2-amino-n-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives acting as a threonyl-t-RNA synthetase inhbitors for the treatment of malaria

Abstract

Representatives of 2-amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide with general formula (I) show potency to inhibit malarial threonyl-tRNA synthetase (ThrRS) in low micromolar to nanomolar concentrations. As such they can be applied as compounds for prevention or treatment of malaria.

Description

[0001] 2-AMINO-N-(BENZO[D]THIAZOL-2-YLSULFONYL)-3-HYDROXYBUTANAMIDE DERIVATIVES ACTING AS A THREONYL-T-RNA SYNTHETASE INHBITORS FOR THE TREATMENT OF MALARIA Field of invention

[0001] The present invention relates to medicine, and in particular to the treatment of malarial infections, more particularly to inhibitors of a threonyl-tRNA synthetase. Even more particularly, the invention relates to 2-amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives and pharmaceutical compositions thereof and their use as inhibitors for threonyl-tRNA synthetase (ThrRS). Background of invention

[0002] 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.; 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; 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.).

[0003] 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. A precondition for the development of new 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.) This could be achieved by targeting functional malarial proteins involved in the blood stage of the parasite life cycle. Aminoacyl t-RNA synthetases have received considerable attention as possible targets for the development of antimalarial drugs (Kwon, N. H.; Fox, P. L.; Kim, S. Aminoacyl-tRNA synthetases as therapeutic targets. Nat. Rev. Drug Disc.2019, 18, 629). Among them, threonyl t-RNA synthethase (ThrRS) has been validated as anti-malarial drug target by the natural product borrelidin and its analogues as these compounds have been shown to feature very potent anti-malarial activity in both infected cell assays and in mice infection models (Novoa, E. M.; Camacho, N.; Tor, A.; Wilkinson, B.; Moss, S.; Marin- Garcia, P.; Azcarate, I. G.; Bautista, J. M.; Mirando, A. C.; Francklyn, C. S.; et al. Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. PNAS 2014, 111 (51), E5508- 5517) Apart from borrelidin and its derivatives other reported inhibitor of malarial threonyl-tRNA synthetase is agrocin 84 toxic moiety analogue (Rodriguez Buitrago, J. A.; Leitis, G.; Kaņepe- Lapsa, I.; Rudnickiha, A.; Parisini, E.; Jirgensons, A. Org. Biomol. Chem., 2023, DOI:10.1039 / D3OB00670K). The present invention

[0004] We have surprisingly discovered that certain novel 2-amino-N-(benzo[d]thiazol-2- ylsulfonyl)-3-hydroxybutanamide derivatives have an excellent ability to inhibit ThrRS. These 2- amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives exhibit pronounced inhibitory properties toward said aminoacyl t-RNA synthetase. These novel compounds can be used for manufacturing of a various pharmaceutical compositions, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients. Summary of the invention

[0005] 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 malarial threonyl-tRNA synthetase (ThrRS).

[0006] 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 malaria threonyl-tRNA synthetase (ThrRS).

[0007] 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 malaria threonyl-tRNA synthetase (ThrRS), in the manufacture of a medicament for treatment or prevention of malaria infections.

[0008] 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 malaria threonyl-tRNA synthetase (ThrRS).

[0009] In one embodiment an inhibitor of malaria threonyl-tRNA synthetase (ThrRS) is a compound of Formula I, generally referred herein as 2-amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3- hydroxybutanamide derivative: General formula I I wherein:

[0010] R is H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl,

[0011] wherein: 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, -NR3or –C(R3)R4, YArepresents oxygen, sulfur, -NR3or –C(R3)R4, ZArepresents oxygen, sulfur, -NR3or –C(R3)R4;

[0012] wherein: R3and R4are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C1-6alkoxyC1-6alkyl, aryloxyarylC1-6alkoxy, C1-6alkylthio, C4-6alkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-C1-6alkylthio, cycloC3-12alkyl-C3-6alkenylthio, C1-6alkoxyC1-6alkylthio, C1-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylC1-6alkylthio, C1-6alkylsulfonyl, cycloC3-12alkyl-C1-6alkylsulfonyl, arylC1-6alkylsulfonyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, C1-C6alkoxy- cycloC3-C12alkylamino, cycloC3-12alkyl-C1-6alkylamino, di-C1-6alkylaminoC1-6alkyl, C1-6alkoxy- C2-6alkylamino, arylamino, arylC1-6alkylamino, N-cycloC3-12alkyl-N-C1-6alkylamino, N-aryl-N- C1-6alkylamino, N-arylC1-6alkyl-N-C1-6alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H- isoindol-2-yl, heteroarylC1-6alkoxy, heteroarylamino, or heteroarylC1-6alkylamino.

[0013] and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. Definitions

[0014] The term “alkyl” refers to a straight or branched hydrocarbon chain, containing the indicated number of carbon atoms. For example, C1-12alkyl indicates that the alkyl group may have from 1 to 12 (inclusive) carbon atoms.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] The term “aryl” refers to refers to phenyl and naphthyl.

[0019] The term “biaryl” refers to two arylgroups linked with a single bond.

[0020] The term “heteroaryl” refers to an aromatic ring having 1-6 heteroatoms.

[0021] 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.

[0022] The term “optical isomers” refers to any stereoisomeric representation of a compound.

[0023] The term “hydrates” refers to a crystal of a compound containing any stoichiometry of water.

[0024] The term “solvates” refers to refers to a crystal of a compound containing any stoichiometry of any solvent.

[0025] The term “polymorphs” refers any type of crystal formed by a compound.

[0026] The term “prodrug” refers to any derivative of a compound that, after intake, is metabolized into a pharmacologically active drug.

[0027] 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.

[0028] In one embodiment, the treatment is treatment of a disease or disorder that is mediated by a malarial threonyl t-RNA synthetase or human threonyl t-RNA synthetase or fungal threonyl t- RNA synthetase or bacterial threonyl t-RNA synthetase. In one embodiment, the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a malarial threonyl t-RNA synthetase or human threonyl t-RNA synthetase or fungal threonyl t-RNA synthetase or bacterial threonyl t-RNA synthetase. In one embodiment, the treatment is treatment of a disease or disorder that is treated by malarial threonyl t-RNA synthetase or human threonyl t-RNA synthetase or fungal threonyl t-RNA synthetase or bacterial threonyl t-RNA synthetase. In another aspect, the invention features a kit comprising a 2-amino-N-(benzo[d]thiazol-2- ylsulfonyl)-3-hydroxybutanamide derivative described herein, preferably provided as a pharmaceutical composition and in a suitable container and / or with suitable packaging. In another aspect, the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. In another aspect, the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. In another aspect, the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein. In another aspect, the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. Detailed description of the invention

[0029] According to this invention, the results from ThrRS inhibition studies demonstrate that 2- amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives are novel class inhibitors of ThrRS. Several example compounds from the present invention display nanomolar to low micromolecular ThrRS inhibitory potency. Stereochemistry

[0030] 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. Combinations

[0031] 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. Examples of Specific Embodiments

[0032] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

[0033] The following 2-amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives 1 were prepared as examples of the current invention. General Synthesis

[0034] 2-Amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide (1.1) was prepared by coupling of benzothiazole sulfonamide 2 with protected threonine 3 to give a protected intermediate 4.1 (Scheme 1). This was deprotected using TFA in DCM (general method A) to give the target compound 1.1. Scheme 1

[0035] 2-Amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivative 1.2 was prepared according to the scheme 2. 2,5-Dibromoaniline (5) was subjected to the reaction with potassium ethyl xanthate to give mercaptothiazole 6. This was oxidized to sulfonylchloride which in turn was transformed to sulfonamide 7 by the reaction with ammonia. Sulfonamide 7 was coupled with protected threonine 3 to give intermediate 8 which was further transformed to boronic acid derivative 9 as a mixture of boronic acid 9a and boronic acid ester 9b by using palladium catalysed coupling with pinacol diborane. This was coupled with pyrimidine derivaitive 10 to give intermediate 4.2. which was subjected to deprotection using method A to give the target compound 1.2. Scheme 2

[0036] 2-Amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivatives 1.3 – 1.14 were prepared according to the scheme 3 starting from intermediate 8. This was coupled with the range of boronic acids to give intermediates 4.3-4.14 (general method B). Deprotection in acidic media (general method A) provided target compounds 1.3-1.14.

[0002] Scheme 3 Synthesis description

[0037] t-Butyl (1-(benzo[d]thiazole-2-sulfonamido)-3-(t-butoxy)-1-oxobutan-2-yl)carba-mate (4.1): To the solution of Boc-Thr(t-Bu)-OH 3 (206 mg, 0.75 mmol) in DMF (5 mL) was added benzo[d]thiazole-2-sulfonamide (2) (145 mg, 0.68 mmol), HBTU (341 mg, 0.9 mmol), DIPEA (0.32 mL, 1.88 mmol) and catalytic amounts of DMAP (18 mg, 0.15 mmol). Reaction mixture was left stirring at rt for overnight. After the completion of reaction, the mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phase was washed with 1.0 M aq. HCl, H2O, sat. aq. NaCl, dried over Na2SO4and concentrated under reduced pressure. The reaction mixture was purified by chromatography (C18 silica gel, 95 / 5- 0 / 100 v / v H2O / MeCN) to giveproduct 4.1 (268 mg, 76%) 1H NMR (400 MHz, CDCl3) ^ 10.73 (s, 1H), 8.24-8.16 (m, 1H), 8.05-7.95 (m, 1H), 7.69-7.54 (m, 2H), 5.30 (d, J=5.8 Hz, 1H), 4.29 (t, J=5.2 Hz, 1H), 4.21-4.12 (m, 1H), 1.40 (s, 9H), 1.34 (s, 9H), 1.07 (d, J=6.5 Hz, 3H).

[0038] 5-Bromobenzo[d]thiazole-2-thiol (6): 2,5-Dibromoaniline (5) (4.00 g, 15.94 mmol) and potassium ethyl xanthate (4.34 g, 27.10 mmol) were dissolved in DMF (26 mL). The reaction mixture was left stirring at 125oC overnight. Then the reaction mixture was cooled to r.t. and filtered. The filtrate was diluted with H2O and the pH was adjusted to 1-2 using aq.2 M HCl. The solid precipitate was collected and washed with H2O and dried to obtain product 6 (3.7 g, 94%).1H NMR (400 MHz, DMSO) δ 13.83 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.5, 1.9 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H).13C NMR (101 MHz, DMSO) δ 190.73, 142.49, 128.74, 126.84, 123.59, 119.82, 114.77.

[0039] 5-Bromobenzo[d]thiazole-2-sulfonamide (7): The solution of compound 6 (1.50 g, 6.09 mmol) in aq. NaOH (292 mg, 7.31 mmol in H2O 30 mL) and 10% NaOCl (6.43 mL, 10.35 mmol) was slowly simultaneously added to 25% aq. NH3(40 mL) while maintaining the temperature of the solution to 0oC. Then the reaction mixture was stirred at 0oC for 40 min (control by LC / MS). The formed precipitate was collected by filtration, washed with cold water and dried in vacuo. The solid was dissolved in THF (50 mL) and m-CPBA (3.00 g, 12.19 mmol) was then added. After the completion of the reaction as monitored by TLC, the reaction mixture was evaporated and diluted with EtOAc, washed with aq. NaHCO3(3x), dried over Na2SO4, and concentrated under reduced pressure. The reaction mixture was purified by chromatography (silica gel, 70 / 30 v / v petrolether / EtOAc) to give product 7 (870 mg, δ 8.42 (d, J = 1.9 Hz, 1H), 8.41 (s, 2H), 8.24 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.7, 1.9 Hz, 1H).13C NMR (101 MHz, DMSO) δ 171.44, 152.96, 134.90, 130.35, 126.60, 125.14, 120.38.

[0040] t-Butyl ((2S,3R)-1-(5-bromobenzo[d]thiazole-2-sulfonamido)-3-(tert-butoxy)-1- oxobutan-2-yl)carbamate (8): To the solution of Boc-Thr(t-Bu)-OH 3 (780 mg, 2.83 mmol) in DMF (8 mL) was added 5-bromobenzo[d]thiazole-2-sulfonamide (7) (830 mg, 2.83 mmol), HBTU (1.07 g, 2.83 mmol), TEA (0.79 mL, 5.66 mmol) and a catalytic amount of DMAP (34 mg, 0.10 mmol). The reaction mixture was left stirring at r.t. overnight. After the completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phase was washed with 1.0 M aq. HCl, H2O, sat. aq. NaCl, dried over Na2SO4 and concentrated under reduced pressure. The reaction mixture was purified by chromatography (C18 silica gel, 95 / 5- 0 / 100 v / v H2O / MeCN) to give product 8 (860 mg, 55%).1H NMR (300 MHz, CD3CN) δ 8.37 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 8.8, 2.0 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 4.16 (d, J = 7.2 Hz, 1H), 4.05 (qd, J = 6.3, 3.2 Hz, 1H), 1.37 (s, 9H), 1.12 (s, 9H), 1.07 (d, J = 6.5 Hz, 3H).13C NMR (101 MHz, CD3CN) δ 171.10, 167.19, 156.40, 153.83, 136.91, 132.16, 128.44, 125.25, 121.80, 80.49, 76.18, 67.94, 61.04, 28.37, 28.26, 19.41.

[0041] t-Butyl ((2S,3R)-3-(t-butoxy)-1-oxo-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo [d]thiazole-2-sulfonamido)butan-2-yl)carbamate and (2-(N-((2S,3R)-3-(t-butoxy)-2- ((t-butoxycarbonyl)amino)butanoyl)sulfamoyl)benzo[d]thiazol-5-yl)boronic acid 9a and 9b: The solution of bis(pinacolato)diboron (90 mg, 0.35 mmol), PdCl2(dppf)CH2Cl2(44 mg, 0.05 mmol), KOAc (80 mg, 0.82 mmol), and compound 8 (150 mg, 0.27 mmol) in DMF (1.5 mL) was flushed with argon and heated at 100 °C for 5 h in a sealed tube. The reaction mixture was filtered through Celite®and concentrated under reduced pressure and purified by chromatography (C18 silica gel, 95 / 5- 0 / 100 v / v H2O / MeCN) 83 mg of mixture of products 9a and 9b. LC-MS: m / z calculated C20H31BN3O8S2[M + H+]: 516.4; found 516.2 and LC-MS: m / z calculated C26H40BN3O8S2[M + H+]: 598.5; found 598.8

[0042] t-Butyl ((2S,3R)-1-(5-(6-aminopyrimidin-4-yl)benzo[d]thiazole-2-sulfonamido)-3-(t- butoxy)-1-oxobutan-2-yl)carbamate (4.2): The a solution of boronic acid 9a and boronic ester 9b (83 mg), Na2CO3(51 mg, 0.48 mmol), 4-amino-6-chloropyrimidine (21 mg, 0.16 mmol), and PdCl2(dppf)CH2Cl2(26 mg, 0.032 mmol) in a mixture of 1,4-dioxane / H2O (3:1, 2.4 mL) was flushed with argon and heated at 110 °C in a sealed tube for 5 h. After the completion of the reaction, the mixture was filtered through Celite®and concentrated under reduced pressure. The reaction mixture was purified by chromatography (C18 silica gel, 95 / 5- 0 / 100 v / v H2O / MeCN) to give product 4.2 (29 mg, 32%).1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 1.7 Hz, 1H), 8.48 (d, J = 1.1 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.11 (dd, J = 8.5, 1.7 Hz, 1H), 7.01 (s, 1H), 6.96 (s, 2H), 5.22 (d, J = 9.8 Hz, 1H), 3.98 (dt, J = 7.1, 3.6 Hz, 1H), 3.62 (dd, J = 9.8, 3.2 Hz, 1H), 1.37 (s, 9H), 1.02 (d, J = 6.2 Hz, 3H), 0.98 (s, 9H).13C NMR (101 MHz, DMSO) δ 175.58, 174.31, 164.49, 160.31, 158.74, 155.02, 152.61, 137.72, 135.97, 124.24, 122.73, 121.19, 100.02, 77.82, 72.74, 68.21, 61.55, 28.45, 28.20, 21.46. LC-MS: m / z calculated C24H33N6O6S2[M + H+]: 565.6; found 565.7.

[0043] General method B. Suzuki-Miyaura coupling of t-butyl ((2S,3R)-1-(5- bromobenzo[d]thiazole-2-sulfonamido)-3-(tert-butoxy)-1-oxobutan-2-yl)carbamate (8) with boronic acids.

[0044] The solution of t-butyl ((2S,3R)-1-(5-bromobenzo[d]thiazole-2-sulfonamido)-3-(tert- butoxy)-1-oxobutan-2-yl)carbamate (8) (1 equiv.), Na2CO3(3 equiv.), boronic acid (1.10 equiv), and PdCl2(dppf)CH2Cl2(15 mol%) in 1,4-dioxane / H2O (3 / 1, v / v) was flushed with argon and heated at 100 °C in a sealed tube for 3 – 5 h (control by LC / MS). After the completion of reaction, the mixture was filtered through Celite® and concentrated under reduced pressure. The reaction mixture was purified by chromatography (C18 silica gel, 95 / 5- 0 / 100 v / v H2O / MeCN). By a method analogous to Method B, the following compounds were obtained: Physicochemical characterization of compounds 4.3-4.14 General method A. N-Boc and t-Bu deprotection: To the solution of compound 4 (1 equiv.) in DCM was added TFA (50 equiv.) at r.t. The reaction mixture was left stirring at rt for ½ – 1 h (control by LC / MS). After the completion of reaction, the mixture was concentrated under reduced pressure. The reaction mixture was purified by chromatography (C18 silica gel, 98 / 2- 0 / 100 v / v H2O / MeCN) or crystallized from MeCN By a method analogous to Method A, the following compounds were obtained: Physicochemical characterization of compounds 1.1-1.14 In vitro Assay

[0045] The compounds have been tested for antimalarial activity in vitro as malarial threonyl-tRNA synthetase inhibitors according to the following process: The bioassay protocol was adapted from literature (J. Guo, B. Chen, Y. Yu, B. Cheng, Y. Ju, J. Tang, Z. Cai, Q. Gu, J. Xu and H. Zhou, Structure-guided optimization and mechanistic study of a class of quinazolinone-threonine hybrids as antibacterial ThrRS inhibitors. Eur. J. Med. Chem., 2020, 207, 112848) The aminoacylation activity of PfThrRS in the presence of compounds was determined by measuring ATP consumption in the enzymatic reaction by using recombinant PfThrRS and P. falciparum cell extract as a source of t-RNA. ATP consumption was determined by Kinase-Glo® Reagent (Promega Inc.). The luminescence was read on a Tecan Infinite M1000 microplate reader. The inhibitory rate was measured in three independent assays. Borrelidin was obtained from commercial sources and used as a reference compound.

[0046] IC50values for selected inhibitors of threonyl-tRNA synthetase inhibitors are given in Table Table 1. Biological activity of 2-amino-N-(benzo[d]thiazol-2-ylsulfonyl)-3-hydroxybutanamide derivative 1.

Claims

Claims A compound of Formula II wherein: R is H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, R1O(CH2)n, R1S(CH2)n, R1OC(=O)(CH2)n, R1N(R2)C(=O)(CH2)n, R1N(R2)(CH2)n, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR1, -O-L-NH2, -O-L-NHR1, -O-L-N(R1)R2, -L-OR1,-O-L-OR1,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR1,-O-L-OR1,-OCF3, -OCH2CF3, -OCF2CF2H, SR1, SCF3, - CN, -NO2, -NO2, -NH2, -NHR1, -NR12, -N(R1)R2, -L-NH2, -L-NHR1, -L-NR12, -L-N(R1) R2,-NH-L-NH2, -NH-L-NHR1, -NH-L-N(R1)R2, -NH-L-N(R1)R2,-NR1-L-NH2, -NR1-L-NHR1, -NR1-L-N(R1)R2, -NR1-L-N(R1)R2, -N(R1)R2, -C(=O)OH, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR1, -C(=O)N(R1)R2, -C(=O)N(R1)R2,-NHC(=O)R1, -NR1C(=O)R2, -NHC(=O)OR1, -NR1C(=O)OR1, -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)N(R1)R1, -OC(=O) R1NR1,-OC(=O)R1, -C(=O)R1,-NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR12, -NHC(=O)N(R1)R2, -NR1C(=O)NH2, -N(R1)C(=O)NHR2, -NR1C(=O)N (R1)R2wherein: 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, -NR3or –C(R3)R4,YArepresents oxygen, sulfur, -NR3or –C(R3)R4, ZArepresents oxygen, sulfur, -NR3or –C(R3)R4; wherein: R3and R4are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C1-6alkoxyC1-6alkyl, aryloxyarylC1-6alkoxy, C1-6alkylthio, C4-6alkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-C1-6alkylthio, cycloC3-12alkyl-C3-6alkenylthio, C1-6alkoxyC1-6alkylthio, C1-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylC1-6alkylthio, C1-6alkylsulfonyl, cycloC3-12alkyl-C1-6alkylsulfonyl, arylC1-6alkylsulfonyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, C1-C6alkoxy- cycloC3-C12alkylamino, cycloC3-12alkyl-C1-6alkylamino, di-C1-6alkylaminoC1-6alkyl, C1-6alkoxy- C2-6alkylamino, arylamino, arylC1-6alkylamino, N-cycloC3-12alkyl-N-C1-6alkylamino, N-aryl-N- C1-6alkylamino, N-arylC1-6alkyl-N-C1-6alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H- isoindol-2-yl, heteroarylC1-6alkoxy, heteroarylamino, or heteroarylC1-6alkylamino; 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. The compound according to Claim 1 or 2 for use as medicament, wherein the compound has a structure:.

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

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

6. The compound according to Claims 1 or 2 for use in the treatment of malaria.

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