (s, 6H).

[0128] 13C NMR (101 MHZ, Chloroform-^ / ) S 191.0, 145.1, 138.0, 134.8, 131.0, 125.9, 123.4, 63.8, 26.0, 18.5, -5.2.

[0129] In a round-bottom flask, to aldehyde S3 (392 mg, 1.19 mmol, 1 equiv.) and TosMIC (256 mg, 1.31 mmol, 1.1 equiv.) in MeOH (3.5 mL), was added K2CO3 (411 mg, 2.97 mmol, 2.5 equiv.) The suspension was allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. After complete conversion, the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was subjected to column chromatography on silica gel (eluent: hexane:EtOAc = 4:1) to provide the corresponding oxazole 12.3 (255 mg, 58%). ’H NMR (400 MHz, Chloroform- ) 5 7.92 (s, 1H), 7.68 (t, J= 1.7 Hz, 1H), 7.54 (dt, J= 1.5, 0.7 Hz, 1H), 7.43 (dp, J = 1.5, 0.9 Hz, 1H), 7.36 (s, 1H), 4.77 - 4.72 (m, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0130] 13C NMR (101 MHZ, Chloroform-c / ) 5 150.9, 150.4, 144.7, 129.5, 129.1, 125.9, 123.1, 122.6, 120.5, 64.1, 26.0, 18.5, -5.1.

[0131] HR-MS (ESI / TOF) calcd for Ci6H23BrNO2Si [M+H]+368.0681, found 368.0691

[0132] Synthesis of intermediates 13, general method M

[0133] Exemplified by the synthesis of 13.1

[0134] To the solution of aryl bromide 11 (312 mg, 1.1 mmol, 1 equiv.) in dry dioxane (6 mL) under argon BiPiro (308 mg, 1.21 mmol, 1.1 equiv ), KOAc (325 mg, 3.31 mmol, 3 equiv.) and Pd(dppf)C12-CH2C12 (45 mg, 0.055 mmol, 5 mol%) was added. Reaction mixture was sealed and heated at 90 °C. After reaction was completed, it was cooled and evaporated. The residue was dissolved in dry THF (20 mL) and (+)-pinanediol (375 mg, 2.2 mmol, 2 equiv.) was added, reaction mixture was then stirred until full transesterification. Solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane:EtOAc mixture 2: 1). The desired compound 13.1 was isolated as a colorless oil (404 mg, 96%).

[0135] By a method analogous to method M the following compounds were obtained:

[0136] Synthesis of intermediates 14.1, 14.2

[0137] Starting material 13.1 (404 mg, 1.06 mmol, 1 equiv.) was dissolved in THF (dry), cooled in ice-water bath, then LAH (530 pL, 1.27 mmol, 1.2 equiv.) was added dropwise. Reaction mixture was left for stirring until full conversion. Reaction mixture was then quenched with sodium potassium tartrate, then extracted with EtjO. Purification by column chromatography on silica gel (hexane:EtOAc 2: 1-1 :l-EtOAc) yielded product S4 (237 mg, 63%).

[0138] ’H NMR (400 MHz, Chloroform-; / ) 8 9.05 (s, 1H), 7.98 (dd, J= 2.3, 1.0 Hz, 1H), 7.94 - 7.90 (m, 2H), 4.85 (d, J = 5.6 Hz, 2H), 4.50 (dd, J = 8.8, 2.0 Hz, 1H), 2.48 - 2.39 (m, 1H), 2.30 - 2.22 (m, 1H), 2.19 - 2.12 (m, 2H), 2.01 - 1.94 (m, 2H), 1.51 (s, 3H), 1.32 (s, 3H), 1.17 (d, J = 11.1 Hz, 1H), 0.90 (s, 3H).

[0139] 13C NMR (101 MHz, Chloroform-; / ) 8 143.2, 140.7, 134.4, 133.9, 125.9, 122.2, 87.2, 78.9, 64.2, 51.5, 39.6, 38.4, 35.5, 28.8, 27.2, 26.6, 24.2.

[0140] HR-MS (ESI / TOF) calcd. for C18H24BN4O3 [M+H]+355.1941, found 355.1954

[0141] The alcohol S4 (226 mg, 0.64 mmol, 1 equiv.) was dissolved in dry THF (10 mL) followed by the addition of triphenylphosphine (335 mg, 1.28 mmol, 2 equiv ). The mixture was cooled to 0 °C with an ice bath then tetrabromomethane (423 mg, 1.28 mmol, 2 equiv.) was carefully added portion wise. The reaction was stirred at rt for 18 h. The solution was poured into water and extracted with EtOAc (3x). The combined organic layers were dried over NaiSCft, filtered and evaporated under vacuum. The compound was purified using column chromatography on silica gel (hexane:EtOAc 20: 1-8:1) to afford the desired compound 14.1 as a colourless oil (92 mg, 35%).

[0142] ’H NMR (400 MHz, Chloroform-; / ) 8 9.05 (s, 1H), 7.98 (dd, J = 2.3, 0.9 Hz, 1H), 7.96 (dd, J = 1.8, 0.9 Hz, 1H), 7.92 (t, J= 2.0 Hz, 1H), 4.56 (s, 2H), 4.51 (dd, J= 8.8, 1.9 Hz, 1H), 2.49 - 2.40 (m, 1H), 2.31 - 2.23 (m, 1H), 2.17 (dd, J= 6.1, 4.9 Hz, 1H), 2.02 - 1.95 (m, 2H), 1.51 (s, 3H), 1.33 (s, 3H), 1.17 (d, J= 11.0 Hz, 1H), 0.90 (s, 3H).13C NMR (101 MHz, Chloroform-tZ) 8 140.6, 140.1, 136.7, 134.0, 126.7, 124.6, 87.4, 79 0, 51.4, 39.6, 38.4, 35.5, 31.5, 28.8, 27.2, 26.7, 24.2.

[0143] HR-MS (ESI / TOF) calcd for CisH23BN4O2Br [M+H]+417.1097, found 417.1100

[0144] Aldehyde 13.2 (1 equiv.) was dissolved in MeOH. To the solution was added NaBH4 (0.5 equiv.) and the mixture was left to stir for 30 min. Afterwards the mixture was concentrated under reduced pressure and the crude was dissolved in CH2C12and washed with 1 M KHSO4. The phases were separated and the aqueous phase extracted with DCM. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.

[0145] The crude alcohol was converted to bromide by the same procedure as 14.1, Yield 14.2: 101 mg, 82%.

[0146] ’H NMR (400 MHz, Chloroform- ) 8 7.84 - 7.82 (m, 1H), 7.77 - 7.73 (m, 1H), 7.52 - 7.49 (m, 1H), 7.40 - 7.33 (m, 1H), 4.51 (s, 2H), 4.46 (dd, J = 1.7, 8.6, 1H) 2.48 - 2.37 (m, 1H), 2.28 - 2.21 (m, 1H), 2.19 - 2.12 (m, 1H), 2.02 - 1.92 (m, 2H), 1.49 (s, 3H), 1.32 (s, 3H), 1.21 (d, J= 10.9 Hz, 1H), 0.90 (s, 3H).

[0147] 13C NMR (101 MHz, Chloroform-t / ) 8 137.2, 135.3, 134.9, 131.9, 128.3, 86.5, 78.4, 51.4, 39.5, 38.2, 35.5, 33.5, 28.7, 27.1, 26.5, 24.1.

[0148] Synthesis of intermediates 14.3-14.5, general method N

[0149] Exemplified by the synthesis of 14.3

[0150] Starting material 13.3 (590 mg, 1.24 mmol, 1 equiv.) was dissolved in dry MeOH (10 mL), then Bi(OTf)3 (17 mg, 0.026 mmol, 2 mol%) was added to the reaction mixture. After full deprotection of TBS group (UPLC-control), reaction mixture was evaporated and the crude alcohol was submitted to the next reaction without additional purification.

[0151] Into a sealed tube alcohol (380 mg, 1.05 mmol, 1 equiv.), triphenylphosphine (330 mg, 1.26 mmol, 1.2 equiv.) and anhydrous acetonitrile (10 mL) were added under an argon atmosphere. 1,2-Diiodoethane (355 mg, 1.26 mmol, 1.2 equiv.) was then added and the reaction mixture was stirred at room temperature. After the completion, the solvent was removed by concentration under reduced pressure. The residue was dissolved in EtOAc, washed with the solution of Na2S2O3, then brine. Organic phase was dried over Na2SO4, filtered, evaporated and subjected to flash column chromatography (hexane:EtOAc 20: 1-8:1) to afford the pure product 14.3 (445 mg, 90%) as an off-white solid. By a method analogous to method N the following compounds were obtained:

[0152] Synthesis of intermediates 15 and benzyl amines 7, general method O

[0153] Exemplified by the synthesis of 15.1

[0154] Starting material 14.1 (84 mg, 0.20 mmol) was dissolved in dry DMF (2 mL), potassium phthalimide (47 mg, 0.25 mmol, 1.25 equiv.) was added and the mixture was left stirring until full conversion (LC-MS control). Reaction mixture was diluted with EtOAc and washed with HjO (2x) and brine. Organic phase was dried over NaiSOr, filtered and evaporated under vacuum. The compound was purified using column chromatography on silica gel (hexane:EtOAc 2: 1-1 :1) to afford the desired compound 15.1.

[0155] By a method analogous to method O the following compounds were obtained:

[0156] Synthesis of benzyl amines 7, general method P Exemplified by the synthesis of 7.1

[0157] Under argon compound 15.1 (87 mg, 0.18 mmol, 1 equiv.) was added to a dry flask containing magnetic stir and dissolved in THF (3 mL). Afterwards, hydrazine hydrate (150 pL, 1.70 mmol, 10 equiv.) was added to the reaction mixture. The reaction was stirred at room temperature overnight. The resulting dried crude material was then re-suspended with chloroform, filtered, and the filtrate was concentrated in vacuum The crude material was submitted to the next reaction without additional purification.

[0158] By a method analogous to method P the following compounds were obtained:

[0159] Route B

[0160] Side chain transformation reactions toward intermediates 16 and 18.1

[0161] Bromide 16 was obtained by the same procedure as 14.1. Yield of 16: 361 mg, 52%

[0162] ’H NMR (400 MHz, Chloroform-d) δ 7.33 (s, 1H), 7.24 - 7.15 (m, 1H), 7.10 - 7.01 (m, 1H), 4.39 (s, 2H)

[0163] Phthalimide 18.1 was obtained according to general method O.

[0164] ’H NMR (400 MHz, Chloroform-^ 8 7.87 (2H, dd, J 5.5, 3.1 Hz), 7.74 (2H, dd, J 5.5, 3.1 Hz), 7.37 - 7.34 (1H, m), 7.16 (1H, ddd, J 8.1, 2.4, 1.7 Hz), 7.11 - 7.05 (1H, m), 4.79 (2H, s, CH2).

[0165] 19F NMR (376 MHz, Chloroform- ) 8 -110.01 - -110.11 (m).13C NMR (101 MHz, Chloroform-cZ) 6 167.8, 162.6 (d, J = 251.5 Hz), 140.0 (d, J = 7.8 Hz), 134.3, 131.9, 127.4 (d, J= 3.3 Hz), 123.6, 122.8 (d, J= 9.6 Hz), 118.7 (d, J = 24.4 Hz), 114.6 (d, J= 21.8 Hz), 40.6 (d, J= 2.0 Hz).

[0166] HR-MS (ESI / TOF) calcd. for CisHjBrFNCh [M+H]+333.9879, found 333.9875.

[0167] Side chain transformation reactions toward intermediate 17.1

[0168] Aldehyde 10.5 (500 mg, 1.89 mmol, 1 equiv.) was suspended in MeOH (10 mL). To the solution was added NaBHj (35 mg, 0.94 mmol, 0.5 equiv.) and the mixture was stirred at room temperature for 30 min. Afterwards the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with IM KHSO4 (10 mL). The phases were separated and the organic phase was washed with water (2><10 mL) and brine (10 mL). The combined organic phase was dried over anhydrous NaiSO4, filtered and concentrated under reduced pressure. The crude alcohol was dissolved in dry DMF (5 mL). To the solution was added imidazole (142 mg, 2.08 mmol, 1.1 equiv.) and TBS-CI (314 mg, 2.084 mmol, 1.1 equiv.) and the mixture was left to stir at room temperature for 3 h. Afterwards the reaction mixture was diluted with water and extracted with EtiO (3x15 mL). The combined organic phase was washed with water (3x15 mL) and brine (15 mL). The combined organic phase was dried over anhydrous NazSCh, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (100% n- hexane). Yield of S7: 688 mg, 93%.

[0169] ’H NMR (400 MHz, Chloroform- ) S 7.55 - 7.52 (m, 1H), 7.41 - 7.37 (m, 2H), 4.67 (d, J = 0.8 Hz, 2H), 0.94 (s, 9H), 0.11 (s, 6H).

[0170] Compound S7 (1.25 g, 3.29 mmol, 1 equiv.) was dissolved in dry ether (20 mL) under argon atmosphere. The solution was cooled to -78 °C and / / -BuLi (2.26 mL, 3.61 mmol, 1.1 equiv.) was added dropwise. After addition the mixture was allowed to stir at the same temperature for 30 min. Then was added ethylene oxide (1.58 mL, 3.95 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction was quenched with the addition of sat. NH4CI (10 mL). The phases were separated and the aqueous phase was extracted with EtiO (2x 15 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous NazSCU, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (' / / -hexane:EtOAc 10:1 to 4: 1). Yield S8: 840 mg, 74%.

[0171] ’H NMR (400 MHz, Chloro form-c / ) S 7.34 (broad s, 1H), 7.27 - 7.25 (broad s, 1H), 7.10 (broad s, 1H), 4.70 - 4.68 (m, 2H), 3.85 (t, J = 6.5 Hz, 2H), 2.83 (t, J= 6.5 Hz, 2H), 0.94 (s, 9H), 0.10 (s, 6H).

[0172] Alcohol S8 (300 mg, 0.86 mmol, 1 equiv.) and DMAP (4.2 mg, 0.03 mmol, 10 mol%) was dissolved in dry CH2Q2 under argon atmosphere. To the solution was added EtsN (0.18 mL, 1.30 mmol, 1.5 equiv ) and the solution was cooled to 0 °C. The was dropwise added PivCl (0. 13 mL, 1.04 mmol, 1.2 equiv.) and the mixture was allowed to warm to room temperature and stir for 1 h. After completion sat. NaHCO3(10 mL) was added. The layers were separated and the aqueous layer was extracted with CH2Q2 (2x10 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (n- hexane:EtOAc 10:1 to 2:1). Yield 17.1: 174 mg, 64%.

[0173] 3H NMR (400 MHz, Chloroform-tZ) 8 7.40 - 7.36 (m, 1H), 7.31 - 7.28 (m, 1H), 7.17 - 7.12 (m, 1H), 4.65 (s, 2H), 4.25 (t, J= 6.7 Hz, 2H), 2.91 (t, J= 6.7 Hz, 2H), 1.16 (s, 9H).

[0174] 13C NMR (101 MHZ, Chloroform- / / ) 8 178.5, 143.2, 140.6, 131.2, 128.0, 126.0, 122.5, 64.4, 64.3, 38.8, 34.7, 27.2.

[0175] HR-MS (ESI) calcd. for Ci4Hi8BrO2[M-0H]+297.0490, found 297.0503.

[0176] Side chain transformation reactions toward intermediate 17.2

[0177] 5-Bromoisophthalaldehyde 10.3 (550 mg, 2.58 mmol, 1 equiv.) was dissolved in EtOH / THF 1: 1.5 (9 mL). The solution was cooled to -10 °C (NaCl / Ice / water) and NaBEL (20 mg, 0.52 mmol, 0.2 equiv.) was added. The reaction mixture was stirred at the same temperature for 1 h. Then was added additional NaBEL (0.05 equiv.). After completion (indicated by TLC) IM EIC1 (10 mL) was added. The THF and EtOEI was evaporated under reduced pressure and the aqueous layer was extracted with EtOAc (2x 10 mL). The combined organic layer was washed with brine, dried over anhydrous NaiSOr, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography ( / / -hexane: EtOAc 10:1 to 1: 1). Yield S9: 271 mg, 49%.

[0178] ’H NMR (400 MHz, Chloroform- ) 5 9.96 (s, 1H), 7.96 - 7.95 (m, 1H), 7.80 - 7.77 (m, 1H), 7.77 - 7.74 (m, 1H), 5.14 (s, 2H), 2.14 (s, 3H).

[0179] 13C NMR (101 MHZ, Chloroform- / ^) 5 190.4, 170.6, 139.4, 138.1, 136.5, 132.1, 127.6, 123.5, 64.5, 20.9.

[0180] HR-MS (ESI) calcd. for C8H6BrO2[M-H]’ 212.9551, found 212.9551.

[0181] Starting material S9 (271 mg, 1.26 mmol, 1 equiv.) was dissolved in dry CH2CI2 (5 mL). To the solution was added Et3N (0.35 mL, 2.52 mmol, 2 equiv.) and AcCl (0.13 mL, 1.89 mmol, 1.5 equiv.) and the reaction mixture was left to stir for 2 h. Afterwards the mixture was quenched with IM HC1 and the phases were separated. The aqueous phase was extracted with CH2Q2 (2x10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography ( / / -hexane: EtOAc 10:1 to 5: 1). Yield S10: 267 mg, 82%.

[0182] ’H NMR (400 MHz, Chloroform- / / ) 8 9.96 (s, 1H), 7.96 - 7.95 (m, 1H), 7.80 - 7.77 (m, 1H), 7.77 - 7.74 (m, 1H), 5.14 (s, 2H), 2.14 (s, 3H).

[0183] 13C NMR (101 MHZ, Chloroform-^ 8 190.4, 170.6, 139.4, 138.1, 136.5, 132.1, 127.6, 123.5, 64.5, 20.9.

[0184] HR-MS (ESI) calcd. for C8H3BrO [M-C2O2H3]+196.9602, found 196.9615. Aldehyde S10 (267 mg, 1.03 mmol, 1 equiv.) was dissolved in MeOH. To the solution was added NaBH4 (20 mg, 0.52 mmol, 0.5 equiv.) and the mixture was left to stir for 30 min. Afterwards the mixture was concentrated under reduced pressure and the crude was dissolved in CH2CI2 and washed with IM KHSO4. The phases were separated and the aqueous phase extracted with CH2O2. The combined organic phase was dried over anhydrous NafoCL, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography («-hexane:EtOAc 10:1 to 4: 1). Yield of 17.2: 205 mg, 76%.

[0185] ’H NMR (400 MHz, Chloroform- / ) S 7.49 - 7.47 (m, 1H), 7.43 - 7.40 (m, 1H), 7.27 - 7.26 (m, 1H), 5.06 (s, 2H), 4.68 (s, 2H), 2.11 (s, 3H).

[0186] 13C NMR (101 MHz, Chloroform- / ) 5 170.8, 143.4, 138.3, 130.1, 129.6, 125.0, 122.7, 65.3, 64.3, 21.0.

[0187] HR-MS (ESI) calcd. for C8H8BrO [M-C2O2H3]+198.9759, found 198.9759.

[0188] Side chain transformation reaction toward intermediate 17.3

[0189] Diester 10.6 (1 g, 3.66 mmol, 1 equiv.) was dissolved in THF (3 mL). The solution was cooled to 0 °C (ice / water) and NaBIfo (208 mg, 5.49 mmol, 1.5 equiv.) was added. Then was added MeOH (1 mL) and the mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with IM HC1 and EtOAc (10 mL) was added. The phases were separated and the aqueous phase extracted with EtOAc (2>< 10 mL). The combined organic phase was washed with brine, dried over anhydrous NaiSO4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (n- hexane:EtOAc 10: 1 to 4:1). Yield 17.3: 620 mg, 69%.

[0190] ’H NMR (400 MHz, Chloroform-; / ) 5 8.10 - 8.05 (m, 1H), 7.96 - 7.91 (m, 1H), 7.73 - 7.70 (m, 1H), 4.73 (d, J= 0.7 Hz, 2H), 3.92 (s, 3H).

[0191] 13C NMR (101 MHZ, Chloroform- ) 5 165.9, 143.5, 134.2, 132.2, 131.7, 126.5, 122.8, 64.1, 52.6.

[0192] Side chain transformation reactions toward intermediate 17.4

[0193] S7 S11 17.4

[0194] Starting material S7 (1.14 g, 3.00 mmol, 1 equiv.) was dissolved in dry THF (20 mL) under argon atmosphere. The solution was cooled to -78 °C and n-BuLi (1.5 mL, 3.61 mmol, 1.1 equiv.) was added dropwise. After addition the mixture was allowed to stir at the same temperature for 45 min. Then SO2 was bubbled through the mixture for 5 min. Afterwards the mixture was allowed to warm to room temperature and stir for 1 h. The solvent was removed under reduced pressure and the crude sulfinate was suspended in dry CH2CI2 (10 mL) and the suspension was cooled to 0 °C. NCS (460 mg, 3.44 mmol, 1.05 equiv.) was added and the reaction mixture was stirred for 2 h at the same temperature before 35% NH3 in water (8 mL) was added. The mixture was allowed to warm to room temperature and stir for an additional 1 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc / water 1:1 (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 x15 mL). The combined organic phase was washed with water (3x 15 mL) and brine (15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude Sil was dissolved in MeOH (5 mL) and cone. HC1 (0.41 mL, 4.92 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 2 h. Then the solvent was concentrated under reduced pressure and the product was purified via silica gel column chromatography (n-hexane:EtOAc 10: 1 to 1: 1). Yield of 17.4: 511 mg, 59%.

[0195] ’H NMR (400 MHz, Methanol-^) 8 7.99 - 7.89 (m, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 4.68 (s, 2H).

[0196] 13C NMR (101 MHZ, Methanol-^) 8 145.7, 145.6, 132.5, 127.2, 122.4, 122.1, 62.3.

[0197] HR-MS (ESI / TOF) ealed. for C7H8BrNO3S [M+H]+265.9487, found 265.9315.

[0198] Side chain transformation reactions toward intermediate 17.5

[0199] Starting material 10.7 (300 mg, 1.5 mmol, 1 equiv.) and NaNs (105 mg, 1.62 mmol, 1.3 equiv.) were dissolved in dry DMF (5 mL). To the suspension was added L-Proline (43 mg, 0.37 mmol, 30 mol%) and the mixture was stirred at 120 °C for 2 h. Afterwards the mixture was allowed to warm to 40 °C and PMB-CI (0.26 mL, 1.87 mmol, 1.5 equiv.) was added. The mixture was stirred for 4 h. Afterwards the reaction mixture was diluted with water and extracted with EtOAc (3 x15 mL). The combined organic phase was washed with water (3 x15 mL) and brine (15 mL). The combined organic phase was dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (n-hexane:EtOAc 10:1 to 1: 1) Yield S12: 356 mg, 71%.

[0200] ’H NMR (400 MHz, Chloroform-^ 8 8.71 (t, J= 1.5 Hz, 1H), 8.46 (t, J= 1.7 Hz, 1H), 8.27 - 8.22 (m, 1H), 7.39 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.75 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H).

[0201] 13C NMR (101 MHZ, Chloroform-^ 8 165.2, 163.5, 160.2, 134.1, 133.8, 132.7, 130.4, 130.1, 129.6, 126.5, 125.1, 123.0, 114.5, 56.7, 55.4, 52.6.

[0202] Starting material S12 (356 mg, 0.88 mmol, 1 equiv.) was dissolved in dry THF (20 mL). The solution was cooled to -20 °C and LiAlHi (0.37 mL, 0.88 mmol, 1 equiv.) was added dropwise. The mixture was stirred at the same temperature for 2 h. Then saturated Rochelle’s salt (10 mL) was added and the mixture was allowed to warm to room temperature and stir for 30 min. Then was added EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc (2x10 mL). The combined organic phase was dried over anhydrous NaiSO4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (n-hexane:EtOAc 4: 1 to 1 :1). Yield of 17.5: 285 mg, 86%.

[0203] ‘H NMR (400 MHz, Chloroform- ) 8 8.19 - 8.16 (m, 1H), 8.05 - 8.02 (m, 1H), 7.63 - 7.59 (m, 1H), 7.38 (d, J = 8.7 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 5.72 (s, 2H), 4.74 (d, J = 0.7 Hz, 2H), 3.80 (s, 3H).

[0204] 13C NMR (101 MHZ, Chloroform-^ 8 164.1, 160.2, 131.4, 130.1, 129.4, 128.8, 128.7, 125.2, 123.6, 123.1, 114.4, 114.0, 64.2, 56.6, 55.4.

[0205] Synthesis of intermediates 18, general method R

[0206] Exemplified by the synthesis of 18.5

[0207] 17.5 18.5

[0208] Alcohol 17.5 (285 mg, 0.76 mmol, 1 equiv.), PPlu (209 mg, 0.80 mmol, 1.05 equiv.) and phthalimide (117 mg, 0.80 mmol, 1.05 equiv.) were dissolved in dry THF (15 mL) under argon atmosphere. The solution was cooled to 0 °C and DIAD (0.16 mL, 0.80 mmol, 1.05 equiv.) were added dropwise. The mixture was allowed to slowly warm up to room temperature After completion (TLC or UPLC control) the mixture was concentrated under reduced pressure and ethanol (10 mL) was added to the crude mixture. The solid was filtered off and washed with additional EtOH (2><20 mL) and EtiO (10 mL). Yield 18.5: 280 mg, 73%.

[0209] By a method analogous to method R the following compounds were obtained:

[0210] Synthesis of intermediates 15 and benzylamines 7; general methods M and P

[0211] By a method analogous to method M the following compounds were obtained:

[0212] By a method analogous to method P the following compounds were obtained:

[0213] Route C

[0214] Side chain transformation reactions toward intermediates 20.

[0215] 17.3 19 20

[0216] Alcohol 17.3 (708 mg, 2.89 mmol, 1 equiv.) was dissolved in dry CH2CI2 (10 mL). The solution was cooled to 0 °C and Et?N (0.42 mL, 3.03 mmol, 1.05 equiv.) was added. Then was slowly added MsCI (0.23 mL, 3.03 mmol, 1.05 equiv.) and the mixture was allowed to stir at the same temperature for 1.5 h. Afterwards the reaction was quenched with IM HC1 (1.5 mL). The phases were separated and the organic phase washed with sat. NaHCCL (5 mL), water (5 mL) and finally brine (5 mL). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.

[0217] The mesylate was dissolved in dry DMF (10 mL) and CS2CO3 (988 mg, 3.03 mmol, 1.05 equiv.) was added. Finally, B0C2NH (649 mg, 3.03 mmol, 1.05 equiv.) was added and the mixture was heated to 50 °C and stirred overnight. Afterwards the reaction mixture was diluted with water and extracted with EtOAc (3x 15 mL). The combined organic phase was washed with water (3x 15 mL) and brine (15 mL). The combined organic phase was dried over anhydrous Na2SC>4. filtered and concentrated under reduced pressure.

[0218] Crude ester was dissolved in CFLCL / MeOH 1 :10 (17 mL). To the solution was added NaOH (462 mg, 11.56 mmol, 4 equiv.) and the reaction mixture was stirred at room temperature for 3 h. Afterwards water (15 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was washed with CH2CI2 (2x15 mL). Then IM HC1 was added until pH = 1. Then the aqueous layer was extracted with EtOAc (3x 15 mL). The combined organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Yield 19: 880 mg, 92 % over 3 steps.

[0219] ’H NMR (400 MHz, Methanol-^) 5 8.02 - 8.00 (m, 1H), 7.92 - 7.90 (m, 1H), 7.68 - 7.65 (m, 1H), 4.27 (s, 2H), 1.47 (s, 9H).

[0220] 13C NMR (101 MHZ, Methanol-^) 8 168.2, 158.3, 144.2, 135.3, 134.3, 132.0, 128.9, 128.1, 123.3, 80.5, 44.2, 28.7.

[0221] HR-MS (ESI / TOF) calcd. for Ci3Hi5BrNO4 [M-H]’ 328.0190, found 328.0194.

[0222] Acid 19 (65 mg, 0.19 mmol, 1 equiv.) was suspended in dry CH2Q2 (2 mL). To the solution was added cat. DMF (10 mol%). The mixture was cooled to 0 °C (ice / water) and COCI2 (0.02 mL, 0.23 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at the same temperature for Ih. Then 35% NH3 in water (3 mL) was added. The mixture was allowed to warm up to room temperature and stir for 1 h. Then water (5 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with DCM (3x5 mL). The combined organic phase was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The product was purified via silica gel column chromatography (n-hexane: EtOAc 4:1 to 1:1). Yield 20: 54 mg, 83%.

[0223] ’l l NMR (400 MHz, Dimethylsulfoxide-cA) 8 7.92 (s, IH), 7.76 (s, IH), 7.63 (s, IH), 4.27 (s, 2H), 3.33 (s, 2H), 1.48 (s, 9H).

[0224] 13C NMR (101 MHZ, Dimethylsulfoxide-t / e) 8 170.6, 158.5, 144.1, 137.3, 134.3, 130.2, 126.3, 123.5, 80.5, 44.3, 28.7.

[0225] HR-MS (ESETOF) calcd. for CnHuBrNzOsNa [M+Na]+351.0315, found 351.0322.

[0226] Synthesis of intermediate 21 (general method M) and benzylamine 7,12 Aryl bromide 20 was submitted to borylation reaction according to general method M.

[0227] Yield 21: 72 mg, 67%.

[0228] ‘H NMR (400 MHz, Chloroform- ) 6 8.08 - 8.03 (m, 1H), 7.95 - 7.92 (m, 1H), 7.88 (s, 1H), 6.15 (bs, 1H), 5.55 (bs, 1H), 4.90 (bs, 1H), 4.47 (dd, J= 8.7, 1.9 Hz, 1H), 4.38 (d, J= 6.0 Hz, 2H), 2.49 - 2.38 (m, 1H), 2.29 - 2.21 (m, 1H), 2.15 (t, J = 6.0 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.56 (s, 3H), 1.46 (s, 9H), 1.32 (s, 3H), 1.18 (d, J= 11.1 Hz, 1H), 0.90 (s, 3H).

[0229] 13C NMR (101 MHZ, Chloroform-^ S 174.8, 156.0,139.2, 137.5, 133.2, 132.1, 129.7, 86.9, 78.7, 51.5, 39.7, 38.4, 35.6, 28.8, 28.6, 27.2, 26.7, 24.2.

[0230] HR-MS (ESI / TOF) calcd. for C23H33BN2O5Na [M+Na]+451.237, found 451.2380.

[0231] Boc-protected amine 21 (70 mg, 0.16 mmol, 1 equiv.) was dissolved in CH2CI2. Then 4 M HC1 in 1,4-dioxane (0.16 mL, 0.65 mmol, 4 equiv.) was added. The mixture was stirred at room temperature for 4 h. Afterwards the solvent was evaporated under reduced pressure and the crude benzyl amine 7.12 was submitted to the next reaction without additional purification.

[0232] In vitro Assay

[0233] The compounds have been tested in vitro as malarial serine protease PfSUBl inhibitors according to the following process.

[0234] Determination of IC50

[0235] [1] Recombinant purified P. falciparum SUB1 (PfSUBl) was produced and purified as previously described (C. Withers-Martinez, C. Suarez, S. Fulle, S. Kher, M. Penzo, J. P. Ebejer, K. Koussis, F. Hackett, A. Jirgensons, P. Finn, M. J. Blackman, International Journal for Parasitology; 2012, 42, 597). The enzyme was diluted in digestion buffer (25 mM CHAPS, 12 mM CaC12, 25 mM Tris-HCl, pH 8.2) and dispensed into a white flat-bottomed 96-well fluorescence microtitre plates (Nunc). Test compounds were solubilized in dimethyl sulfoxide (DMSO), serially diluted and added at 2 % to the well. The rhodamine-labelled fluorogenic substrate SERA4stlF-6R12 was added at a final concentration of 0.1 pM in a final volume of 100 pl and the rate of hydrolysis was monitored with a Cary Eclipse spectrofluorimeter (Varian, UK) as previously described. Excitation and emission wavelengths used were 552 nm and 580 nm respectively.

[0236] Results are given in Table 1.

[0237] Table 1 Biological activity of 3-(acetylamidomethyl)phenylboronic acid derivatives.

Claims

Claims1. A compound of Formula Iwherein: wherein:R, R1R2, R3are independently is H, C1-6alkyl, cycloC3-i2alkyl, cycloC3-12alkyl-Ci. ,-,alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylCb- 6alkynyl, heteroaryl, heteroarylC1-6 alkyl, hctcroaryIC2-6alkcnyl, R4O(CH2)n, R4S(CH2)n, R4OC(=O)(CH2)n, R4N(R5)C(=O)(CH2)n,R4N(R5)(CH2)n, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR4, -O-L-NH2, -O-L-NHR4, -O-L-N(R4)R5, -L-OR4,-O-L-OR4,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR4,-O-L-OR4,-OCF3, -OCH2CF3, -OCF2CF2H, SR4, SCF3, - CN, -NO2, -NO2, -NH2, -NHR4, -NR42, -N(R4)R5, -L-NH2, -L-NHR4, -L-NR42, -L-N(R4)R5,-NH-L-NH2, -NH-L-NHR4, -NH-L-N(R4)R5, -NH-L-N(R4)R5,-NR4-L-NH2, -NR4-L-NHR4, -NR4-L-N(R4)R5, -NR4-L-N(R4)R52, -N(R4)R5, -C(=O)OH, -C(=O)OR5, -C(=O)NH2, -C(=O)NHR5, -C (=O)N(R4)R5, -C(-O)N(R4)R5,-NHC(-O)R5, -NR5C(=O)R5, -NHC(=O)OR4, -NR4C(=O)OR4, -OC(=O)NH2, -OC(=O)NHR4, -OC(=O)N(R4)R5, -OC(=O) R4NR4,-OC(=O)R5, -C(=O)R4,-NHC(=O)NH2, -NHC(=O)NHR4, -NHC(-O)NR42, -NHC(=O)N(R4)R5, -NR4C(=O)NH2, -N(R4)C(=O)NHR5, -NR4C(=O)N (R4)R5wherein: n is an integer selected from 1 to 6;L represents -WA-XA-YA-ZA-; or -WA-XA-YA-, or -WA-XA- or -WA- wherein:WA- represents a single bond, oxygen, sulfur, -NR3or -CR3R4,XArepresents oxygen, sulfur, -NR4or -C(R4)R5, YArepresents oxygen, sulfur, -NR4or -C(R4)R5, ZArepresents oxygen, sulfur, -NR4or -C(R4)R5; wherein:R4and R5are independently H, Ci^alkyl, cycloCa-nalkyl, cycloCa-ualkyl-Ci-ealkyl, C2- ealkenyl, CT-ealkynyl, aryl, biaryl, arylCi-6 alkyl, arylC2-ealkenyl, arylC2-ealkynyl, heteroaryl, heteroarylCi-ealkyl, heteroarylC2-ealkenyl, heteroarylthio, 2, 3 -dihydro- 1H- indenyl, Ci-ealkoxyCi-ealkyl, aryloxyarylCi -ealkoxy, Ci -ealkylthio, C4-ealkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-Ci-ealkylthio, cycloCs-nalkyl-Cs-ealkenylthio, Ci- ealkoxyCi-ealkylthio, Ci-ealkoxyCs -ealkenylthio, arylCs -ealkenylthio, heteroarylCi. ealkylthio, Ci-ealkylsulfonyl, cycloCs-nalkyl-Ci-ealkylsulfonyl, arylCi-ealkylsulfonyl, Ci -ealkylamino, di-Ci -ealkylamino, cycloCa-ualkylamino, Ci-Cealkoxy-cycloCs- Ci2alkylamino, cycloC3-i2alkyl-Ci -ealkylamino, di-Ci-ealkylaminoCi-ealkyl, Ci- ealkoxy-C2-ealkylamino, arylamino, arylCi -ealkylamino, N-cycloCs-nalkyl-N-Ci- ealkylamino, N-aryl-N-Ci-ealkylamino, N-arylCi-ealkyl-N-Ci-ealkylamino, 2- indanylamino, tetrahydrofiiryl, pyrrolidine, piperidino, 4-arylpiperidino, 4- heteroarylpiperidino, morpholino, piperazino, 4-Ci-ealkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, l,3-dihydro-2H-isoindol-2-yl, heteroarylCi- ealkoxy, heteroarylamino, or heteroarylCi. ealkylamino. and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

2. The compound according to Claim 1, where the compound is selected from the group comprising:

3. A pharmaceutical composition comprising the compound according to Claim 1 or 2 and a pharmaceutically acceptable salt, solvate, morphological form and prodrug thereof and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to Claim 3 wherein said medicament is administered to a human.

5. A compound according to Claims 1 or 2 for use in the treatment of malaria.

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