CA3144846A1

CA3144846A1 - Novel boronic acid containing peptidomimetics as malarial serine protease inhibitors

Info

Publication number: CA3144846A1
Application number: CA3144846A
Authority: CA
Inventors: Aigars Jirgensons; Elina LIDUMNIECE; Chrislaine Withers-Martinez; Michael BLACKMAN; Paul William Finn
Original assignee: Latvian Institute of Organic Synthesis
Current assignee: Latvian Institute of Organic Synthesis
Priority date: 2019-07-01
Filing date: 2020-04-09
Publication date: 2021-01-07
Also published as: LV15544A; WO2021001697A1; DE112020003182T5

Abstract

The invention relates to novel boric acid-containing peptidomimetics I, (I) acting as inhibitors of the malaria subtilisin-related serine protease (SUB). They are useful as medicinal preparations or as ingredients for the treatment of malaria.

Description

NOVEL BORONIC ACID CONTAINING PEPTIDOMIMETICS AS MALARIAL SERINE
PROTEASE INHIBITORS
Field of invention [1] 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 boronic acid containing peptidomimetics and pharmaceutical compositions thereof and their use as inhibitors for subtilisin-like serine proteases (SUB).
Background of invention

[2] 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. 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)

[3] 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 active-site 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 VL, Vizcay-Barrena G, Fleck RA, Snijders AP, Saibil HR, Blackman MJ. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells.
Nat Microbiol.
2018, 3(4),447-455).

[4] Several inhibitors for SUB subtype PfSUB1 have been developed (Kher, S.
S.;
Penzo, M.; Fulle, S.; Finn, P. W. ; Blackman, M. J.; Jirgensons, A. Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUB1.Bioorg.
Med. Chem.
Lett., 2014, 24(18), 4486-4489), however, so far none of them have advanced to clinical trial.
Summary of the invention

[5] 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).

[6] 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).

[7] 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.

[8] 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).

[9] In one embodiment the inhibitor of subtilisin-like serine proteases (SUB) is a compound of Formula I, generally referred herein as boronic acid containing peptidomimetic:

[10] General formula I

Rio R7 H 0 R4 R2 H 1 N.-.LNH.iNB,Ri R6 R5 ,.., n rµ
[ i 1] wherein:
[12] R4 is H or Me;
[13] R3 is H, Ci_6alkyl, cycloC3_12alkyl, cycloC3_12alkyl-Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, aryl, biaryl, arylCi_6alkyl, ary1C2_6alkenyl, ary1C2_6alkynyl, heteroaryl, heteroarylCi_6alkyl, heteroary1C2_6alkenyl, R120(CH2)õ, R12S(CH2)., R120C(=0)(CH2),, R12N(R13)C(=0)(CH2), R12N (R13)(CH2), Wherein R12 and R13 are independently H, Ci_6alkyl, cycloC3_12alkyl, cycloC3_12alkYl-C1-6alkyl, C2_6alkenyl, C2_6alkynyl, aryl, biaryl, arylCi_6alkyl, ary1C2_6alkenyl, ary1C2_6alkynyl, heteroaryl, heteroarylCi_6alkyl, heteroary1C2_6alkenyl [14] n is an integer selected from 1 to 6;
[15] R1, R2, R5,R6, R7, R8, R9, R10, R11 are independently -H, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-0-L-OH, -0R14, -0-L-NH2, -0-L-NHR14, -0-L-NR142, -0-L-R14NR15, -L-0R14,-0-L-0R14,-0CF3, -OCH2CF3, -0CF2CF2H, -L-0R14,-0-L-0R14,-0CF3, -OCH2CF3, -0CF2CF2H, SR14, SCF3, -CN, -NO2, -NO2, -NH2, -NHR14, -NR142, -N(R14)R15, -L-NH2, -L-NHR14, -L-NR142, -L-N(R14) R15,-NH-L-NH2, -NH-L-NHR14, -NH-L-NR142, -NH-L-N(R14)R15, -NR14-L-NH2, -NR14-L-NHR14, -NR14-L-NR142, -NR14-L-N(R14)R15, L-N(R14)R15, -C(=0)0H, -C(=0)0R14, -C(=0)NH2, -C(=0)NHR14, -C(=0)NR142, -C(=0)N(R14)R15,-NHC(=0)R14, -NR14C(=0)R15, -NHC(=0)0R14, -NR14C(=0)0R15, -0C(=0)NH2, -0C(=0)NHR14, -0C(=0)NR142, -0C(=0) R14NR15,-0C(=0)R14, -C(=0)R13,-NHC(=0)NH2, -NHC(=0)NHR14, -NHC(=0)NR142, -NHC(=0)N(R14)R15, -NR14C(=0)NH2, -N(R14)C(=0)NHR15, -NR14C(=0)NR142, -NR14C(=0)N
-NHS(=0)2R14, -N(R14)S(=0)2R15,-S(=0)2NH2, -S(=0)2NHR14, -S(=0)2NR142, -S(=0)2N(R14)R15,-S(=0)R14, -S(=0)2R14,-0S(=0)2R14,-S(=0)20R14, [16] Ci_6a1ky1, cyc1oC3_12alky1, cycloC3_12alkyl-Ci_6alky1, C2_6alkeny1, C2_6alkyny1, aryl, biaryl, arylCi_6alkyl, ary1C2_6a1keny1, ary1C2_6a1kyny1, heteroaryl, heteroarylCi_6alkyl, heteroary1C2_6a1keny1, heteroarylthio, 2,3-dihydro-1H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1_6a1ky1piperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1 ,3-dihydro-2H-isoindo1-2-y1;
or R5, R7, R8, are independently =0,=NR14,=NOH, or =N0R14;
[17] L represents -W-X-Y-Z-; or -W-X-Y, or or -W-X
Ri and R2 or R1 and R3 or R5 and R6 or R7 and R8 or R7 and R11 or R8 and R9 or R9 and R1 or Rlo and R11 taken together represent -W-X-Y-Z-, or -W-X-Y-, or -W-X- or wherein W represents a single bond, oxygen, sulfur, -NR14 or -CR14R15, X represents oxygen, sulfur, -NR14 or -C(R14)R15, Y represents oxygen, sulfur, -NR14 or -C(R14)R15, Z represents oxygen, sulfur, -NR14 or -C(R14)R15;
[18] R14 and R15 are independently H, Ci_6alkyl, cycloC3_12alkyl, cycloC3_12alkyl-Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, aryl, biaryl, arylCi_6alkyl, ary1C2_6alkenyl, ary1C2_6alkynyl, heteroaryl, heteroarylCi_6alkyl, heteroary1C2_6alkenyl, heteroarylthio, 2,3-dihydro- 1 H-indenyl, Ci_6alkoxyCi_6alkyl, aryloxyarylCi_6alkoxy, Ci_6alkylthio, C4_6alkenylthio, cycloC3_12alkylthio, cycloC 3- 12 alkyl-C 1_6a1ky1thio, cycloC 3- 12 alkyl-C 3_6alkenylthio, Ci_6alkoxyCi_6alkylthio, C 1-6alkoxyC3_6alkenylthio, ary1C3_6alkenylthio, heteroarylCi_6alkylthio, Ci_6alkylsulfonyl, cycloC3_12alkyl-C1_6a1ky1su1fony1, ary1C 1_6 alkylsulfonyl, C 1_6 alkylamino, di-Ci_6alkylamino, cycloC3_12alkylamino, C 1 -C6alkoxy-cycloC3-C 12 alkylamino, cycloC3_12alkyl-C
1_6 alkylamino, di-Ci_6alkylaminoCi_6alkyl, Ci_6alkoxy-C2_6alkylamino, arylamino, arylCi_6alkylamino, N-cycloC3-12 alkyl-N-C 1_6 alkylamino, N-aryl-N-C 1_6 alkylamino, N- ary1C 1_6a1ky1-N-C 1-6a1ky1amino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci_6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindo1-2-yl, heteroarylCi_6alkoxy, heteroarylamino, or heteroarylCi_6alkylamino;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[19] In one embodiment, the treatment is treatment of a disease or disorder that is mediated by a malarial serine protease or human serine proteases.
[20] In one embodiment, the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a malarial serine protease or human serine protease.
[21] In one embodiment, the treatment is treatment of a disease or disorder that is treated by a malarial serine protease or human serine protease inhibitor;
pharmaceutical composition intended for parenteral or peroral administration to humans.
[22] In another aspect, the invention features a kit comprising a boronic acid containing peptidomimetic as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
[23] 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.
[24] 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.
[25] In another aspect, the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
[26] In another aspect, the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
[27] 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.
Description of invention [28] Subtilisin-like serine (SUB) proteases are malarial serine proteases which have been identified as a group of promising biological targets for the development of new anti-malarial agents as these are involved in parasite egress from infected erythrocytes (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 active-site structure, specificity and function of a pan-malaria drug target.
International Journal for Parasitology 2012, 42, 597-612. Kher, S. S.; Penzo, M.; Fulle, S.;
Finn, P. W. ; Blackman, M. J.; Jirgensons, A. Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUB1. Bioorg. Med. Chem. Lett., 2014, 24(18), 4486-4489; Thomas JA, Tan MSY, Bisson C, Borg A, Umrekar TR, Hackett F, Hale VL, Vizcay-Barrena G, Fleck RA, Snijders AP, Saibil HR, Blackman MJ. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nat Microbiol. 2018, 3(4), 447-455).
[29] When testing the novel boronic acid containing peptidomimetic derivatives for their ability to inhibit SUB we have unexpectedly discovered, that said derivatives exhibit pronounced inhibitory properties toward said serine proteases and inhibition of parasite growth in red cells, and thus are useful in treatment of malaria.
[30] According to this invention, the results from SUB inhibition studies demonstrate that boronic acid containing peptidomimetic derivatives are novel class inhibitors of serine proteases. Several example compounds from the present invention display nanomolar to low micromolecular inhibitory potency.
Stereochemistry [31] 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 [32] 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 [33] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

[34] The following boronic acid containing peptidomimetic derivatives 9.1, 10.2-10.8 and

11.1-11.8 were prepared as examples of the current invention:
ID Cmpd. No Structure Me Me EP-529 o Xmer o 9.1.
Me)N H H
NN.,(1\113,(if: me t-BuO
H = H II -0 /7 Me 0 -ile 10.2 nneAirl ,. r..r uON y 6-0H
0 /Me 7, 0 2e tB

EP-783 10.3 H 1 meAN i<ANThrNyB4OH
H = H
0 BuO /-Me 0 Me t EP-827 10.4 H 1 meAN i<ANThrNyB4OH
H = H

uOMe 0 Ph tB

EP-860 10.5 OH
meAN NN.1\113,0E1 H = H H

tBuO Me 0 H H I
EP-834 10.6 me AN N-LNNB..,c)Ei H =Hili tBuO Me 0 --4-(Me0)C6H4/0 O H II H ? H
MeAN NN N B.
OH
H i 1-1( i EP-850 10.7 o uO /-Me 0 ---tB
--, 4 (Me0)C6H4) EP-851 10.8 H H I
me AN 1\1:AN.rNB,c) H = H
tBuO Me Me EP-530 11.1 MeAN
N H I
H , NThr , OH
0 N-ile HO Me H H ?H
11.2 MeNXININ
¨ .
H i N").r E OH
0 ===:- " 0 lc/le HO Me EP-785 o H on H ?H
11.3 MeNIX(NN N Bs 0 ...7 " 0 Me HO Me EP-833 o H 1? X v CA,.., H 1 õ
HO Me 11.4a MeI\IrN
).L
H i ,,-).i -r 0u , 0 , r0 Ph CF3 H ?I H ?H
11.4b Me)I\IX(N
H i r)*1NBsOH
0 0 Ph HO Me EP-863 o 0 OH
11.5 H H 1 Me)N1 N.LI\JrNB'OH
H = H
0HOMe 0 EP-837 o ti. 0 OH
11.6 N B ,......õ s Mel\I N.(1\11F1 I

H = H
0HOMe 0 -3-----/
EP-861 o H J OH
me)N N
11.7 H 1 Nr1\1,B4O
H 0 H 0 i) HO Me EP-852 Lo H J OH
me)N N
11.8 H 1 1\1(1\1B4O
H = H
0HOMe 0 General Synthesis [35] Boronic acid derivatives 9-11 were prepared according to scheme 1.
Coupling of amino acid derivatives 1 and 2 provided protected dipeptide 3. This was N-deprotected and subjected to coupling with amino acid 4 leading to protected tri-peptide 5.
This was N-deprotected and modified at the nitrogen to give intermediate 6. 0-deprotection gave acid 7 which was coupled with aminoboronic acid derivative 8. The resulting intermediate 9 was subjected to the cleavage of boronic ester and amino acid side chain protection leading to products 10 and 11.

Scheme 1 1. Deprotection , R9 Rs R4 -.R10 - R7 H2Nr0Pg OH op, rs9 8 R
0 0 R4 PgNH 4 R10 -- R7 H 0 R4 PgHNOH 2 0 PgHN.1.-11, N coupling ,--Lr-OPg 0 agent NjN)y)Pg R6..^.....R5 coupling agent H 0 . PgNH

Re R5 R6 R5 1 Method A 3 Method B 5

12 B, R9 Rs H2N y R1 R9 Rs Rio R7 H 0 R4 R3 Rio R7 H 0 R4 N-modification Deprotection Njr\irOH 8 Deprotection N
Nr0Pg __ I' RIME! H
RIME! 0 coupling agent .."..... c 0 :L)E1 0 Method C R6 R5 Method D Methods E, F

R9 Rs R9 Rs Rio R2 Cleavage of boronic ester and R7 0 R4 Rio R7 H

RIME! (yRi _________ H H 1 side chain deprotection -)..- Nj=LNHNB, )1.- RiiN1-1 N,ANNyB,Ri k..) -'N0 R3 Methods G,H, I 0 0 R
' R6 R5 R6NR5 10,11 Pg = Protecting group Synthesis of intermediates 3, general method A
[36] Exemplified by the synthesis of 3.1:
o o o HH2CI FmocHNN j=L
OMe ,OMe FmocHNJOH 2.1 . N"

t-BuOMe HATU, DIPEA, t-BuOMe DCM, it 1.1 3.1 [37] A mixture of glycine methyl ester hydrochloride (2.1) (401 mg, 3.2 mmol), Fmoc-Thr(tBu)-OH 1.1 (1.30 g, 3.2 mmol, 1 eq.), HATU (1.34 g, 3.5 mmol, 1.1 eq.) and DIPEA
(1.66 mL, 9.6 mmol, 3 eq.) in DCM (40 mL) was stirred for 2 h at room temperature. The reaction mixture was washed with H20 (2x20 mL) and then with brine (20 mL).
Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane: Et0Ac, 4:1 - 1:1 (Rf=-0.5, when Hex:Et0Ac 2:1) to provide 3.1 (1.37 g, 92 %) as a solid compound.
[38] 1H NMR (400 MHz, Chloroform-d) 6 7.76 (d, J = 7.4 Hz, 2H), 7.68 - 7.57 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 6.00 (d, J = 4.9 Hz, 1H), 4.45 - 4.34 (m, 2H), 4.28 - 4.16 (m, 3H), 4.16 - 4.00 (m, 2H), 3.78 (s, 3H), 1.31 (s, 9H), 1.09 (d, J = 6.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) 6 170.0, 169.8, 156.1, 144.0, 143.8, 141.45, 141.43, 127.8, 127.2, 125.3, 120.12, 120.10, 75.8, 67.1, 66.7, 58.7, 52.5, 47.3, 41.5, 28.3, 16. 9.

HR-MS (ESI/TOF) calcd for C26H33N206 [M+H] 469.2339, found 469.2337.
[39] By a method analogous to Method A, the following compounds were obtained:
Compound Procedure Precursor Structure No 3.1. A 1.1 and 2.1 FmocHNJ-NOMe = H II

t-BuOMe JL
3.2. A 1.1 and 2.2 FmocHN . N -0Et = H

t-BuOMe Synthesis of intermediates 5, general method B
[40] Exemplified by the synthesis of 5.1:
Me 0 XV:er 0 H
FmocHN,......õ-11, Me 1 DMF, 120 C OMe FmocHN
t-BuOMe 0 2 Fmoc-Ile-OH (4.1), HATU,DIPEA, 0 0 t-BuO Me 3.1 DMF, it 5.1 [41] A mixture of 3.1 (279 mg, 0.60 mmol) in DMF (4 mL) was refluxed at 120 C
for 2 h (till full conversion, LC-MS control) then reaction mixture was cooled to rt.
Under an argon atmosphere. N-Fmoc-L-isoleucine (4.1.) (211 mg, 0.60 mmol, 1 eq.), HATU (272 mg, 0.72 mmol, 1.2 eq.) and D1PEA (310 tL, 1.80 mmol, 3 eq.) were added to the solution of free intermediate amine (147 mg, 0.60 mmol). The reaction mixture was stirred for 4 h at room temperature, then diluted with Et0Ac (20 mL) washed with H20 (3x10 mL) and then with brine (10 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo.
The residue was purified by flash chromatography on silica gel eluting with hexane: Et0Ac, 2:1 - 1:1 - Et0Ac to provide 5.1 (253 mg, 73 %) as a solid compound.
[42] 1H NMR (400 MHz, Chloroform-d) 6 7.76 (d, J = 7.2 Hz, 2H), 7.68 (t, J =
5.2 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 6.93 (d, J =
5.7 Hz, 1H), 5.44 (d, J = 8.3 Hz, 1H), 4.45 (dd, J = 10.6, 7.4 Hz, 1H), 4.41 -4.31 (m, 2H), 4.25 -4.18 (m, 2H), 4.14 (dd, J = 8.3, 5.6 Hz, 1H), 4.11 -3.99 (m, 2H), 3.75 (s, 3H), 1.94 -1.79 (m, 1H), 1.60 - 1.45 (m, 1H), 1.30 (s, 9H), 1.28 - 1.12 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.98 - 0.87 (m, 6H).
13C NMR (101 MHz, Chloroform-d) 6 171.1, 170.0, 169. 7, 156.3, 144.1, 143.9, 141.4, 127.8, 127.2, 125.3, 125.2, 120.12, 120.10, 75.8, 67.2, 66.1, 59.7, 57.6, 52.4, 47.3, 41.5, 38.1, 28.3, 25.1, 17.2, 15.6, 11.7.

HR-MS (ESI/TOF) calcd for C32H43N307Na [M+Na] 604.2999, found 604.3001.
[43] By a method analogous to Method B, the following compounds were obtained:
Compound Procedure Precursor Structure No Me Xvi.er 5.1. B 3.1 and 4.1 H
N FmocHN ,OMe t-BuO Me H
5.2. B 3.2 and 4.2 N OEt FmocHN N
Hr t-BuO Me Synthesis of intermediates 6, general method C
[44] Exemplified by the synthesis of 6.1:
Me Me Xvle Me r H 0 0 H 0 FmocHN N j.L N 1 ome 2 ADc M 20F,, 1D2i0 C II pEA, r\Ae NN Nj=L OMe H H II
0 0 DMF, rt 0 /7 0 t-Buo Me t-BuO Me 5.1 6.1 [45] A mixture of dipeptide 5.1 (246 mg, 0.42 mmol) in DMF (4 mL) was refluxed at 120 C for 2 h (till full conversion) then reaction mixture was cooled to rt. Under an argon acetic anhydride (60 tL, 0.63 mmol, 1.5 eq.) and D1PEA (146 tL, 0.84 mmol, 2 eq.) were added to the solution of amine (152 mg, 0.42 mmol, based on a theoretical yield of 100 %). Reaction mixture was stirred for 5 h at room temperature, then diluted with Et0Ac (20 mL) washed with H20 (3x10 mL) and then with brine (10 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:Et0Ac 1:1 - Et0Ac to provide intermediate 6.1 (114 mg, 67 %) as a solid compound.
[46] 1H NMR (400 MHz, Chloroform-d) 6 7.66 (t, J = 5.2 Hz, 1H), 6.91 (d, J =
5.8 Hz, 1H), 6.25 (d, J= 8.3 Hz, 1H), 4.43 -4.33 (m, 2H), 4.16 (qd, J= 6.4, 3.8 Hz, 1H), 4.15 - 3.97 (m, 2H), 3.75 (s, 2H), 2.02 (s, 3H), 1.87 - 1.76 (m, 1H), 1.57 - 1.42 (m, 1H), 1.28 (s, 9H), 1.25- 1.08 (m, 1H), 1.04 (d, J= 6.4 Hz, 3H), 0.96 - 0.85 (m, 6H).
13C NMR (101 MHz, Chloroform-d) 6 171.2, 170.1, 170.0, 169.6, 75.7, 66.2, 57.8, 57.6, 52.4, 41.5, 38.1, 28.3, 25.3, 23.4, 17.2, 15.5, 11.6.
LC-MS (ESI) calcd for C19H36N306 [M+H] 402.51, found 402.55.
[47] By a method analogous to Method C, the following compounds were obtained:

Compound Procedure Precursor Structure No Me rView 0 6.1. C 5.1 AcHNXi\i,A
. NrOMe z H

t-BuO Me H
6.2. B 5.2 1\1,(0Et AcHN
z H

t-BuO Me Synthesis of intermediates 7, general method D
[48] Exemplified by the synthesis of 7.1:
Me Me 0 X\11; 0 Li0H, 0 X7H 0 A EN1J'L Me N ome THF: Me N
H20 (20:1) .._ A i\JJL 1.(OH
N . N -H z H H z H
0 j, , 0 0 /7.,. 0 t-BuO me t-BuO me 6.1 7.1 [49] Tripeptide 6.1 (114 mg, 0.28 mmol) was dissolved in THF:H20 (20:1, 5 mL), then LiOH (68 mg, 2.84 mmol, 10 eq.) was added and reaction was stirred at room temperature for 20 h. Then water (5 mL) was added and mixture was acidified to pH=-2 by addition of 1 M
HC1, then it was extracted with Et0Ac (4x5mL). Organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to provide product 7.1 (107 mg, 97 %) as a white solid.
[50] By a method analogous to Method D, the following compounds were obtained:
Compound Procedure Precursor Structure No Me 7.1 D 7.1 A ENLA
Me N . N.,(OH
H z H
0 /7, , 0 t-BuO me 7.2 D 7.2 meAN Nj=Lrer0H
H z H
t-BuO Me [51] Physicochemical characterization of compounds 7.1-7.2 Compound Physicochemical characterization No 1H NMR (400 MHz, Chloroform-d) 6 7.66 (t, J = 4.9 Hz, 1H), 7.54 (d, J = 6.5 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.56 (dd, J =
8.8, 7.0 Hz, 1H), 4.46 (dd, J = 6.6, 3.7 Hz, 1H), 4.19 - 4.04 (m, 3H), 2.05 (s, 3H), 1.84 - 1.72 (m, 1H), 1.57 - 1.46 (m, 1H), 1.26 (s, 9H), 1.21 - 1.08 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H), 0.96 - 0.83 7.1 (m, 6H).
13C NMR (101 MHz, Chloroform-d) 6 171.7, 171.6, 171.0, 169.8, 75.6, 66.4, 57.8, 42.0, 38.1, 28.3, 25.1, 23.3, 17.5, 15.5, 11.4.
HR-MS (ESI/TOF) calcd for C18H33N306Na [M+Na] 410.2267, found 410.2275.
1H NMR (400 MHz, Chloroform-d) 6 10.85 (br s, 1H), 7.69 (t, J =
5.0 Hz, 1H), 7.63 (d, J = 6.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 4.59 (t, J = 8.5 Hz, 1H), 4.46 (dd, J = 6.5, 3.9 Hz, 1H), 4.21 - 4.04 (m, 2H), 2.15 (h, J = 8.3 Hz, 1H), 2.03 (s, 3H), 1.75 - 1.55 (m, 4H), 1.56 - 1.42 (m, 2H), 1.41 - 1.29 (m, 2H), 1.27 (s, 9H), 1.00 7.2 (d, J= 6.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) 6 172.2, 171.5, 171.1, 169.7, 75.7, 66.5, 57.7, 56.9, 43.4, 42.0, 29.4, 29.0, 28.2, 25.3, 24.9, 23.2, 17.3.
HR-MS (ESI/TOF) calcd for C19H33N306Na [M+Na] 422.2267, found 422.2268.
Synthesis of boronic acid esters 9, general method E
[52] Exemplified by the synthesis of 9.1:
HCI :C11)<Me Me I-12N (YµNle Me Me Me 8.1 XV:erH HATU, DIPEA j t X7H 0". me H cp<
me,-% N [NirOH ________ Me' -N Ni g.11\*-'d. Me H DCM
t-guO/Me 0 z o t-BuOMe 7.1 9.1 [53] A mixture of (+)-pinanediol (1R)- (1-aminoethyl)boronate hydrochloride (8.1) (40 mg, 0.15 mmol), 7.1 (60 mg, 0.15 mmol, 1 eq.), HATU (71 mg, 0.19 mmol, 1.2 eq.) and DIPEA

13 (80 tL, 0.46 mmol, 3 eq.) in DCM (4 mL) was stirred for 2 h at room temperature. The reaction mixture was washed with H20 (2x10 mL) and then with brine (10 mL).
Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-5 % Me0H in Et0Ac to provide 9.1 (50 mg, 55 %) as a solid compound.
[54] 1H NMR (400 MHz, Chloroform-d) 6 7.78 (d, J = 6.4 Hz, 1H), 7.62 (t, J =
5.5 Hz, 1H), 7.54 (d, J = 4.1 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 4.68 (dd, J = 8.5, 6.1 Hz, 1H), 4.40 (dd, J = 6.3, 3.9 Hz, 1H), 4.26 (dd, J = 8.8, 2.1 Hz, 1H), 4.23 - 4.00 (m, 3H), 3.07 - 2.95 (m, 1H), 2.36 - 2.26 (m, 1H), 2.20 - 2.09 (m, 1H), 2.06 - 1.96 (m, 4H), 1.90 -1.70 (m, 3H), 1.56 - 1.45 (m, 1H), 1.37 (s, 3H), 1.35 - 1.23 (m, 13H), 1.20- 1.15 (m, 3H), 1.14-1.05 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 - 0.80 (m, 9H).
13C NMR (101 MHz, Chloroform-d) 6 171.4, 170.2, 170.0, 169.4, 85.2, 77.5, 75.6, 66.5, 58.0, 57.5, 51.8, 41.6, 39.8, 38.7, 38.3, 36.0, 33.8, 28.8, 28.9, 27.4, 26.5, 25.0, 24.2, 23.6, 17.6, 16.7, 15.5, 11.7.
HR-MS (ESI/TOF) calcd for C30H54BN407 [M+H] 593.4086, found 593.4089.
Synthesis of boronic acid esters 9, general method F
[55] Exemplified by the synthesis of 9.2:
H2N,. 20.
HCI 5;13= =
Me O's Me Me e 0 0 8.1 H O'''VMee iA Me N OH T3P, NMM Ij) N
H H Et0Ac M n,iThr"-B-0'. me t-BuO me t-BC)uOme 0 ICile 7.2 9.2 [56] An acid 7.2 (100 mg, 0.25 mmol, 1 eq.) was dissolved in 5 mL Et0Ac, then N-methylmorpholine (85 tL, 3 eq.) and a solution of propylphosphonic acid anhydride (300 2 eq., 50 % by weight in Et0Ac) was added sequentially. Reaction mixture was stirred for 30 min before (+)-pinanediol (1R)-(1-aminoethyl)boronate hydrochloride (8.1) (78 mg, 0.30 mmol, 1.20 eq.) was added. After reaction was complete (LC-MS control) it was diluted with mL of H20, and HOAc (pH = 3-4) were added. Layers were separated and the aq.
layer was extracted with Et0Ac (2x5 mL). The combined organic layers were washed with sat.
NaHCO3 (10 mL), brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. Crude mixture was purified by flash chromatography on silica gel eluting with 0-5 % Me0H in Et0Ac to provide 9.2 (97 mg, 64 %) as a solid compound.
[57] By a method analogous to Method F, the following compounds were obtained:

14 Compound Procedure Precursors Structure No Me H
9.2 F 7.2 and 8.1 me-)N N H
H ' [\ijThiNIB'O'µ. Me 0 0 Met-BuO Me Me Me 0 Me AK
H
H V "
9.3 F 7.2 and 8.2 Me"-IN w H 7 Xr N
i [NryNyg.,0,.=
t-Ru0".:Nne 0 Me Me H
9.4 F 7.2 and 8.4 me---ILN Nj=( H
H i r)f-NYBV. Me 0 =,.. t-BuO Me 0 Ph cyle H V H ?". Me 9.5 F 7.2 and 8.5 MeAN N
H ' [\iiThrN13'd.. Me t-BuO, Me M_e O 0 01"
H H 7' 9.6 F 7.2 and 8.6 meAN 1\1:).LNI0Ve H z H II

t-BuO Me 0 C6H4(0Me)-4õ./0 cyle O Me MeAN E El 01"
H Me 9.7 F 7.2 and 8.7 o o t-BuO Me -..,o 4 (Me0)C6H4) .. illie 01" F H i O Xr 0 \ Me _../ Me Me N2 A J'L . NN13--.0,=.\--i' 9.8 F 7.2 and 8.8 H z H i 0 ,7 0 t-BuO Me 0 OtBu [58] Physicochemical characterization of compounds 9.2-9.8 Compound Physicochemical characterization No 1H NMR (400 MHz, Chloroform-d) 6 7.86 (d, J = 6.4 Hz, 1H), 7.63 - 7.52 (m, 2H), 6.39 (d, J = 8.5 Hz, 1H), 4.71 (t, J = 8.0 Hz, 9.2 1H), 4.41 (dd, J = 6.5, 4.0 Hz, 1H), 4.26 (dd, J = 8.8, 2.1 Hz, 1H), 4.25 - 4.06 (m, 2H), 4.07 - 3.98 (m, 1H), 3.07 - 2.97 (m, 1H), 2.36 - 2.25 (m, 1H), 2.23 - 2.08 (m, 2H), 2.06 - 1.96 (m, 4H), 1.91 - 1.78 (m, 2H), 1.71 - 1.53 (m, 4H), 1.53 - 1.43 (m, 2H), 1.38 (s, 3H), 1.36 - 1.24 (m, 15H), 1.19 (d, J = 7.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H).
13C NMR (101 MHz, CDC13) 6 171.8, 170.1, 170.0, 169.4, 85.2, 77.5, 75.6, 66.6, 58.0, 56.3, 51.8, 44.1, 41.7, 39.8, 38.3, 36.0, 33.8, 29.2, 28.9, 28.8, 28.3, 27.3, 26.5, 25.2, 24.9, 24.2, 23.6, 17.5, 16.7.
HR-MS (ESI/TOF) calcd for C31H54BN407 [M+H]+ 605.4086, found 605.4103 1f1 NMR (400 MHz, Chloroform-d) 6 7.93 (d, J = 6.3 Hz, 1H), 7.67 (t, J = 5.2 Hz, 1H), 7.49 (d, J = 3.9 Hz, 1H), 6.36 (d, J = 8.5 Hz, 1H), 4.73 (t, J = 8.1 Hz, 1H), 4.39 (dd, J = 6.3, 3.9 Hz, 1H), 4.25 (dd, J= 8.8, 2.2 Hz, 1H), 4.24 - 3.99 (m, 3H), 3.14 - 3.04 (m, 1H), 2.38 - 2.26 (m, 1H), 2.20 - 2.09 (m, 2H), 2.06 - 1.97 (m, 4H), 1.92 - 1.80 (m, 2H), 1.74 - 1.53 (m, 4H), 1.53 - 1.43 (m, 2H), 1.39 (s, 3H), 1.36 - 1.23 (m, 15H), 1.20 (d, J = 7.4 Hz, 3H), 9.3 0.93 (d, J = 6.5 Hz, 3H), 0.84 (s, 3H).
13C NMR (101 MHz, Chloroform-d) 6 171.8, 170.1, 169.7, 169.4, 85.3, 77.6, 75.6, 66.5, 58.0, 56.3, 51.8, 44.2, 42.1, 39.8, 38.3, 35.9, 33.4, 29.2, 28.9, 28.7, 28.3, 27.3, 26.5, 25.2, 24.9, 24.2, 23.6, 17.6, 16.6.
HR-MS (ESI/TOF) calcd for C31H54BN407 [M+H] 605.4086, found 605.4084 1t1 NMR (300 MHz, Chloroform-d) 6 8.20 - 7.99 (m, 1H), 7.97 -7.77 (m, 1H), 7.77 - 7.55 (m, 1H), 7.36 - 7.11 (m, 5H, overlaps with solvent), 6.37 - 6.22 (m, 1H), 4.82 - 4.65 (m, 1H), 4.54 -4.32 (m, 2H), 4.31 - 3.96 (m, 4H), 2.30 - 1.92 (m, 4H), 1.92 -1.82 (m, 3H), 1.80 - 1.43 (m, 8H), 1.41 - 1.09 (m, 18H), 0.98 -9.4 0.87 (m, 3H), 0.80 (s, 3H).
13C NMR (101 MHz, CDC13) 6 171.9, 171.5, 170.3, 169.6, 140.3, 128.4, 126.6, 126.2, 84.9, 77.5, 75.7, 66.6, 58.0, 56.2, 52.0, 45.8, 44.2, 41.1, 39.8, 38.3, 36.0, 29.2, 28.9, 28.7, 28.2, 27.3, 26.4, 25.2, 24.9, 24.2, 23.4, 17.4.
HR-MS (ESI/TOF) calcd for C36H56BN407 [M+H] 667.4242, found 667.4243 1H NMR (400 MHz, Chloroform-d) 6 7.83 (d, J = 6.1 Hz, 1H), 7.68 (t, J = 5.0 Hz, 1H), 7.01 (s, 1H), 6.31 (d, J = 8.5 Hz, 1H), 4.72 (t, J = 8.2 Hz, 1H), 4.41 (dd, J = 6.3, 3.9 Hz, 1H), 4.30 (dd, J
= 8.7, 2.0 Hz, 1H), 4.22 - 4.01 (m, 3H), 2.93 - 2.77 (m, 2H), 2.37 - 2.26 (m, 1H), 2.24 - 2.09 (m, 2H), 2.03 (s, 4H), 1.93 - 1.82 (m, 2H), 1.71 - 1.33 (m, 11H), 1.30 (s, 9H), 1.28 (s, 3H), 1.21 (d, J =
9.5 10.9 Hz, 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H).
13C NMR (101 MHz, Chloroform-d) 6 171.8, 170.0, 169.5, 169.3, 86.4, 78.2, 75.6, 66.4, 57.9, 56.3, 51.5, 44.2, 42.9, 39.6, 38.3, 35.5, 29.2, 29.0, 28.7, 28.3, 27.2, 26.5, 25.2, 25.0, 24.9, 24.2, 23.6, 17.4 LC-MS (ESI) calcd for C30I-151BN407 [M+H] 591.39, found 591.79 1H NMR (400 MHz, Chloroform-d) 6 7.57 (t, J = 5.2 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.39 (s, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.21 (d, J = 8.2 Hz, 1H), 4.57 (t, J = 8.0 Hz, 1H), 4.47 - 4.38 (m, 2H), 4.38 - 4.32 (m, 1H), 4.24 (dd, J = 8.8, 2.1 Hz, 1H), 4.20 - 3.94 (m, 3H), 3.80 (s, 3H), 3.53 (t, J = 6.1 Hz, 2H), 3.15 - 3.04 (m, 1H), 2.37 - 2.23 (m, 1H), 2.22 - 2.07 (m, 2H), 2.07 - 1.96 (m, 4H), 1.97 - 1.72 (m, 4H), 1.71 - 1.45 (m, 6H), 9.6 1.31 (d, J= 32.0 Hz, 18H), 0.96 (d, J= 6.4 Hz, 3H), 0.83 (s, 3H).
13C NMR (101 MHz, Chloroform-d) 6 171.7, 170.1, 170.0, 169.4, 159.3, 130.6, 129.4, 113.9, 85.2, 77.5, 75.6, 72.6, 68.4, 66.3, 58.0, 56.5, 55.4, 51.8, 43.8, 41.6, 39.8, 38.3, 36.9, 36.0, 30.9, 29.3, 28.9, 28.8, 28.3, 27.3, 26.5, 25.2, 24.9, 24.3, 23.5, 17.6.
HR-MS (ESI/TOF) calcd for C40H64BN409 [M+H] 755.4766, found 755.4771 1t1 NMR (400 MHz, Chloroform-d) 6 7.92 (d, J = 6.3 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.61 (t, J = 5.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 8.5 Hz, 1H), 4.73 (t, 9.7 J = 8.1 Hz, 1H), 4.45 - 4.35 (m, 3H), 4.32 - 4.21 (m, 2H), 4.09 -3.98 (m, 2H), 3.79 (s, 3H), 3.43 (t, J = 5.7 Hz, 2H), 2.94 - 2.86 (m, 1H), 2.36 - 2.26 (m, 1H), 2.19 - 2.07 (m, 2H), 2.02 - 1.96 (m, 4H), 1.89 - 1.78 (m, 2H), 1.76 - 1.41 (m, 10H), 1.41 - 1.22 (m, 18H), 0.92 (d, J = 6.3 Hz, 3H), 0.84 (s, 3H).
13C NMR (101 MHz, Chloroform-d) 6 171.8, 170.2, 170.0, 169.3, 159.2, 130.79, 129.3, 113.8, 85.0, 77.4, 75.6, 72.6, 70.1, 66.5, 58.0, 56.1, 55.4, 51.8, 44.2, 41.5, 39.9, 39.0, 38.3, 36.0, 29.2, 28.9, 28.8, 28.3, 28.2, 27.7, 27.4, 26.6, 25.2, 24.9, 24.3, 23.5, 17.4.
HR-MS (ESI/TOF) calcd for C41H65BN409 [M+H] 769.4923, found 769.4936 11-1 NMR (400 MHz, Chloroform-d) 6 7.98 (d, J = 3.9 Hz, 1H), 7.91 (d, J = 6.2 Hz, 1H), 7.62 (t, J = 5.2 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 4.74 (t, J = 8.1 Hz, 1H), 4.39 (dd, J = 6.2, 4.1 Hz, 1H), 4.32 (dd, J = 17.4, 6.0 Hz, 1H), 4.25 (dd, J = 8.8, 2.1 Hz, 1H), 4.14 - 3.97 (m, 2H), 2.90 - 2.80 (m, 1H), 2.44 - 2.24 (m, 3H), 2.19 - 2.07 (m, 2H), 2.04 - 1.96 (m, 4H), 1.97 - 1.69 (m, 5H), 1.71 - 1.51 (m, 5H), 1.39 (d, J = 13.5 Hz, 15H), 1.28 (s, 9H), 1.26 9.8 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.84 (s, 3H).
13C NMR (101 MHz, Chloroform-d)) 6 173.0, 171.8, 170.6, 170.1, 169.3, 84.9, 80.2, 77.4, 75.6, 66.6, 58.0, 56.0, 51.8, 44.4, 41.2, 39.9, 38.8, 38.3, 36.1, 33.6, 29.1, 28.89, 28.85, 28.3, 28.2, 27.3, 26.9, 26.6, 25.1, 24.8, 24.3, 23.5, 17.5.
HR-MS (ESI/TOF) calcd for C37H64BN409 [M+H] 719.4766, found 719.4765 Synthesis of boronic acids 10, general method G
[59] Exemplified by the synthesis of 10.2:
A NH PI"VMee iBuB(OH)2 X AN
Me N jL1,11,H B . r HCI M'irr\j- Bµ H
t-BuO Me 0 Me t-C)BuOMe 0 Me 9.2 10.2 [60] A solution of 9.2 (73 mg, 0.12 mmol) in MeCN/n-hexane (1:1, 8 mL) was treated with isobutylboronic acid (37 mg, 0.36 mmol, 3 eq.) and 1 M HC1 (500 lL). After 18 h at RT, the MeCN phase was washed with n-hexane (3x10 mL) and the n-hexane layer was washed with MeCN (3x10 mL). The combined methanol phase was evaporated in vacuo. Crude product was purified by reversed phase column chromatography to give 10.2 as a white solid (36 mg, 66 %).

[61] By a method analogous to Method G, the following compounds were obtained:
Compound Procedure Precursor Structure No O XrH 0 OH
10.2 G 9.2 H 1 meAN 1\j:AN= NI3'0H
..
0 2.- 0 me tBuO Me O XrH 0 OH
10.3 G
meAN 1\i'!jLle= NyB'OH
H : H H
0 j.- 0 Me tEWO Me O XrH 0 OH
10.4 G 9.4 H 1 me)LN N'!jLIe= NOH
tBuO Me O XiH 0 OH

10.5 G 9.5 meAN INk!j(NNELOH
tBuO Me O X.rEi 0 H ?"
10.6 G 9.6 meAN 1\1:AN= NI':''B'OH

u0 'Me 0 -..
4-(MeO)C6H4./0 O XrH 0 OH
H I
me)LN NI..AN lNõB.0E1 10.7 G 9.7 H T
o ,-,' [I oi -,-, tBuO Me ---"'O
4-(Me0)C6H4) O X.r 0 OH
10.8 G 9.8 H u meAN NNr11-1`--,'ILO
H ' H
tBuO Me [62] Physicochemical characterization of compounds 10.2-10.8 Compound Physicochemical characterization No 1H NMR (400 MHz, Methanol-d4) 6 4.34 (d, J= 3.9 Hz, 1H), 4.24 (d, J = 17.6 Hz, 1H), 4.18 (d, J= 9.1 Hz, 1H), 4.15 - 4.10 (m, 1H), 10.2 4.06 (dd, J=17.7, 1.7 Hz, 1H), 2.69 (q, J= 7.2 Hz, 1H), 2.24 (h, J
= 8.9 Hz, 1H), 2.00 (s, 3H), 1.88 - 1.77 (m, 1H), 1.77 - 1.50 (m, 5H), 1.44 - 1.27 (m, 2H), 1.25 (s, 9H), 1.14 (d, J = 6.4 Hz, 3H), 1.10 (d, J= 7.2 Hz, 3H).
13C NMR (101 MHz, Methanol-d4) 6 176.3, 174.4, 173.6, 172.1, 76.5, 68.3, 59.6, 59.3, 42.6, 41.8, 39.7, 30.4, 30.3, 28.5, 26.2, 25.9, 22.3, 19.2, 16Ø
HR-MS (ESI/TOF) calcd for C21tL0BN407 [M-H2O+H]+
453.2884, found 453.2880 Yield: 39 mg, 64 %.
1H NMR (400 MHz, Methanol-d4) 6 4.36 - 4.28 (m, 1H), 4.25 -4.06 (m, 4H), 2.76 - 2.64 (m, 1H), 2.26 (h, J = 8.9 Hz, 1H), 2.01 (s, 3H), 1.89 - 1.78 (m, 1H), 1.77 - 1.52 (m, 5H), 1.46 - 1.28 (m, 2H), 1.23 (s, 9H), 1.14 (d, J= 6.3 Hz, 3H), 1.12- 1.07 (m, 3H).
10.3 13C NMR (101 MHz, Methanol-d4) 6 176.1, 174.6, 173.7, 172.5, 76.1, 68.2, 60.0, 59.4, 42.5, 41.8, 39.8, 30.4, 28.6, 26.2, 25.9, 22.3, 19.6, 16Ø
HR-MS (ESI/TOF) calcd for C21H40BN407 [M-H2O+H]+
453.2884, found 453.2889 Yield: 41 mg, 45 %.
1H NMR (400 MHz, Methanol-d4) 6 7.32 - 7.19 (m, 2H), 7.19 -7.08 (m, 3H), 4.48 - 4.14 (m, 4H), 4.15 - 4.07 (m, 1H), 3.81 -3.74 (m, 1H), 2.29 - 2.12 (m, 1H), 1.99 (s, 3H), 1.86 - 1.75 (m, 1H), 1.74 - 1.49 (m, 5H), 1.42 - 1.25 (m, 2H), 1.27 - 1.17 (m, 10.4 9H), 1.18 - 1.06 (m, 3H).
13C NMR (101 MHz, Methanol-d4) 6 178.2, 174.5, 173.6, 172.3, 141.9, 129.1, 127.3, 126.8, 76.5, 68.3, 59.6, 59.2, 53.7, 42. 6, 39.6, 30.4, 30.3, 28.4, 26.2, 25.9, 22.3, 19.1.
HR-MS (ESI/TOF) calcd for C26H42BN407 [M-H2O+H]+
515.3041, found 515.3051 Product was set in the next reaction without purification.
10.5 LC-MS (ESI) calcd for C20H36BN406 [M-H2O+H] 439.27, found 439.61.
Product was set in the next reaction without purification.
10.6 LC-MS (ESI) calcd for C30H48BN408 [M-H2O+H] 603.36, found 603.73.

Product was set in the next reaction without purification.
10.7 LC-MS (ESI) calcd for C31H50BN408 [M-H2O+H] 617.37, found 617.72.
1H NMR (400 MHz, Methanol-c/4) 6 4.35 - 4.24 (m, 2H), 4.24 -4.09 (m, 3H), 2.88 (t, J = 4.2 Hz, 1H), 2.34 - 2.15 (m, 3H), 2.01 (s, 3H), 1.88 - 1.77 (m, 3H), 1.77 - 1.52 (m, 5H), 1.45 - 1.28 (m, 2H), 1.24 (s, 9H), 1.14 (d, J= 6.3 Hz, 3H).
10.8 13C NMR (101 MHz, Methanol-c/4) 6 179.8, 176.6, 173.8, 76.4, 68.2, 59.7, 59.4, 42.7, 42.5, 39.5, 30.4, 30.3, 29.2, 28.5, 26.2, 26.0, 25.5, 22.3, 19.5.
LC-MS (ESI) calcd for C23H40BN408 [M-H2O+H] 511.29, found 511.72 Synthesis of boronic acids 11, general method H
[63] Exemplified by the synthesis of 11.1:
Me M Me o 0""Q<Mee 0 Me OH

meNXIV(ieN)Z Nr 0 13, BBõ meNX11-\11,A
Me ___________________________________________ , II OH
0 H 0 Me DCM, -78 oC to rt OHOMe 0 Me t-BuO Me 9.1 11.1 [64] To a solution of 9.1 (50 mg, 0.08 mmol) in DCM (5 mL), BBr3 (180 tL, 1M
solution in DCM) was added dropwise at -78 C. The mixture was stirred while the temperature was slowly warmed up to ambient temperature. After 2 h, the reaction was quenched with water (10 mL) and the mixture extracted with Et20 (3x10 mL). The aqueous solution was concentrated in vacuo affording 29 mg (85 %) of the product 11.1 as a yellow solid.
[65] 1H NMR (400 MHz, Methanol-c/4) 6 4.31 -4.07 (m, 5H), 2.82 -2.71 (m, 1H), 2.05 (s, 3H), 1.94 - 1.83 (m, 1H), 1.61 - 1.50 (m, 1H), 1.28 - 1.22 (m, 1H), 1.20 (d, J
= 6.3 Hz, 3H), 1.12 (d, J= 7.2 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H), 0.92 (t, J= 7.4 Hz, 3H).
13C NMR (101 MHz, Methanol-c/4) 6 176.9, 174.3, 174.2, 173.1, 68.1, 60.5, 60.0, 39.7, 37.6, 26.1, 22.2, 19.91, 15.9, 15.7, 11.4.
HR-MS (ESI/TOF) calcd for C16H30BN406 [M-H2O+H] 385.2258, found 385.2263 Synthesis of boronic acids 11, general method I
[66] Exemplified by the synthesis of 11.2:

H V \.,H H
¨,..- Me A N NH jk0 H I
meAN H I TFA Xr N ...rN B
u = NNIB'OH
H = H 'OH DCM - H
0 me 0 õ.= 0 Met-BuO Me HO Me 10.2 11.2 [67] A solution of 10.2 (17 mg, 0.038 mmol) in dry DCM (2mL) was treated with TFA
(500 lL). Reaction was stirred till completion (LC-MS control). Toluene (5 mL) was added to the reaction mixture and then the solvents were removed. Crude mixture was treated with Et20 (3x5 mL, the precipitate was separated by centrifugation after each addition) to give product 11.2 as a white solid (11 mg, 74 %).
[68] By a method analogous to Method I, the following compounds were obtained:
Compound Procedure Precursor Structure No oo OH
H I
11.2 I 10.2 meANXi H I
H N
? N B
-.....-- .
, N').r E OH
0 ==.: " 0 MeHO Me O OH
11.3 I 10.3 meANX( 0 H H I
N 1.

H N'rNyB\OH
0 ...7 " 0 Me HO Me H ?I H I 0õ
11.4a I 10.4 MeANXIN N Bs ,Y
H F\lir 0 C)¨CF3 0 Ph HO Me -O OH
H on H I
11.4b I 10.4 N B
MeAFIX(N: N'r 1 'OH
- H
0 .,.= 0 Ph HO Me OH

11.5 I 10.5 meAN N,.(1\1eNB,0Ei H = H II
0HOMe 0 OH_ H OH
11.6 I 10.6 meAN N.(N..iNB\
H = H
0HOMe 0 ="----/-11.7 I 10.7 meAN N.(NNB,(:) H 0 H 8 E) HO Me 11.8 I 10.8 me 9 NX,r,õ 9 N H 9,E1 )CF1 F1Y_ 0HOMe 0 [69] Physicochemical characterization of compounds 11.2-11.8 Compound Physicochemical characterization No NMR (400 MHz, Methanol-d4) 6 4.26 (d, J = 4.5 Hz, 1H), 4.24 - 4.02 (m, 4H), 2.67 (q, J = 7.1 Hz, 1H), 2.26 (h, J = 8.7 Hz, 1H), 2.00 (s, 3H), 1.88- 1.77 (m, 1H), 1.77- 1.51 (m, 5H), 1.44- 1.28 (m, 2H), 1.20 (d, J= 6.4 Hz, 3H), 1.10 (d, J= 7.2 Hz, 3H).
11.2 13C NMR (101 MHz, Methanol-d4) 6 176.3, 174.9, 173.7, 173.1, 68.2, 60.5, 59.3, 42.7, 41.9, 39.8, 30.3, 26.3, 26.0, 22.3, 19.9, 15.9.
HR-MS (ESI/TOF) calcd for C17H30BN406 [ M-H2O+H
397.2258, found 397.2265 NMR (400 MHz, Methanol-d4) 6 4.39 - 3.79 (m, 5H), 2.75 -2.62 (m, 1H), 2.34 - 2.17 (m, 1H), 1.99 (s, 3H), 1.89 - 1.77 (m, 1H), 1.76 - 1.50 (m, 5H), 1.45 - 1.26 (m, 2H), 1.24 - 1.16 (m, 3H), 1.14- 1.05 (m, 3H).
11.3 13C NMR (101 MHz, Methanol-d4) 6 176.3, 174.9, 173.7, 173.0, 68.2, 60.6, 59.4, 42.7, 41.9, 39.8, 30.5, 30.3, 26.2, 25.9, 22.3, 19.9,

15.9.
HR-MS (ESI/TOF) calcd for C17H30BN406 [ M-H2O+H
397.2258, found 397.2264 NMR (400 MHz, Methanol-d4) 6 7.29 - 7.05 (m, 5H), 4.52 -4.07 (m, 5H), 3.78 (s, 1H), 2.28 - 2.15 (m, 1H), 2.03 - 1.91 (m, 3H), 1.87 - 1.47 (m, 7H), 1.44 - 1.24 (m, 1H), 1.22 - 1.14 (m, 3H).
13C NMR (101 MHz, Methanol-d4) 6 178.2, 174.8, 173.8, 173.2, 11.4a 158.54 (q, J = 41.2 Hz), 156.60 (q, J = 41.7 Hz) 142.1, 129.1, 127.0, 126.6, 116.3 (q, 286.3 Hz), 115.9 (q, J = 286.5 Hz). 68.2, 60.3, 59.3, 53.8, 42.6, 39.7õ 30.3, 26.3, 26.0, 22.3, 19.9.
HR-MS (ESI/TOF) calcd for C26H313N409F6Na [M-H2O+Na]
691.1986, found 691.2001 1t1 NMR (400 MHz, Methanol-c/4) 6 7.30 - 7.21 (m, 2H), 7.17 -7.09 (m, 3H), 4.43 - 4.11 (m, 5H), 3.81 - 3.75 (m, 1H), 2.31 -2.16 (m, 1H), 1.97 (s, 3H), 1.85 - 1.52 (m, 6H), 1.47 - 1.28 (m, 2H), 1.22- 1.15 (m, 3H).
11.4b 13C NMR (101 MHz, Methanol-c/4) 6 178.2, 174.8, 173.8, 173.2, 142.1, 129.1, 127.0, 126.6, 68.2, 60.3, 59.3, 53.8, 42.6, 39.7, 30.3, 30.3, 26.3, 26.0, 22.3, 19.9.
HR-MS (ESI/TOF) calcd for C22H32BN406 [M-H2O+H]+
459.2415, found 459.2418 1t1 NMR (400 MHz, Methanol-c/4) 6 4.31 - 3.98 (m, 5H), 2.38 (s, 2H), 2.32 - 2.20 (m, 1H), 2.00 (s, 3H), 1.90 - 1.77 (m, 1H), 1.76 -1.51 (m, 5H), 1.45 - 1.27 (m, 2H), 1.19 (d, J= 6.3 Hz, 3H).
11.5 13C NMR (101 MHz, Methanol-c/4) 6 176.6, 174.9, 173.7, 173.1, 68.1, 60.5, 59.3, 42.8, 40.4, 31.5, 30.4, 30.3, 26.3, 26.0, 22.3, 19.9.
LC-MS (ESI) calcd for C16H28BN406 [M-H2O+H] 383.21, found 383.51.
1H NMR (400 MHz, Methanol-c/4) 6 4.33 - 4.08 (m, 5H), 3.91 -3.77 (m, 1H), 3.57 - 3.45 (m, 1H), 2.85 (d, J = 6.2 Hz, 1H), 2.26 (h, J= 8.9 Hz, 1H), 2.00 (s, 3H), 1.93- 1.51 (m, 8H), 1.45- 1.27 (m, 2H), 1.20 (d, J= 6.4 Hz, 3H).
11.6 13C NMR (101 MHz, Methanol-c/4) 6 178.2, 174.9, 173.7, 173.1, 68.1, 64.6, 60.4, 59.3, 43.5, 42.7, 39.6, 34.4, 30.4, 30.3, 26.3, 26.0, 22.3, 19.9.
HR-MS (ESI/TOF) calcd for C18H303N407Na [M+Na] 499.2183, found 499.2170 1t1 NMR (400 MHz, Methanol-c/4) 6 4.28 (d, J = 4.3 Hz, 1H), 4.24 -4.13 (m, 2H), 4.15 - 3.99 (m, 2H), 3.89 -3.71 (m, 2H), 2.63 (t, J
= 5.5 Hz, 1H), 2.26 (h, J = 8.6 Hz, 1H), 2.00 (s, 3H), 1.89 - 1.28 (m, 12H), 1.22- 1.16 (m, 3H).
11.7 13C NMR (101 MHz, Methanol-c/4) 6 176.0, 174.8, 173.7, 173.0, 68.2, 64.6, 60.4, 59.3, 42.7, 40.7, 40.6, 30.4, 30.3, 28.8, 26.3, 26.0, 24.7, 22.3, 19.9.
LC-MS (ESI) calcd for C19H32BN406 [M-H2O+H] 423.24, found 423.55.

1H NMR (400 MHz, Methanol-d4) 6 4.30 ¨ 4.01 (m, 5H), 2.56 (t, J
= 7.3 Hz, 1H), 2.47 (t, J = 7.6 Hz, 2H), 2.26 (h, J = 8.8 Hz, 1H), 2.00 (s, 3H), 1.90 ¨ 1.53 (m, 8H), 1.44 ¨ 1.26 (m, 2H), 1.20 (d, J =
6.3 Hz, 3H).
11.8 13C NMR (101 MHz, Methanol-d4) 6 176.8, 175.9, 174.9, 173.6, 173.2, 68.0, 61.1, 58.9, 45.6, 42.9, 39.9, 32.9, 30.3, 30.2, 27.2, 26.3, 25.9, 22.3, 19.9.
LC-MS (ESI) calcd for C19H32BN408 [M+H] 455.23, found 455.61 In vitro Assay [70] The compounds have been tested in vitro as malarial serine protease PfSUB1 inhibitors according to the following process.
Determination of ICso [71] Recombinant purified P. falciparum SUB1 (PfSUB1) 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 CaCl2, 25 mM Tris-HC1, 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 SERA4st1F-6R12 was added at a final concentration of 0.1 1.tM in a final volume of 100 Ill 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.
PfSUB1 - EP_530 15 IC50 = 69.43 nM
p io # 5 EP_530 concentration (nM) Results are given in Table 1.
Determination of EC50 in parasite growth assays [72] The effects of compounds on growth of blood-stage Plasmodium falciparum (clone 3D7) was assessed using a SYBR Green I assay. Test compounds (dissolved in DMSO at concentrations ranging from 1 mM-0.1 uM) were added in triplicate to wells of flat bottomed, 96 well microtitre plates (1 i.iL per well). Wells were then supplemented with 100 0_, per well of a synchronous P. falciparum parasite culture at 0.1 % parasitaemia, 1 %
haematocrit.
[73] Each assay plate also included DMSO only control wells, as well as additional control wells containing uninfected erythrocytes only. Plates were incubated in sealed humidified gassed chambers at 37 C for 96 h to allow the parasites to undergo two entire cycles of erythrocytic growth. Wells were then supplemented with 100 i.iL of a 1:5,000 dilution of stock SYBR Green I (Life Technologies, catalogue #S7563) diluted in 20 mM Tris-HC1 pH 7.5, 5 mM EDTA, 0.008 % (w/v) saponin, 0.08 % (v/v) Triton X100. Plates were agitated to mix, incubated for a further 1 h in the dark at room temperature, then transferred to a Cary Eclipse fluorescence spectrophotometer (Varian) equipped with a 96-well microplate reader accessory for fluorescence readings (Ex 485 nm, Em 530 nm). EC50 values were determined from dose-response curves obtained after subtracting background fluorescence values (obtained from the erythrocyte only wells) from all experimental readings. Results are given in Table 1.
1. table. Biological activity of boronic acid containing peptidomimetics Savienojuma P. falciparum ID PfSUB1 nr. pieaugums (nM) (iiM) EP-530 11.1 69 2.0 EP-784 11.2 5.5 -EP-837 11.6 2.9 -EP-863 11.5 43.6 -EP-785 11.3 4.5 -EP-833 11.4a 213.7 -EP-842 11.4b 106.9 -EP-852 11.8 14.4 -EP-861 11.7 117.9

Claims

1. A compound with general formula I
wherein:
R4 is H or Me;
R5 is OH;
R8 and R9 taken together represent -CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, R3, R6 , R7 is H, Ci_olkyl, cyc1oC3_12a1ky1, cyc1oC3_12a1ky1-Ci_6a1ky1, C2_6a1keny1, C2-6alkynyl, aryl, biaryl, arylCi_olkyl, ary1C2_6a1keny1, ary1C2_6a1kyny1, heteroaryl, heteroarylCi_olkyl, heteroary1C2_6a1keny1, R120(CH2),, R12S(CH2), R120C(=0)(CH2)., R12N(R13)C(=0)(CH2), R12N (R13)(CH2), Wherein R12 and R13 are independently H, Ci_olkyl, cyc1oC3_12a1ky1, cyc1oC3_12a1ky1-Ci_6alkyl, C2_6a1keny1, C2_6a1kyny1, aryl, biaryl, arylCi_olkyl, ary1C2_6a1keny1, ary1C2_ 6alkynyl, heteroaryl, heteroarylCi_olkyl, heteroary1C2_6a1keny1;
n is an integer selected from 1 to 6;
R1, R2, R10, R11 are independently -H, -F, -C1, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-0-L-OH, -0R14, -0-L-NH2, -0-L-NHR14, -0-L-NR142, -0-L-R14NR15, -L-0R14,-0-L-0R14,-0CF3, -0 CH2CF3, -0CF2CF2H, -L-0R14,-0-L-0R14,-0CF3, -OCH2CF3, -0CF2CF2H, Se, SCF3, -CN, -NO2, -NO2, -NH2, -NHR14, -NR142, -N(R14)R15, -L-NH2, -L-NHR14, -L-NR142, -L-N(R14) R15,-NH-L-NH2, -NH-L-NHR14, -NH-L-NR142, -NH-L-N(R14)R15, -NR14-L-NH2, -NR14-L-NHR14, -NR14-L-NR142, -NR14-L-N(R14)R15, L-N(R14)R15, -C(=0)0H, -C(=0)0R14, -C(=0)NH2, -C(=0)NHR14, -C(=0)NR142, -C(=0)N(R14)R15,-NHC(=0)R14, -NR14C(=0)R15, -NHC(=0)0R14, -NR14C(=0)0R15, -0C(=0)NH2, -0C(=0)NHR14, -0C(=0)NR142, -0C(=0) R14NR15,-0C(=0)R14, -C(=0)R13,-NHC(=0)NH2, -NHC(=0)NHR14, -NHC(=0)NR142, -NHC(=0)N(R14)R15, -NR14C(=0)NH2, -N(R14)C(=0)NHR15, -NR14C(=0)NR142, -NR14C(=0)N
-NHS (=0)2R14, N(R14)s(K 0)2-15, S(=0)2NH2, -S(=0)2NHR14, -S(=0)2NR142, _s(=0)2N(R14)R15, s(_0)R14, s(_0)2R14, K 0s(_0)2- 14, S(=0)20R14, Ci_6alkyl, cyc1oC3_12a1ky1, cyc1oC3_12a1ky1-Ci_6alkyl, C2_6a1keny1, C2_6a1kyny1, aryl, biaryl, arylCi_olkyl, ary1C2_6a1keny1, ary1C2_6a1kyny1, heteroaryl, heteroarylCi_olkyl, heteroary1C2_6a1keny1, heteroarylthio, 2,3-dihydro-1H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci_6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindo1-2-y1;
L represents -W-X-Y-Z-; or -W-X-Y, or -W-X;
R1 and R2 or R1 and R3 or R7 and R1 or R7 and R11 or R1 and R11 taken together represent -W-X-Y-Z-, or -W-X-Y-, or -W-X- or wherein W represents a single bond, oxygen, sulfur, _NR or _CR14R15, X represents oxygen, sulfur, -NR14 or -C(R14)R15, Y represents oxygen, sulfur, -NR14 or -C(R14)R15, Z represents oxygen, sulfur, -NR14 or -C(R14)R15;
R14 and K-15 are independently H, Ci_olkyl, cyc1oC3_12a1ky1, cyc1oC3_12a1ky1-Ci_6a1ky1, C2_6alkeny1, C2_6alkyny1, aryl, biaryl, arylCi_olkyl, ary1C2_6a1keny1, ary1C2_6a1kyny1, heteroaryl, heteroary1C1_6alkyl, heteroary1C2_6alkeny1, heteroarylthio, 2,3-dihydro- 1H-indenyl, Ci_6alkoxyC1_6alkyl, aryloxyary1C1_6alkoxy, C1_6alkylthio, C4_6a1keny1thio, cyc1oC3_12a1ky1thio, cycloC3_12alkyl-C1_6alkylthio, cyc1oC3_12a1ky1-C3_6a1keny1thio, Ci_ 6a1koxyC 1_6alkylthio, C 1_6 alkoxyC 3_6alkenylthio, ary1C 3_6 alkenylthio, hetero ary1C 1_ 6alkylthio, C 1_6 alkylsulfonyl, c ycloC 3_ ualkyl-C i_olkylsulfonyl, ary1C
1_6 alkylsulfonyl, C1_6alkylamino, di-Ci_olkylamino, cyc1oC3_12alky1amino, C1-C6alkoxy-cycloC3-C i2alkylamino, c ycloC 3_ ualkyl-C 1_6alkylamino, di-C 1_6a1ky1aminoC 1_6 alkyl, C 1-6alkoxy-C2_6alkylamino, arylamino, ary1C1_6alkylamino, N-cyc1oC3_12a1ky1-N-Ci-6alkylamino, N-aryl-N-Ci_olkylamino, N- ary1C
1_6alkyl-N-C 1_6 alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci_6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindo1-2-yl, heteroarylCi_ 6alkoxy, heteroarylamino, or heteroarylCi_6alkylamino and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

2. The compounds according to Claim 1 for use in the treatment of malaria.

3. A pharmaceutical composition, which contains a compound according to Claim and pharmaceutically acceptable carrier for use in the treatment of malaria.

4. The pharmaceutical composition, according to claim 3, wherein said composition is intended for parental or peroral administration.