LV15544B - NEW PORPIDOMIMETERS CONTAINING BORIC ACID AS MALARIUM SERINE PROTEASE INHIBITORS - Google Patents

Abstract

The invention relates to novel boric acid-containing peptidomimetics (I) that act as inhibitors of malaria subtilisin-related serine protease (SUB). They can be used as medicinal preparations or as ingredients for the treatment of malaria.

Description

DESCRIPTION OF THE INVENTION

The invention relates to medicine, in particular to the treatment of malaria infection, more particularly to malaria serine protease inhibitors. In particular, the invention relates to novel boronic acid-containing peptidomimetics, their pharmaceutical compositions and their use as subtilisin-related serine protease (SUB) inhibitors.

Prior art

Widespread resistance to virtually all currently used drugs has fueled the search for new antimalarial agents with a new mechanism of action. ^1,2,3 In the endemic regions of malaria, resistance to current antimalarial reagents continues to spread, indicating that current therapies will soon be completely ineffective. The basic rule in the development of new antimalarial drugs is the inhibition of the life cycle of the parasite by a mechanism that differs from the current mechanism of action of therapeutic agents. ⁴

[003] This can be achieved by targeting malaria proteins involved in the developmental cycle of the parasite. Malaria enzymes, such as subtilisin-related serine protease (SUB), are considered to have promising molecular targets for the development of new drugs. ^5,6 [004] Several inhibitors of the SUB subtype PfSUB 1 have been identified, ⁷ but none has been approved to date as a candidate drug for use in clinical trials.

Purpose and essence of the invention

In one aspect, the invention provides a method of treating malaria infections in a human or animal by administering to a human or animal in need thereof a therapeutically effective amount of a compound or prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. wherein the compound is a subtilisin-related serine protease (SUB) inhibitor.

In another aspect, the invention provides a pharmaceutical composition for treating malaria infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, and (ii) a pharmaceutically acceptable carrier, wherein the compound is a subtilisin-related serine protease (SUB) inhibitor.

In another aspect, the invention describes the use of a compound or prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, of said compound or prodrug, wherein said compound is a subtilisin-related serine protease (SUB) inhibitor, in the manufacture of a medicament for the treatment of malaria infections. and prevention.

In another aspect, the invention provides the use of a compound or prodrug thereof, or a pharmaceutically acceptable salt or ester of said compound or prodrug, wherein said compound is a subtilisin-related serine protease (SUB) inhibitor, for the treatment and prevention of malaria infections.

In one embodiment of the invention, the subtilisin-related serine protease (SUB) inhibitor is a compound of formula (I), generally referred to herein as a boric acid-containing peptomimetic.

General formula (I):

in which:

R ⁴ is H or Me;

R ³ is H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 26 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C 2-6 arylalkenyl, C 2-6 aryl, C 2-6 aryl 6heteroarylalkyl, C 2-6 heteroarylalkenyl, R ¹² O (CH 2) n, R ¹² S (CH 2) n, R ¹² OC (= O) (CH 2) n, R ¹² N (R ¹³ ) C (= O) (CH 2) n , R ¹² is N (R ¹³ ) (CH 2) n wherein R ¹² and R ¹³ are independently H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 16 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, Cl -6arylalkyl, C26-6alkenyl, C2-6arylalkynyl, heteroaryl, C1-6heteroarylalkyl, C26heteroarylalkenyl;

N is an integer from 1 to 6;

R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently:

-H, -F, -Cl, -Br, -I, -CF 3, -CH 2 CF 3, -CF 2 CF 2 H, -OH, -L-OH, -OL-OH, -OR ¹⁴ , -OL-NH 2, -OL-NHR ¹⁴ , -OL-NR ¹⁴ 2, -OLR ¹⁴ NR ¹⁵ , -L-OR ¹⁴ , -OL-OR ¹⁴ , -OCF 3, -OCH 2 CF 3, -OCF 2 CF 2 H, L-OR ¹⁴ , -OL-OR ¹⁴ , -OCF 3, -OCH2CF3, -OCF2CF2H, SR ¹⁴ , SCF3, -CN, -NO2, -NO2, -NH2, NHR ¹⁴ , -NR ¹⁴ 2, -N (R ¹⁴ ) R ¹⁵ , -L-NH 2, -L-NHR ¹⁴ , -L-NR ¹⁴ 2, -LN (R ¹⁴ ) R ¹⁵ , -NH-L-NH 2, -NHL-NHR ¹⁴ , -NH-L-NR ¹⁴ 2, -NH-LN (R ¹⁴ ) R ¹⁵ , -NR ¹⁴ -L-NH 2, -NR ¹⁴ -L-NHR ¹⁴ , -NR ¹⁴ -L-NR ¹⁴ 2,

NR ¹⁴ -LN (R ¹⁴ ) R ¹⁵ , LN (R ¹⁴ ) R ¹⁵ , -C (= O) OH, -C (= O) OR ¹⁴ , -C (= O) NH 2, -C (= O) NHR ¹⁴ , C (= O) NR ¹⁴ 2, -C (= O) N (R ¹⁴ ) R ¹⁵ , -NHC (= O) R ¹⁴ , -NR ¹⁴ C (= O) R ¹⁵ , -NHC (= O) OR ¹⁴ , NR ¹⁴ C (= O) OR ¹⁵ , -OC (= O) NH 2, -OC (= O) NHR ¹⁴ , -OC (= O) NR ¹⁴ 2, -OC (= O) r ¹⁴ No. ¹⁵ , OC (= O) R ¹⁴ , -C (= O) R ¹³ , -NHC (= O) NH 2, -NHC (= O) NHR ¹⁴ , -NHC (= O) NR ¹⁴ 2, NHC (= O) N (R ¹⁴ ) R ¹⁵ , -NR ¹⁴ C (= O) NH 2, -N (R ¹⁴ ) C (= O) NHR ¹⁵ , -NR ¹⁴ C (= O) NR ¹⁴ 2, NR ¹⁴ C ( = O) -NHS (= O) 2 R ¹⁴ , -N (R ¹⁴ ) S (= O) 2 R ¹⁵ , -S (= O) 2 NH 2, -S (= O) 2 NHR ¹⁴ , -S (= O ) 2NR ¹⁴ 2, -S (= O) 2N (R ¹⁴ ) R ¹⁵ , -S (= O) R ¹⁴ , -S (= O) 2 R ¹⁴ , -OS (= O) 2 R ¹⁴ , -S (= O) 2OR ¹⁴ ;

C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 2-6 alkenyl, aryl, biaryl, C 1-6 arylalkyl, C 2-6 arylalkenyl, C 26 arylalkynyl, C 26 arylalkynyl , 2,3-dihydro-1H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidine, piperidine, 4-arylpiperidine, 4-heteroarylpiperidine, morpholinomethene, piperazine, benzyl, 4-C1-6alkylpiperazine, 4-aryl -dihydro-2H-isoindol-2-yl;

or R ⁵ , R ⁷ , R ⁸ are independently = O, = NR ¹⁴ , = NOH or = NOR ¹⁴ ;

L is -W-X-Y-Z- or -W-X-Y, or -W-X,

R ¹ and R ² , or R ¹ and R ³ , or R ⁵ and R ⁶ , or R ⁷ and R ⁸ , or R ⁷ and R ¹¹ , or R ⁸ and R ⁹ , or R ⁹ and R ¹⁰ , or R ¹⁰ and R ¹¹ taken together are -WXYZ- or -WXY- or -WX-, or in which:

W is a single bond, oxygen, sulfur, -NR ¹⁴ or -CR ¹⁴ R ¹⁵ ,

X is oxygen, sulfur, -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ ,

Y is oxygen, sulfur, -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ ,

Z is oxygen, sulfur -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ ;

R ¹⁴ and R ¹⁵ are independently H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 16 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C 26 arylalkenyl, C 2-6 arylalkyl, C 2-6 alkynyl C1-6heteroarylalkyl, C26heteroarylalkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C1-6alkoxyC14

6alkyl, C 1-6 aryloxyalkoxy, C 1-6 alkylthio, C 4-6 cycloalkylthio, C 3-8 cycloalkyl-C 1-6 alkylthio, C 3-6 cycloalkyl-C 3-6 alkenylthio, C 1-6 alkoxyC 1-6 alkyloxy 6alkylsulfonyl, C 3-12 cycloalkyl-C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl.

6arylalkylsulfonyl, C 1-6 alkylamino, di-C 1-6 alkylamino,

C 3-12 cycloalkylamino, C 1 -C 6 alkoxy-C 3 -C 12 cycloalkylamino, C 3-12 cycloalkylC 1-6 alkylamino, di-C 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkylamino, arylamino, C 1-6 arylamino, C 1-6 arylalkyl 6-alkylamino, N-aryl-NC1-6alkylamino, N-C1-6arylalkyl-N-C1-6alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidine, piperazine, 4-arylpiperidine, 4-heteroarylpiperidine, morpholyl hexamethyleneimine, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, C 1-6 heteroarylalkoxy, heteroarylamino or C 1-6 heteroarylalkylamino. and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

[0i8] In one embodiment, the treatment is for the treatment of a disease or dysfunction involving a malaria serine protease or a human serine protease.

[0019] In one embodiment, the treatment is a treatment for a disease or dysfunction mediated by inhibition of a malaria serine protease or a human serine protease.

In one embodiment, the treatment is for the treatment of a disease or dysfunction treated with inhibitors of malaria serine protease or human serine protease; a pharmaceutical composition for parenteral or oral administration to a human.

In another aspect, the invention provides a kit comprising boronic acid-containing peptidomimetics as described herein, preferably as a pharmaceutical composition in a suitable container and / or packaging.

[022] In another aspect, the invention provides compounds obtainable by the synthetic methods described herein or methods comprising the synthetic method described herein.

[023] In another aspect, the invention provides compounds obtained by the method of synthesis described herein, or a method comprising the method of synthesis described herein.

[024] In another aspect, the invention provides novel intermediates described herein that are suitable for use in the synthetic methods described herein.

[025] In another aspect, the invention relates to the use of novel intermediates as described herein in the synthetic methods described herein.

[026] As will be appreciated by those skilled in the art, the features and preferred embodiments of one aspect of the invention will apply to other aspects of the invention.

Examples of implementation of the invention

Subtilisin-related serine (SUB) proteases are malaria serine proteases that have been identified as a promising biological target for the development of new anti-malarial drugs because of their involvement in the escape of the parasite from infected erythrocytes. ^5,6,7

[028] When testing new boronic acid-containing derivatives of peptide mimetics and obtaining data on their ability to inhibit SUB, we unexpectedly found that these derivatives show pronounced inhibitory properties against said serine proteases and also inhibit parasite growth in red blood cells, so they are important in the treatment of malaria. .

[029] According to the results of the present invention, SUB inhibition studies demonstrate that boric acid-containing peptidomimetic derivatives are a new class of serine protease inhibitors. Several compounds of this invention exhibit nanomolar or low micromolar inhibitory activity.

Stereochemistry

One or more specific stereochemical configurations are indicated for several of the structures shown herein. Also, the stereochemical configuration of several of the structures shown here is not shown. Like many chemical structures, stereochemical configurations at one or more positions are shown, while at other positions the configuration is not shown at one or more positions. If the stereochemical configuration of a chemical structure is not shown, the structure should be considered to include all possible stereoisomers both individually and as a mixture of stereoisomers (eg racemic mixtures).

Combinations

[031] Each and any compatible combination of the above is clearly disclosed herein as if each and every combination were listed individually and directly.

[032] The following examples further illustrate the invention, but should not be construed as limiting the scope of the invention in any way.

The following boronic acid-containing peptidomimetic derivatives (9.1), (10.2-10.8) and (11.1-11.8) were obtained as examples of the present invention:

ID Connection no. Structure EP-529 9.1. Me _, Me C _Me ļ ļ V-Me? ! H 9 H 9 V ^N '- ^ ^{Me H} ° Α. _λ ^H O Me t-BuO Me

EP-782 10.2 9 YH 9 H 9 ^H Me ^ '^ ^H ° Ā .. ^H O Me tBuO Me EP-783 10.3 9 ^H 9 H 9 ^H Me ^ A ^ A ^^ ^H ° Ύλ ^H O Me tBuO Me EP-827 10.4 9 YH 9 H 9 ^H Me ^ '^ ^{H 0 H} O Ph tBuO Me EP-860 10.5 Ο Y | _i Ο II OH ΛΥΑγΑ ^H ο Λ ^H o tBuO Me EP-834 10.6 9 YH 9 H? ^H Me ^ AAf ^ν ^ ήΑτ ^ν ^ ^β Α> η ^H ο A ^H Ο A tBuO Me η 4- (MeO) C ₆ H ₄ ^ ° EP-850 10.7 Ο Ο OH mAnV ^ nV · ^ ™ ^H o A ^H o <tBuO Me> Ό 4- (MeO) C ₆ H ₄ ^ EP-851 10.8 9 YH 9 H 9 ^H Μβ ^ ΝΥ < ^Ν Υ ^ Ν ^ Α ^Ν Α ⁶ '9 ^{H 0} Ά ^{H 0} tBuO Me ^υ EP-530 11.1 Me Ϊ V'h ϊ H? ^H H « ^N 1 AtA ' ^oh Ο O Me HO Me ^e EP-784 11.2 ° o OH Me ^ N ^ NΥ ^Me Η Υ y oh ^ O ^ Me ° Μθ EP-785 11.3 ° o OH Me ^ N ^ NY ^Me Η Π i γ OH ^Ο ΗΟ ^ 'Μβ ° ^Me

EP-833 11.4a Λ.Ϋ h A h 'Me · ^^^ ° HO ^ Me ^{O Ph} CF ³ EP-842 11.4b Ο Ά Ο OH ° HO ^ Me ° ^Ph EP-863 11.5 9 YH 9 H 9 ^{H H} 1 A ^H 0 ΉΟ Me EP-837 11.6 9 | H 9 H 9 ^H Me ^ N ^N 'Ά' n ^N % ^H έ A ^H O ΗΟ Me EP-861 11.7 9 γ H 9 H 9 ^H Me ^ YYf ^H ο. A ^H ο M ΉΟ Me EP-852 11.8 0 lf _u 0 _u OH ^H ο A ^H ο AA ΗΟ Me

General description of the synthesis

[034] Boric acid derivatives (9-11) are synthesized according to Scheme 1. Dipeptide (3) is obtained by welding amino acids (1) and (2). The resulting product is deprotected and the amine is welded to the next amino acid (4) to form tripethide (5). After the next deprotection, N-acylation is performed to form an intermediate (6). The hydrolysis yields an acid (7) which is further welded to the aminoboric acid derivative (8). For the resulting intermediate (9), the boronic acid ester protecting group as well as the amino acid side chain protecting groups are cleaved to form products (10) and (11).

Scheme 1:

1. Removing the protecting group ο

OH

R ⁴

N ^: '

O welding reagent

Method A

PgHN

2. R ⁹ R ⁸ , r10V ^r7

X. OH ο R ⁴ PgNH Y

O ^OPg welding

reagent

R ⁶ R ⁵

Method B ^R9 R ⁸

R1oA / R ⁷ .. OR ⁴

NNNV ^Pg ο A. / o

R ⁶ R ⁵

1. Removal of a protecting group

2. N-modification

Method C

Removal of a protecting group

Method D ^R 9 R8 r ¹⁰ A)

R ²

H2N b. _r1

R11

R ⁶

OH

R ³ welding reagent

Method E, F

Removal of boric acid ester and removal of side chain protecting groups

Method G, H, I

Pg = Protective group

Synthesis of intermediates (3), general method A:

Synthesis of compound (3.1) as an example:

o FmocHN., JL _: OH f-BucA'Me oh ₂ n. JL, HCl ^0Me 2.1

O

FmocHN

HATU, DIPEA, DCM, ist.t.

f-BuO Me

R ⁹ R8 r ¹⁰ \ /

R11

R ⁶ R ⁵

10, 11

R ²

HI ^B R

R ³

1.1

3.1

Glycine methyl ester hydrochloride (2.1) (401 mg, 3.2 mmol), Fmoc-Thr (tBu) -OH (1.1) (1.30 g, 3.2 mmol, 1 equiv.), HATU (1, 34 g, 3.5 mmol, 1.1 equiv) and DIPEA (1.66 mL, 9.6 mmol, 3 equiv) are dissolved in DCM (40 mL) and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2 ^χ 20 mL) and then with sat. NaCl (20 ml). The organic phase is dried over Na2SO4, decanted and then evaporated under reduced pressure. The dry residue was purified by column chromatography on silica gel eluting with hexane: EtOAc, 4: 1-1: 1 (Rf = 0,50.5 when hexane: EtOAc 2: 1) to give (3.1) (1.37 g, 92 as a white solid.

1 H NMR (400 MHz, chloroform-d) δ 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) m.d.

¹³ C NMR (101 MHz, chloroform-d) δ 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 md

HR-MS (ESI / TOF) calcd for C 26 H 33 N 2 O 6 [M + H] + 469.2339, found 469.2337. [038] The following compounds were obtained according to General Method A:

Connection no. Method Raw materials Structure 3.1. A 1.1 and 2.1 0 FmocHN Yk, OMe NKA ^H O t-BuO Me 3.2. A 1.1 and 2.2 O FmocHN, A _0Et NKA ^H 0 t-BuO Me

Synthesis of intermediates (5), general method B:

[039] Synthesis of compound (5.1) as an example:

Me

O ^ ^Me o

FmocHN. ^ 1, DMF, 120 ° C__ Λ.Ν.1, ^, ΟΜθ: ΰ [] FmocHN γ N Y

O 2. Fmoc-lle-OH (4.1), Ο ^{Ξ H} O t-BuO Me HATU.DIPEA, t-BuO Me

3.1 DMF, rt ₅₁ .

Compound (3.1) (279 mg, 0.60 mmol) dissolved in DMF (4 mL) was heated at 120 ^° C for 2 h (until complete conversion, LC-MS control), then the reaction mixture was cooled to room temperature. Under argon, N-Fmoc-L-isoleucine (4.1) (211 mg, 0.60 mmol, 1 equiv), HATU (272 mg, 0.72 mmol, 1.2 equiv) and DIPEA (310 μL, 1 , 80 mmol, 3 equiv.) Is added to a solution of the amine (147 mg, 0.60 mmol, assuming 100% of theory) in DMF. The reaction mixture was stirred at room temperature for 4 h, then diluted with EtOAc (20 mL), washed with H2O (3 ^χ 10 mL) and sat. NaCl (10 ml). The organic phase is dried over Na2SO4, decanted and then evaporated under reduced pressure. The dry residue was purified by column chromatography on silica gel eluting with hexane: EtOAc 2: 1-1: 1-EtOAc to give the product (5.1) (253 mg, 73%) as a white solid.

1 H NMR (400 MHz, chloroform-d) δ 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) m.d.

¹³ C NMR (101 MHz, chloroform-d) δ 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 md

HR-MS (ESI / TOF) calcd for C 32 H 43 N 3 O 7 Na [M + Na] + 604.2999, found 604.3001.

[042] The following compounds were obtained according to General Method B:

Connection no. Method Raw materials Structure 5.1. B 3.1 and 4.1 Me Ϋ'η s ο Λ », ^H ° t-BuO ^Me 5.2. B 3.2 and 4.2 Ϋ H j? FmocHN ^/ Y ^N V ^ N ^ OE ^OEt O ^H ° t-BuO ^Me Synthesis of Intermediates (6), General Method C: Synthesis of Compound (6.1) as Example: Me Me ^ Me Ο O ^ Y ^Me 0 FmocHN [f; N γ 2. Ac ₂ O, DIPEA, ^Me N Π - η Π Ο O DMF, ist.t Ο ^Μ O t-BuO ^Me t-BuO ^Me 5.1 6.1

A solution of the dipeptide (5.1) (246 mg, 0.42 mmol) in DMF (4 mL) was heated at 120 ^° C for 2 h (until complete conversion, LC-MS control), then the reaction mixture was cooled to room temperature. To a solution of the amine (152 mg, 0.42 mmol, assuming 100% of theory) in DMF under argon was added acetic anhydride (60 μl, 0.63 mmol, 1.5 equiv) and DIPEA (146 μL, 0, 84 mmol, 2 equiv.). The reaction mass was stirred at room temperature for 5 h, then diluted with EtOAc (20 mL), washed with H2O (3 x 10 mL) and brine. NaCl (10 ml). The organic phase is dried over Na2SO4, decanted and then evaporated under reduced pressure. The dry residue was purified by column chromatography on silica gel eluting with hexane: EtOAc 1: 1-EtOAc to give compound (6.1) (114 mg, 67%) as a white solid.

1 H NMR (400 MHz, chloroform-d) δ 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) m.d.

¹³ C NMR (101 MHz, chloroform-d) δ 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 md

LC-MS (ESI) calcd for C 19 H 36 N 3 O 6 [M + H] ⁺ 402.51, found 402.55.

[046] The following compounds were obtained according to General Method C:

Connection no. Method Raw materials Structure 6.1. C 5.1 Me Ϋ'η Ϊ AcHN ^^ N ^ ⁰ ^ ⁰ A », ^{H 0} t-BuO ^Me 6.2. C 5.2 VH? t-BuO ^Z ' ^M e °

Synthesis of intermediates (7), general method D:

[047] Synthesis of compound (7.1) as an example:

Me

6.1

LiOH,

THF: H ₂ O (20: 1),

Dissolve the tripeptide (6.1) (114 mg, 0.28 mmol) in THF: H 2 O (20: 1, 5 mL), then add LiOH (68 mg, 2.84 mmol, 10 equiv.) And the reaction mass stir at room temperature for 20 h. Water (5 mL) was added to the reaction mixture, then acidified to pH 22 with 1 M HCl and extracted with EtOAc (4 x 5 mL). The organic phase is washed with pie. NaCl solution, dried over Na2SO4, decanted and evaporated under reduced pressure to give acid 7.1 (107 mg, 97%) as a white solid.

The following compounds were obtained according to General Method D:

Connection no. Method Raw materials Structure 7.1 D 7.1 Me „k ^ Me„ 9 f H 9 Me ^A NV ^ N ^ ° ^{H H} ο A ^H o t-BuO ^Me 7.2 D 7.2 9 γ H 9 μ _θ ^Λ νΥ ^ν ^ ν ^ ^{οη H} 0 A ^H o t-BuO ^Me

Characteristics of compounds (7.1) to (7.2):

Connection no. Characteristics 7.1 1 H NMR (400 MHz, chloroform-d) δ 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 (m, 6H) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 md HR-MS (ESI / TOF) calcd for C 18 H 33 N 5 O 6 Na [M + Na] ⁺ 410.2267, found 410.2275. 7.2 1 H NMR (400 MHz, chloroform -d) δ 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 (d, J = 6) 4 Hz, 3H) md ¹³ C NMR (101 MHz, chloroform -d) δ 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 md HR-MS (ESI / TOF) calcd for C 19 H 33 N 3 O 6 Na [M + Na] ⁺ 422.2267, found 422.2268.

Synthesis of Intermediates (9), General Method E: [051] Synthesis of Compound (9.1) as an Example:

7.1 9.1

(+) - Pinanediol (1R) - (1-aminoethyl) boronate hydrochloride (8.1) (40 mg, 0.15 mmol), 7.1 (60 mg, 0.15 mmol, 1 equiv), HATU (71 mg, 0.19 mmol, 1.2 eq.) and DIPEA (80 μl, 0.46 mmol, 3 eq.) were dissolved in DCM (4 mL) and stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2 * 10 mL) and sat. NaCl (10 ml). The organic phase is dried over Na2SO4, decanted and evaporated under reduced pressure. The dry residue was purified by column chromatography on silica gel eluting with 0-5% MeOH / EtOAc to give 9.1 (50 mg, 55%) as a white solid.

1 H NMR (400 MHz, chloroform-d) δ 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), 2.362.26 (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) ) m.d.

¹³ C NMR (101 MHz, chloroform-d) δ 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 md

HR-MS (ESI / TOF) calcd for C 30 H 54 BN 4 O 7 [M + H] + 593.4086, found 593.4089.

Synthesis of intermediates (9), general method F:

[054] Synthesis of compound (9.2) as an example:

Dissolve the acid (7.2) (100 mg, 0.25 mmol, 1 equiv) in 5 mL of EtOAc, then add a solution of N-methylmorpholine (85 μL, 3 equiv.) And propylphosphonic anhydride (300 μL, 2 equiv., 50 mL) sequentially. % solution in EtOAc). Stir the reaction at room temperature for 30 min, then add (+) pinanediol (1R) - (1-aminoethyl) boronate hydrochloride (8.1) (78 mg, 0.30 mmol, 1.20 equiv). At the end of the reaction (LC-MS control), the reaction mixture is diluted with 5 mL of H2O, and the pH is adjusted to 3-43-4 with AcOH. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 x 5 mL). The combined organic phase is washed with pie. NaHCO3 (10 mL), sat. NaCl (10 ml), dried over Na2SO4, decanted and evaporated under reduced pressure. The dry residue was purified by column chromatography on silica gel eluting with 0-5% MeOH / EtOAc to give (9.2) (97 mg, 64%) as a white solid.

[056] The following compounds were obtained according to General Method F:

Connection no. Method Raw materials Structure 9.2 F 7.2 and 8.1 A JL Η ϊ H \ Ϊ AMe Me N ^A f Η Π sh li - θ Me t-BuO ^ Me ⁰ Μθ

9.3 F 7.2 and 8.2 / \ Me Me Π? _h AA A / nVA t-BuO ^ Me ° ^Me 9.4 F 7.2 and 8.4 0 V Ο AA ^e 11 ļ η 9 _H o <; A _M e Μθ Ν ^ Α H lļ ξ η Π V ° ^Μ θ t-BuO ^ Me ° ^Ph 9.5 F 7.2 and 8.5 A? H? _H rOĪ. t-BuO Me ^u 9.6 F 7.2 and 8.6 9 Ζ-Λ Me 9 YH 9 H ° VY Me ^ A ^ 'A ^N ''^ Me ^H ο A ^H ok t-BuO Me η O ^ _/ .4- (MeO) C ₆ H ₄ 9.7 F 7.2 and 8.7 (7 / -Λ Me 9 YH 9 H f V / ^Me Me ^ 'N ^ f ^N ' ^ ^N '· ^ Me ^H o A ^H ok t-BuO Me η 0 4- (MeO) C ₆ lY 9.8 F 7.2 and 8.8 ΓΛ Me 9 YH 9 HY ^ ^Me Me ^ '' N ^ 'A ^N ~' ^ ^{Me H} ο A ^H ok t-BuO Me η O ^ OtBu

[057] Characteristics of compounds (9.2) to (9.8):

Connection no. Characteristics 9.2 ¹ H NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 6.4 Hz, 1H), 7.63-7.52 (m, 2H), 6.39 (d, J = 8 Δ 5 Hz, 1H), 4.71 (t, J = 8.0 Hz, 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) ), 2.362.25 (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) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 m.d. HR-MS (ESI / TOF) calcd for C 31 H 54 BN 4 O 7 [M + H] + 605.4086, found 605.4103. 9.3 1 H NMR (400 MHz, chloroform-d) δ 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), 0.93 (d, J = 6.5 Hz, 3H), 0.84 (s, 3H) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 md HR-MS (ESI / TOF) calcd for C 31 H 54 BN 4 O 7 [M + H] ⁺ 605.4086, found 605.4084. 9.4 1 H NMR (300 MHz, chloroform-d) δ 8.20-7.99 (m, 1H), 7.977.77 (m, 1H), 7.77-7.55 (m, 1H), 7.36- 7.11 (m, 5H, overlapping 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), 0.98-0.87 (m, 3H), 0.80 (s, 3H) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 md HR-MS (ESI / TOF) calcd for C36H56BN4O7 [M + H] ⁺ 667.4242, found 667.4243. 9.5 1 H NMR (400 MHz, chloroform-d) δ 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, 1 H); 4.22-4.01 (m, 3H), 2.93-2.77 (m, 2H), 2.372.26 (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 = 10.9 Hz, 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H) md ¹³ C NMR (101 MHz, chloroform) -d) δ 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 md LC-MS (ESI) calcd for C 30 H 51 BN 4 O 7 [M + H] + 591.39, found 591.79. 9.6 1 H NMR (400 MHz, chloroform-d) δ 7.57 (t, J = 5.2 Hz, 1H), 7.54-7.46 (m, 1H), 7.39 (s, 1H), δ , 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), 2.071.96 (m, 4H), 1.97-1 , 72 (m, 4H), 1.71-1.45 (m, 6H), 1.31 (d, J = 32.0 Hz, 18H), 0.96 (d, J = 6.4 Hz, 3H), 0.83 (s, 3H) md ¹³ C NMR (101 MHz chloroform-d) δ 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 md HR-MS (ESI / TOF) calcd for C 40 H 64 BN 4 O 9 [M + H] ⁺ 755.4766, found 755.4771. 9.7 1 H NMR (400 MHz, chloroform-d) δ 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 Δ 5 Hz, 1H), 4.73 (t, J = 8.1 Hz, 1H), 4.45-4.35 (m, 3H), 4.32-4.21 (m, 2H), 4.093 , 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) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 m.d. HR-MS (ESI / TOF) calcd for C41H65BN4O9 [M + H] + 769.4923, found 769.4936. 9.8 1 H NMR (400 MHz, chloroform-d) δ 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), 2.192.07 (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 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.84 (s, 3H) md ¹³ C NMR (101 MHz, chloroform-d) δ 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 md HR-MS (ESI / TOF) calcd for C37H64BN4O9 [M + H] ⁺ 719.4766, found 719.4765.

Synthesis of boric acid derivatives (10), general method G: [058] Synthesis of compound (10.2) as an example:

9.2 10.2

To a solution of compound (9.2) (73 mg, 0.12 mmol) in MeCN / n-hexane (1: 1, 8 mL) was added isobutylboronic acid (37 mg, 0.36 mmol, 3 equiv.) And 1 M HCl ( 500 μΐ). After 18 h at room temperature, separate the layers. The MeCN phase is washed with n-hexane (3 ^χ 10 mL), then the combined n-hexane layers are washed with MeCN (3 ^χ 10 mL). The acetonitrile extracts are combined and evaporated, the dry residue is purified on C18 silica gel using H2O: MeCN 100: 0-0: 100 as eluent to give (10.2) as a white solid (36 mg, 66%).

The following compounds were obtained according to General Method G:

Connection no. Method Raw materials Structure

10.2 G 9.2 ° VH 9 H 9 ^{H N} '< ^H Ο A ^H O Me tBuO Me 10.3 G 9.3 9 YH 9 H 9 ^H Μβ ^ Ν ^ γ ^Ν 'r ^' N ^ A ^H ° ^H O Me tBuO Me 10.4 G 9.4 9 γ H 9 h 9 ^H μθ ^ νΥπ ^ ν ^^^ α ⁶ ^ ^{H 0} A /> ^H O Ph tBuO Me 10.5 G 9.5 9 YH 9 H 9 ^H Me ^ N ^ A ^H ο A ^H O tBuO Me 10.6 G 9.6 9 YH 9 H? ^H Me ^ 'N ^ A ^^ ^H ο A ^H Ο A tBuO Me η 4- (MeO) C ₆ H ₄ ^ / ° 10.7 G 9.7 9 YH 9 H? ^H Me ^ N ^H o A ^H o A tBuO Me η 0 4- (MeO) C ₆ H ₄ ^ 10.8 G 9.8 9 YH 9 H 9 ^H Me ^ 'uA ^' ^ tBuO ^ 'Me °

[061] Characteristics of compounds (10.2) to (10.8):

Connection no. Characteristics 10.2 1 H NMR (400 MHz, methanol-A) δ 4.34 (d, J = 3.9 Hz, 1H), 4.4 (d, J = 17.6 Hz, 1H), 4.18 (d, J = 9.1 Hz, 1H), 4.15-4.10 (m, 1H), 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) md ¹³ C NMR (101 MHz, methanol-A) δ 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; 16.0 m.d. HR-MS (ESI / TOF) calcd for C 21 H 40 BN 4 O 7 [M-HiO + HT 453.2884, found 453.2880. 10.3 Yield: 39 mg, 64%. 1 H NMR (400 MHz, methanol-d 4) δ 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, 1 H), 2.01 (s, 3 H), 1.89-1.78 (m, 1 H), 1.77-1.52 (m, 5 H) , 1.46-1.28 (m, 2H), 1.23 (s, 9H), 1.14 (d, J = 6.3 Hz, 3H), 1.12-1.07 (m, 3H) md ¹³ C NMR (101 MHz, methanol-d 4) δ 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; 16.0 md HR-MS (ESI / TOF) calcd for C 21 H 40 BN 4 O 7 [M-H 2 O + H] ⁺ 453.2884, found 453.2889. 10.4 Yield: 41 mg, 45%. 1 H NMR (400 MHz, methanol-d 4) δ 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), 1.741.49 (m, 5H), 1.42-1.25 (m, 2H), 1.27-1.17 (m, 9H), 1.18- 1.06 (m, 3H) md ¹³ C NMR (101 MHz, methanol-d 4) δ 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 md HR-MS (ESI / TOF) calcd for C 26 H 42 BN 4 O 7 [M-H 2 O + H] ⁺ 515.3041, found 515.3051. 10.5 The product was used in the further reaction without purification and full characterization LC-MS (ESI) calculated for C20H36BN4O6 [M-H2O + H] ⁺ 439.27, found 439.61. 10.6 The product was used in the further reaction without purification and full characterization LC-MS (ESI) calculated for C30H48BN4O8 [M-H2O + H] ⁺ 603.36, found 603.73.

10.7 The product was used in the further reaction without purification and full characterization LC-MS (ESI) calculated for C31H50BN4O8 [M-H2O + H] ⁺ 617.37, found 617.72. 10.8 Yield: 65 mg, 69%. 1 H NMR (400 MHz, methanol-δ) δ 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) md ¹³ C NMR (101 MHz, methanol-d 4) δ 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 md LC-MS (ESI) calcd for C23H40BN4O8 [M-H2O + H] ⁺ 511.29, found 511.72.

Synthesis of boron derivative (11), general method H: Synthesis of compound (11.1) as an example:

9.1 11.1

To a solution of compound (9.1) (50 mg, 0.08 mmol) in DCM (5 mL) at -78 ° C was added a solution of BBrs (180 μL, 1M) in DCM. The mixture is slowly warmed to room temperature. After 2 h, methanol (3 x 2 mL) is added to the reaction and evaporated after each addition, then water (10 mL) is added to the residue and the mixture is extracted with Et2O (3 ^x 10 mL). The aqueous phase was evaporated under reduced pressure to give product 11.1 (29 mg, 85%) as a yellowish solid. 1 H NMR (400 MHz, methanol-d 4) δ 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), ) md

¹³ C NMR (101 MHz, methanol-d4) δ 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 md

HR-MS (ESI / TOF) calcd for C 16 H 30 BN 4 O 6 [M-H 2 O + H] + 385.2258, found 385.2263.

Synthesis of boric acid derivatives (11), general method I:

[065] Synthesis of compound (11.2) as an example:

TFA

DCM

10.2

11.2

Boric acid (10.2) (17 mg, 0.038 mmol) is reacted with dry DCM (2 mL) with TFA (500 μΐ). The reaction mass was stirred until complete conversion of the starting material was achieved (LC-MS control). The reaction mixture is evaporated, then toluene (2 ^χ 5 ml) is added and re-evaporated after each addition. The dry residue was treated with Et2O (3 ^χ 5 mL, the residue was removed after each centrifugation) to give product 11.2 as a white solid (11 mg, 74%).

[067] The following compounds were obtained according to General Method I:

Connection no. Method Raw materials Structure 11.2 I 10.2 ⁰ Υ Ο OH ^Me NY i T OH ° HO ^ 'Me ⁰ Μθ 11.3 I 10.3 ⁰ 'Ο Ο OH ^Me Η Υ ΥβΑί Ύ ^οη θΗΟ ^ Μθ ^{0 Me} 11.4a I 10.4 Ο Α Α I ^Η ? ^Η Ī ° o ° HO ^ Me ^{0 Ph CF3} 11.4b I 10.4 ⁰ 'Ά Ο ΟΗ mAvJ ^Me Η Υ; ΗΑί Τ ^0Η ° HO ^ Me ^{0 Ph} 11.5 I 10.5 Η Υ Η 9 Η 9 ^Η Μβ ^ Α ^ 'Υ ^Η έ Λ ^Η Ο ΗΟ Me 11.6 I 10.6 Λ ļf _u Ο _u ΟΗ Λ JANAI ^Μ θ ηΑτ i νΑτ Υ> Ο ^ Ο ΗΟ Me 11.7 I 10.7 Η Υ Η 9 Η 9 ^Η MeA _N ΑΑ '^ ^Ν ΑΑ' ^ ^Η Ο Α ^Η ο Μ ΗΟ Me

11.8 I 10.8 Η 1 H 9 H 9 ^{H H} 1 A ^H o vA ΉΟ Me

[068] Characteristics of compounds (11.2) to (11.8):

Connection no. Characteristics 11.2 1 H NMR (400 MHz, metal-d 4) δ 4.26 (d, J = 4.5 Hz, 1H), 4.244.02 (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) md ¹³ C NMR (101 MHz, methanol-d4) δ 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 md HR-MS (ESI / TOF) calcd for C17H30BN4O6 [M-H2O + H] + 397.2258, found 397.2265. 11.3 1 H NMR (400 MHz, methanol-A) δ 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), 1.141.05 (m, 3H) md ¹³ C NMR (101 MHz, methanol-A) δ 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 md HR-MS (ESI / TOF) calcd for C17H30BN4O6 [M-H2O + H] ⁺ 397.2258, found 397.2264. 11.4a 1 H NMR (400 MHz, methanol-A) δ 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) md ¹³ C NMR (101 MHz, methanol-A) δ 178.2; 174.8; 173.8; 173.2; 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; 39.7; 30.3; 26.3; 26.0; 22.3; 19.9 md HR-MS (ESI / TOF) calcd for C 26 H 31 BN 4 O 9 F 6 Na [M-H 2 O + Na] ⁺ 691.1986, found 691.2001.

11.4b ¹ H NMR (400 MHz, methanol-δ) δ 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), 1.221.15 (m, 3H) md ¹³ C NMR (101 MHz, methanol) δ 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 md HR-MS (ESI / TOF) calcd for C22H32BN4O6 [M-H2O + H] + 459.2415, found 459.2418. 11.5 ¹ H NMR (400 MHz, methanol-d 4) δ 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), 1.761.51 (m, 5H), 1.45-1.27 (m, 2H), 1.19 (d, J = 6); .3 Hz, 3H) md ¹³ C NMR (101 MHz, methanol) δ 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 md LC-MS (ESI) calcd for C 16 H 28 BN 4 O 6 [M-H 2 O + H] ⁺ 383.21, found 383.51. 11.6 ¹ H NMR (400 MHz, methanol-d 4) δ 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) md ¹³ C NMR (101 MHz, methanol-d 4) δ 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 md HR-MS (ESI / TOF) calcd for C 18 H 31 BN 4 O 7 Na [M + Na] ⁺ 499.2183, found 499.2170. 11.7 ¹ H NMR (400 MHz, methanol-d 4) δ 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) md ¹³ C NMR (101 MHz, methanol-d 4) δ 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 md LC-MS (ESI) calculated for C19H32BN4O6 [M-H2O + H] ⁺ 423.24,

found 423.55. 11.8 NMR (400 MHz, methanol-d ₄ ) δ 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) md ¹³ C NMR (101 MHz, methanol-d ₄ ) δ 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 md LC-MS (ESI) calculated for C ₁₉ H 32 BN 40 O [M + H] ⁺ 455.23, found 455.61

[0691 In vitro tests:

The compounds were tested for subtilisin-related serine protease (pfSUB1) inhibitory activity in vitro according to the procedure described.

[070] Determination of IC ₅ o:

Pure recombinant P. falciparum SUB1 (PfSUB1) was obtained and purified as described above. ^The enzyme is dissolved in digestion buffer (25 mM CHAPS, 12 mM CaCl 2, 25 mM TrisHCl, pH 8.2) and distributed in a 96-well microtiter plate with a flat bottom (Nunc). Test compounds are dissolved in dimethyl sulfoxide (DMSO), diluted and added to 2% in each well. The rhodamine-labeled fluorogenic substrate SERA4stlF-6R12 is added at a final concentration of 0.1 μΜ in a volume of 100 μΐ and the rate of hydrolysis is measured with a Cary Edipse spectrofluorometer (Varian, UK) as described above. Excitation and emission wavelengths are 552 nm and 580 nm, respectively.

EP-530 concentration (nM)

The results are shown in Table 1.

[071] Determination of EC50 in parasite growth assays:

The effect of the compounds on the growth of the blood parasite Plasmodium falciparum (clone 3D7) was assessed by the SYBR Green I test. Test compounds (dissolved in DMSO to a final concentration of 1 mM to 0.1 μM) are added to three parallel 96-well microtiter plates with a flat bottom (1 μl in each well). The wells are supplemented with 100 μl of P. falciparum parasite culture to 0.1% parasitemia, 1% hematocrit.

[072] Each test plate also includes a control well filled with DMSO as well as an additional control well containing only uninfected erythrocytes. The plates are incubated in a sealed humidified chamber for 96 hours at 37 ^o C, allowing the parasites to undergo two complete cycles of erythrocyte growth. The wells are then supplemented with 100 μl of a dilute (1: 5000) standard solution of SYBR Green I (Life Technologies, catalog code # S7563) diluted in 20 mM Tris-HCl pH 7.5, 5 mM EDTA, 0.008% (w / v) saponin, 0.08% (v / v) Triton X100. The plates are shaken until mixed, then incubated for 1 h in the dark at room temperature, then transferred to a Cary Eclipse fluorescence spectrophotometer (Varian) equipped with a 96-well microtiter plate reader for reading fluorescence measurements (Ex 485 nm, Em 530 nm). EC50 values were determined from the dose-response curve obtained by subtracting the background fluorescence value (obtained from the erythrocyte control well) from all experimentally read values. The results are shown in Table 1.

Table 1. Biological activity of boric acid - containing peptidomimetics.

ID Connection no. IC50 PfSUB1 (nM) EC50 Growth of P. falciparum (pM) 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

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3. 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.

4. N. K. Sahu, S. Sahu and D. V. Kohli, Novel Molecular Targets for Antimalarial Drug. Chem. Biol. Drug. Des., 2008, 71, 287-297.

5. 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.

6. 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 the release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nat Microbiol. 2018, 3 (4), 447-455.

7. Kher, S. S .; Penzo, M .; Fulle, S .; Finn, P. W.; Blackman, M. J .; Jirgensons, A. Substrate derived peptidic α-ketoamides as inhibitors of the malarial protease PfSUB1.Bioorg. Med. Chem. Lett., 2014, 24 (18), 4486-4489.

Claims (5)

Compounds of general formula (I): I where: R ⁴ is H or Me; R ³ is H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C 2-6 arylalkenyl, heteroalkyl, C 26 arylalkyl -6heteroarylalkenyl, R ¹² O (CH 2) n, R ¹² S (CH 2) n, R ¹² OC (= O) (CH 2) n, R ¹² N (R ¹³ ) C (= O) (CH 2) n, R ¹² N (R ¹³ ) (CH 2) n wherein R ¹² and R ¹³ are independently H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 16 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C26arylalkenyl, C2-6arylalkynyl, heteroaryl, C1-6heteroarylalkyl, C26heteroarylalkenyl; n is an integer from 1 to 6; R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently: -H, -F, -Cl, -Br, -I, -CF 3, -CH 2 CF 3, -CF 2 CF 2 H, -OH, -L-OH, -OL-OH, -OR ¹⁴ , -OL-NH 2, -OL-NHR ¹⁴ , -OL-NR ¹⁴ 2, -OLR ¹⁴ NR ¹⁵ , -L-OR ¹⁴ , -OL-OR ¹⁴ , -OCF 3, -OCH 2 CF 3, -OCF 2 CF 2 H, -L-OR ¹⁴ , -OL-OR ¹⁴ , -OCF 3 , -OCH2CF3, -OCF2CF2H, SR ¹⁴ , SCF 3, -CN, -NO 2, -NO 2, -NH 2, NHR ¹⁴ , -NR ¹⁴ 2, -N (R ¹⁴ ) R ¹⁵ , -L-NH 2, -L-NHR ¹⁴ , -L-NR ¹⁴ 2, -LN (R ¹⁴ ) R ¹⁵ , -NH-L-NH 2, -NHL-NHR ¹⁴ , -NH-L-NR ¹⁴ 2, -NH-LN (R ¹⁴ ) R ¹⁵ , -NR ¹⁴ -L-NH 2, -NR ¹⁴ -L-NHR ¹⁴ , -NR ¹⁴ -LNR ¹⁴ 2, NR ¹⁴ -LN (R ¹⁴ ) R ¹⁵ , LN (R ¹⁴ ) R ¹⁵ , -C (= O ) OH, -C (= O) OR ¹⁴ , -C (= O) NH 2, -C (= O) NHR ¹⁴ , C (= O) NR ¹⁴ 2, -C (= O) N (R ¹⁴ ) R ¹⁵ , -NHC (= O) R ¹⁴ , -NR ¹⁴ C (= O) R ¹⁵ , -NHC (= O) OR ¹⁴ , NR ¹⁴ C (= O) OR ¹⁵ , -OC (= O) NH 2, - OC (= O) NHR ¹⁴ , -OC (= O) NR ¹⁴ 2, -OC (= O), r ¹⁴ No. ¹⁵ , OC (= O) R ¹⁴ , -C (= O) R ¹³ , -NHC ( = O) NH 2, -NHC (= O) NHR ¹⁴ , -NHC (= O) NR ¹⁴ 2, - NHC (= O) N (R ¹⁴ ) R ¹⁵ , -NR ¹⁴ C (= O) NH 2, -N (R ¹⁴ ) C (= O) NHR ¹⁵ , -NR ¹⁴ C (= O) NR ¹⁴ 2, NR ¹⁴ C (= O) N, -NHS (= O) 2 R ¹⁴ , -N (R ¹⁴ ) S (= O) 2 R ¹⁵ , -S (= O) 2 NH 2, -S (= O) 2 NHR ¹⁴ , S ( = O) 2NR ¹⁴ 2, -S (= O) 2N (R ¹⁴ ) R ¹⁵ , -S (= O) R ¹⁴ , -S (= O) 2 R ¹⁴ , -OS (= O) 2 R ¹⁴ , -S (= O) 2OR ¹⁴ , C 16 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 2-6 alkenyl, C 26 alkynyl, biarylalkyl, C 1-6 arylalkyl, C 2-6 arylalkenyl, C 26 arylalkyl , heteroarylthio, 2,3-dihydro-1H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidine, piperidine, 4-arylpiperidine, 4-heteroarylpiperidinyl, morpholine, piperazine, 4-C1-6alkylpiperazine, 4-C1-6alkyl , 3-dihydro-2H-isoindol-2-yl; or R ⁵ , R ⁷ , R ⁸ are independently = O, = NR ¹⁴ , = NOH, are = NOR ¹⁴ ; L is -W-X-Y-Z-; and -W-X-Y, and -W-X, R ¹ and R ² , or R ¹ and R ³ , or R ⁵ and R ⁶ , or R ⁷ and R ⁸ , or R ⁷ and R ¹¹ , or R ⁸ and R ⁹ , or R ⁹ and R ¹⁰ , or R ¹⁰ and R ¹¹ taken together are -WXYZ- or -WXY- or -WX-, or in which: W is a single bond, oxygen, sulfur, -NR ¹⁴ or -CR ¹⁴ R ¹⁵ , X is oxygen, sulfur, -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ , Y is oxygen, sulfur, -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ , Z is oxygen, sulfur -NR ¹⁴ or -C (R ¹⁴ ) R ¹⁵ ; R ¹⁴ and R ¹⁵ are independently H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, C 1-6 arylalkyl, C 26 arylalkenyl, C 2-6 aryl, C 2-6 aryl -6heteroarylalkyl, C26heteroarylalkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C1-6alkoxyC16alkyl, C1-6alkylthioalkyl, C4-6alkenylthio, C312cycloalkyl, C3-12cycloalkyl , C16 alkoxyC1-6alkylthio, C1-6alkoxyC3-6alkenylthio, C3-6arylalkenylthio, C16heteroarylalkylthio, C1-6alkylsulfonyl, C3-12cycloalkyl-C1-6alkylsulfonyl, C16-6alkylsulfonyl, C16-6alkylsulfonyl C 3-12 cycloalkylamino, C 1 -C 6 alkoxy-C 3 -C 12 cycloalkylamino, C 3-12 cycloalkylC 1-6 alkylamino, di-C 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkylamino, arylamino, C 1-6 arylalkylamino, N-alkyl 6-alkylamino, N-aryl-NC1-6alkylamino, N-C1-6arylalkyl-N-C1-6alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidine, piperazine, 4-arylpiperidine, 4-heteroarylpiperidine, morpholyl, morpholyl , hexamethyleneimine, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, C 1-6 heteroarylalkoxy, heteroarylamino or C 1-6 heteroarylalkylamino and their optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs. Compounds according to claim 1 for use in the treatment of diseases associated with the inhibition of serine proteases. Compounds according to any one of the preceding claims, wherein the disease associated with the inhibition of serine proteases is malaria. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier for use in the treatment of malaria. A pharmaceutical composition according to claim 4 for parenteral or oral administration.