LV15146B - N-acyl-diarylsulfonamide derivatives as aminiacyl-t-rna synthetase inhibitors - Google Patents

Abstract

The present invention relates to novel N-acyl-diarylsulfonamides acting as inhibitors of bacterial aminoacyl-t-RNA synthetase. These can be used as medicines or as constituent of medicines for the treatment of bacterial infections.

Description

DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION

The invention relates to the development of medical preparations, in particular inhibitors of bacterial aminoacyl-ARNS synthesis for the treatment of bacterial infections. In particular, the present invention relates to novel N-acyl-diarylsulfonamides, their pharmaceutical compositions and their use as inhibitors of aminoacyl-ARNS synthesis.

Grounds for the Invention

The development of resistance to current antimicrobial agents has triggered the search for new chemotherapeutic agents for which resistance develops slowly or is completely blocked. This could be achieved by targeting functional bacterial proteins that mutate to reduce bacterial fitness. Bacterial enzymes called aminoacyl-ARNS synthetases (aaRS) have been recognized as such molecular targets for the development of new drugs (Gadakh, B. Van Aerschot, A. Aminoacyl-tRNA synthetase inhibitors as antimicrobial agents. Opin. Ther. Patents 2012, 22, 1453-1465, Vondenhoff, GHM; Van Aerschot A. Aminoacyl-RNA synthetase inhibitors as potential antibiotics, Eur. J. Med. Chem. 2011, 46, 5227-5236. Pham, J. S., Dawson. , KL; Jackson, KE; Lim, EE; Pasaje, CFA; Turner, KEC; Ralph, SA Aminoacyl-tRNA synthetases as drug targets in eukaryotic parastases Int J Parasitol Drugs Drug Resist 2014, 4, 41-13 .) Isoleicyl-ARNS synthetase (IleRS) inhibitor Mupirocin is a clinically approved drug for the treatment of a broad spectrum of Gram-positive bacterial infections. A number of inhibitors have been developed to inhibit other bacterial t-RNA syntheses, but none have been approved and used in drug clinics to date.

Summary of the Invention

The invention provides a method of treating bacterial infections in humans or animals by administering a therapeutically effective amount of a compound. This compound is an aminoacyl-ARNS synthetase inhibitor and can be administered in the form of a drug precursor, a pharmaceutically acceptable salt, a hydrate or a solvate, and any of its polymorphs.

In another aspect, the invention provides a pharmaceutical composition for the treatment of bacterial infections comprising a therapeutically effective amount of a composition comprising (i) a drug or drug precursor or a pharmaceutically acceptable salt, hydrate, solvate or drug polymorph thereof; (ii) a pharmaceutically acceptable carrier, wherein the drug is an aminoacyl-ARNS synthetase inhibitor.

In another aspect, the invention provides a medicament for widespread use in the treatment or prophylaxis of bacterial infections, including a composition comprising a drug, a precursor thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or drug polymorph thereof comprising an aminoacyl - / - RNA synthetase inhibitor.

In another aspect, the invention provides a drug as a precursor, or a pharmaceutically acceptable salt or ester thereof, for treating or preventing a bacterial infection wherein the drug is an aminoacyl-r-RNA synthetase inhibitor.

In one embodiment, the aminoacyl-ARNS synthetase inhibitor is a compound of Formula I, which will be referred to herein as an N-acyl-diarylsulfonamide derivative:

General formula I:

R2

R3 R4 ₅

Formula I in which:

AI and arylgrap

Q is a covalent bond or linker;

A2 is an aryl group which is a linking group;

R1 and R2 are optional substituents on the methylene group;

R3 and R4 are optional amino substituents;

and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms and drug precursors of these derivatives.

Arilgrapa (AI)

Arylgrapa (AI) is an optionally substituted C5-2oarylgrapa.

In one embodiment, AI is an optionally substituted C5-2oheteroaryl, or AI is an optionally substituted C5-2oheteroaryl monocyclic, or AI is an optionally substituted C5-2ocarboaryl, or AI is an optionally substituted C5-2ocarboaryl monocyclic, or A1 is optionally substituted substituted C monocyclic C 8 -Carboaryl, or A 1 is optionally substituted phenyl, or A 1 is C 5-20 aryl, derived from one of the following:

pyrimidine, pyridine, triazine, 9H-purine, pyran, imidazole, naphthalene, quinoline, indole, benzimidazole, quinazoline.

In one embodiment, AI is an optionally substituted pyrimidyl group of the formula:

4 '

wherein n is a number from 0 to 3, and each R ^A is an unrelated substituent as defined herein.

Alternatively, AI is an optionally substituted pyrimidyl group, Q is a covalent bond or a linker; A2 is aryl which is a linker group, R1 and R2 are methylene substituents, R3 and R4 are aminogroup substituents and the compound has the following general formula:

4 '

R3 ^ to R4 wherein in one embodiment, n is a number from 0 to 3;

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is 0 or 1;

in one embodiment, n is a number from 1 to 3;

in one embodiment, n is 1 or 2;

in one embodiment, n is 3;

in one embodiment, n is 2;

in one embodiment, n is 1;

in one embodiment, n is 0.

If the pyridyl group is not completely substituted by the ring substituents R ^A , they can be arranged in any combination. For example, when n is 1, R ^A may be in the 2-, 4-, or 5'- position. Similarly, when n is 2, the two R ^a groups may be, for example, at the 2 ', 4'-, 2', 5'-, or 4 ', 5'- positions.

In one embodiment, n is 1 and the R ^A group is in the 2'-position.

In one embodiment, n is 2 and one R ^A group is at the 4 'position and the other R ^A group is at the 2' position.

Each aryl substituent R ^A is as defined herein.

Preferred ring substituents R ^A include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, , trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e. -CONH2), acetamido, acetyl, nitro, sulfonamido (unsubstituted, i.e., -SO2NH2), and phenyl.

In one embodiment, Al is an optionally substituted imidazopyrimidyl group of the general formula:

8 '

wherein n is a number from 0 to 3, and each R ^A is an independent substituent as defined herein.

In one embodiment, Al is an optionally substituted imidazopyrimidyl group, Q is a covalent bond or a linker; A2 is an aryl group which is a linking group; R1 and R2 are methylene substituents; R3 and R4 are amino substituents; and the compound has the following general formula:

in one embodiment, n is a number from 0 to 3;

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is 0 or 1;

in one embodiment, n is a number from 1 to 3;

in one embodiment, n is 1 or 2;

in one embodiment, n is 3;

in one embodiment, n is 2;

in one embodiment, n is 1;

in one embodiment, n is 0.

If the imidazo group is not completely substituted by the ring substituents R ^A , they can be placed at any position. For example, when n is 1, R ^A may be in the 2 ', 7', or 8 'position. Similarly, when n is 2, the two R ^A groups may be, for example, at the 2 ', 7'-, 2', 8'-, or 7 ', 8'- positions.

Each aryl substituent R ^A is as defined herein.

Examples of preferred ring substituents R ^A include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, Z-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy -, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, ie -CONH2), acetamido, acetyl, nitro, sulfonamide - (unsubstituted, i.e. -SO 2 NH 2), and phenyl.

In one embodiment, Al is an optionally substituted 4-pyridyl group of the general formula:

6 '

3 'wherein n is a number from 0 to 4 and each R ^A is an independent substituent as defined herein.

In one embodiment, A 1 is an optionally substituted 4-pyridyl group, Q is a covalent bond or linker, A 2 is an aryl group which is a linking group, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino substituents and have the following general formula:

6 '

R3 ^ ^ R4 ₅ wherein:

in one embodiment, n is a number from 0 to 4;

in one embodiment, n is a number from 0 to 3;

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is 0 or 1;

in one embodiment, n is a number from 1 to 4;

in one embodiment, n is a number from 1 to 3;

in one embodiment, n is 1 or 2;

in one embodiment n or 4;

in one embodiment n or 3;

in one embodiment n or 2;

in one embodiment n or 1;

in one of the variants, n or 0.

If the pyridine group is not completely substituted by the ring substituents R ^A , they can be placed at any position. For example, when n is 1, R ^A may be in the 2'-, 3'-, 5'- or 6'- position. Similarly, when n is 2, the two R ^A groups may be, for example, at the 2 ', 3'-, 2', 5'-, 2 ', 6'-, or 3', 5'- positions.

In one embodiment, n is 1 and one R ^A group is in the 2'-position.

Each loop substituent, R ^A , is as defined herein.

Examples of preferred ring substituents R ^A include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido ( unsubstituted, i.e. -SO 2 NH 2) and phenyl.

In one embodiment, AI is an optionally substituted 2-pyridyl derivative having the following general formula:

4 '

wherein n is a number from 0 to 4, and each R ^A is an independent substituent as defined herein.

In one embodiment, A 1 is an optionally substituted 2-pyridyl group, Q is a covalent bond or linker, A 2 is an aryl group which is a linker, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino substituents and has the following general formula:

in one embodiment, n is a number from 0 to 4;

in one embodiment, n is a number from 0 to 3;

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is 0 or 1;

in one embodiment, n is a number from 0 to 4;

in one embodiment, n is a number from 0 to 3;

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is 0 or 1;

in one embodiment, n is a number from 1 to 4;

in one embodiment, n is a number from 1 to 3;

in one embodiment, n is 1 or 2;

in one embodiment, n is 4;

in one embodiment, n is 3;

in one embodiment, n is 2;

in one embodiment, n is 1;

in one embodiment, n is 0.

If the pyridine group is not completely substituted by the ring substituents R ^A , they can be located at any position. For example, when n is 1, R ^A may be in the 3-, 4'-, 5- or 6'- position. Similarly, when n is 2, the two R ^A groups may be, e.g., 3 ', 4'-, 3', 5'-, 3 ', 6'-, 4', 5'-, 4 ', 6'- or at the 5 ', 6' position.

In one embodiment, n is 0.

In one embodiment, n is 1 and one R ^A group is at the 6 'position.

Each cycle substituent R ^A is as defined herein.

Examples of preferred ring substituents, R ^A , include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, , isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido- (unsubstituted, i.e. -SO 2 NH 2) and phenyl.

In one embodiment, AI is an optionally substituted 1,3,5-triazinyl group with the following general formula:

4 '

n is a number from 0 to 2 and each R ^A is an independent substituent as defined herein.

In one embodiment, A1 is an optionally substituted 1,3,5-triazinyl group, Q is a covalent bond or linker, A2 is an aryl group which is a linker, R1 and R2 are methylene substituents, R3 and R4 are amino substituents and the linkage is as follows general formula:

4 '. N ^ N „ ^R -ίαV

N Q .S.

^X aZ N

H

R3 ^ ^ R4 wherein:

in one embodiment, n is a number from 0 to 2;

in one embodiment, n is a number from 0 to 1;

in one embodiment, n is 0 or 1;

in one embodiment, n is 1 or 2;

in one embodiment, n is 2;

in one embodiment, n is 1;

in one embodiment, n is 0.

If the triazine group is not completely substituted by the ring substituents R ^A , they can be placed at any position. For example, when n is 1, R ^A may be in the 3'-, 4'-, 5'- or 6'- position. Similarly, when n is 2, the two groups R ^a may be, for example, 3 ', 4'-, 3', 5'-, 3 ', 6'-, 4', 5'-, 4 ', 6'- or at the 5 ', 6' position.

In one embodiment, n is 0.

In one embodiment, n is 1 and one R ^A group is at the 6 'position.

Each substituent on the cycle, R ^A , is as defined herein.

Examples of preferred ring substituents R ^A include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido ( unsubstituted, i.e. -SO 2 NH 2) and phenyl.

Linker (О)

As noted above, in several embodiments, Q is a covalent bond or linker; in several embodiments, Q is a covalent bond; in several embodiments, Q is a linker.

In one embodiment, Q is a covalent bond.

In one embodiment, Q is an optionally substituted C 1-4 alkyl group.

In one embodiment, Q is an optionally substituted methylene group.

Aryl which is a linking group (A2)

The aryl group which is a linking group (A2) is an optionally substituted C5-20 arylene group.

In one embodiment, A2 is an optionally substituted C5-2oheteroarylene. In one embodiment, A2 is a monocyclic and optionally substituted C5-2oheteroarylene. In one embodiment, A2 is a monocyclic and optionally substituted Cs-6 heteroarylene.

In one embodiment, A2 is an optionally substituted C5-2carboarylene. In one embodiment, A2 is a monocyclic and optionally substituted C5-2carboarylene. In one embodiment, A2 is a monocyclic and optionally substituted C5-6carboarylene. In one embodiment, A2 is an optionally substituted phenylene group.

Phenylene which is a linking group may be in the ortho, meta, or / or position, phenylene optionally substituted with aryl substituents R ^B :

meta-paraortho In one embodiment, the phenylene group which is the linking group is meta-phenylene or paraphenylene. In one embodiment, the phenylene group which is a linking group is a γ-phenylene group. In one embodiment, the phenylene group which is a linking group is a w, etha-phenylene group.

In one embodiment, m is a number from 0 to 4.

In one embodiment, m is a number from 0 to 3.

In one embodiment, m is a number from 0 to 2.

In one embodiment, m is 0 or 1.

In one embodiment, m is a number from 1 to 4.

In one embodiment, m is a number from 1 to 3.

In one embodiment, m is 1 or 2.

In one embodiment, m is 4.

In one embodiment, m is 3.

In one embodiment, m is 2.

In one embodiment, m is 1.

In one embodiment, m is 0.

Each aryl substituent R ^B is as defined herein.

Examples of preferred aryl substituents R ^B include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, ributyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy -, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl.

When Q is a covalent bond or a linker, A2 is a meta-phenylene group, the compound has the following general formula:

when Q is a covalent bond, A2 is a meta-phenylene group, the compound has the following general formula:

Each alkyl and amino substituent R 1, R 2, R 3 and R 4 is as defined herein.

Examples of preferred substituents, R1-R4, include, but are not limited to, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, ributyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, , trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl.

Stereochemistry

Several of the structures shown here depict their specific stereochemical configuration. Similarly, several of the structures shown here do not depict their specific stereochemical configuration. Similarly, for many chemical structures, stereochemical configurations are shown at one or more positions, while for other positions, the configuration is not shown. Unless the stereochemical configuration of the chemical structure is depicted, the structure should be considered to include all possible stereoisomers, individually or as a mixture of stereoisomers.

Substitutes

C5-2oaryl: The term C5-2oaryl, as used herein, refers to a monovalent group obtained when C5. The 2-aromatic compound is deprived of one hydrogen atom and is composed of one, two or more rings (e.g., fused rings) and is comprised of 5 to 20 atoms, and wherein at least one ring is an aromatic ring. Preferably, each ring has 5 to 7 atoms.

In this context, prefixes (e.g., C3-20, C5-7, C5-6, etc.) refer to the number or range of ring atoms, both carbon atoms and heteroatoms. For example, the term C5-6aryl as used herein refers to an aryl group consisting of 5 or 6 ring atoms. Examples of aryl groups include C 1 -C 2 ap 1, C 5 -aryl, C 5 -C 6 aryl.

Cyclic atoms may all be carbon atoms, as is the case for carboaryl groups (e.g., C5-2carboaryl). Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphthacene (С 18) and pyrene (С 16).

Examples of aryl groups having fused rings of which at least one is aromatic include, but are not limited to, groups derived from indene (C9), isoindene (C9) and fluorene (C13).

Alternatively, ring atoms may be one or more heteroatoms including but not limited to oxygen, nitrogen or sulfur as in "heteroaryl" groups. In this case, the group may be termed a C52oheteroaryl group, where C5-20 indicates and the number of ring atoms, which may be both carbon and heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.

Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6);

01: furan (oxole) (C5);

SI: thiophene (thiol) (C5);

N101: oxazole (C5), isoxazole (C5), isoxazine (C6);

N201: oxadiazole (furazane) (C5);

N301: oxatriazole (C5);

N1S1: thiazole (C5), isothiazole (C5);

N2: imidazole (1,3 diazole) (C5), pyrazole (1,2 diazole) (C5), pyridazine (1,2 diazine) (C6), pyrimidine (1,3 diazine) (C6) (eg, cytosine, thymine, uracil), pyrazine (1,4 diazine) (C6);

N3: triazole (C5), triazine (C6); and

N4: tetrazole (C5).

Combinations

Each and every combination compatible with the variants described above is clearly indicated here, as if each and every combination were individually and directly listed.

Specific examples of variants

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

As examples of the present invention, the following N-acyl-diarylsulfonamide derivatives are shown in 8.18.18:

ID Sav. number Structure IK-580 8.1 nA, o. , 9 9, II \ Sf / 0 ĀH ₂ 1 IK-617 8.2 ^X 0 'N As 0. .0 0 Il JV JL nh ₂ ¹ IK-587 8.3 N • ^ 1 0. .0 0 ji J _л V Ā / nh ₂ ¹ K-615 8.4 № \ 1 NH 0. .0 0 11 J _л V А / āh ₂ ¹ IK-621 8.5 nAs o, .0 Q ian ₂ I BM-13 8.6 ООО. 2Н ₂ IK-625 8.7 N As о. О О ii J _л у / 1 / χΥ Йн ₂ ¹ IK-636 8.8 N ^ 4 0. .0 0 у JV Л / ЙН ₂ 1

IK-634 8.9 А VX / nh ₂ ¹ IK-635 8.10 h ₂ n ^ n | | Й 1 ЧА nh ₂ I IK-627 8.11 nh ₂ N А 0. .0 о jl AVX /. / hjn ^ nAv ^ цАХА ЙН ₂ 1 DG-435 8.12 νη ₂ nA ООО [1 _Z XVX / s. / ifY нХХ ΙχΥ Йн ₂ 1 DG-437 8.13 N Ал О _ч О о J! / 1 _л VX hAnav ^ XX АА Йн ₂ 1 DG-440 8.14 N ^ N 0 _х .0 о 1 \ VX / η ₂ νΆ AAf ^ч й XX АА йи ₂ 1 DG-444 8.15 11 А VX / qA ^ n'A / AU ^ ΆΑΑ NH ₂ I DG-445 8.16 She XX / Ηθ ^Λ ΝΑγ ЙΧ | ΑΑ νη ₂ ι DG-455 8.17 A nA ο 0 ο II JVX / ΑΑй ₂ 1 DG-453 8.18 α N Α1 ° χ / ° 9 Ji JVX / ΑΧν Α'ΧΧ ^ ΑΑ 2н ₂ *

General description of syntheses

1. Scheme

DCM, i.t (Method A)

25% NH4OH

PdCl ₂ (dppf) ₂ Na ₂ CO ₃ . water Dioxane, 110 ° C (Method E) ^R 3x. / Ρθ N ноос ' ^/ т ₂

Pin ₂ B _2i PdCI ₂ (dppf) ₂

KOAc, Dioxane 110'C (Method C)

(Method G)

HBTU, TEA, DMAP (cat.) DMF, i.t.

Synthesis of Intermediates 2, General Method A

Demonstrated on the example of compound 2.1 syntheses:

3-Bromobenzosulfonamide (2.1)

Br

/ ^Cl

1.1

Br

/ 'NH ₂

2.1

To a solution of 3-Bromobenzo-1-sulfonylhlonda (1.1) (4.073 g, 15.94 mmol) in DCM (67 mL) is added 25% NH4OH in water (3.7 mL, 57.15 mmol) in a cooled ice bath. Stir the reaction mass for 0.5 h, then stir at room temperature for 6 h. A precipitate formed which was filtered off, washed with water and dried in a stack above P2O5. 3-Bromobenzosulfonamide (2.1) (3.270 g, 87%) is obtained as a colorless crystalline solid. 1 H NMR (DMSO-d 6) δ: 7.97 (t, J = 1.9 Hz,

1H), 7.84-7.80 (m, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.50 (b s, 2H). LCMS (ESI) m / z: 235.98 [?] -.

By a method analogous to Method A, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 2.1 A 1.1 ° w ° ^ΒΓ ^ Ο ^ ^ΝΗ2

Synthesis of Intermediates 3, General Method В

Demonstrated on the synthesis example of compound 3.1:

(S) -tert-butyl (1- (3-bromophenylsulfonamido) -4-methyl-1-oxopentan-2-yl) carbamate (3.1)

2.1 3.1

To a solution of BOC-L-leucine monohydrate (0.592 g, 2.37 mmol) in DMF (5 mL) was successively added 3-bromobenzosulfonamide (0.561 g, 2.37 mmol), HBTU (0.900 g, 2.37 mmol), TEA (0.66). ml, 4.75 mmol), and a catalytic amount of DMAP (0.029 g, 0.237 mmol). The reaction mass was stirred for 24 h and poured into water (70 mL). The mixture is extracted with EtOAc (3 ^x 75 mL), and the combined organic extracts are washed with IN aq. HCl (20 mL), water (2 x 100 mL), app. aq. NaCl (100 mL) and dried over (Na 2 SO 4). The solvents are evaporated and the residue (0.988 g) is purified by Biotage purification system (C18HS 40 + M column, eluent: water-methanol, gradient 1: 1 to 0: 100). 0.660 g (61.8%) of ((S) -tert-butyl (1- (3-bromophenylsulfonamido) -4-methyl-1-oxopentan-2-yl) carbamate (3.1) are obtained as a foam. Ή NMR (CDCl ₃ ) δ: 9.57 (bs, 1H), 8.16 (t, J = 1.8z, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.75 (ddd, Δ = 7.9; 1.8; 1.0 Hz, 1H); 7.40 (t, δ = 7.9 Hz, 1H); 4.70 (unresolved d, δ = 6.4 Hz, 1H) , 4.06-3.92 (m, 1H), 1.70-1.52 (m, 3H), 1.44 (s, 9H), 0.91 (d, J = 6.3 Hz, 3H) ), 0.87 (d, J = 6.3 Hz, 3H) LCMS (ESI) m / z: 449.2 [MH] +.

By the method analogous to method В, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 3.1 В 2.1 ΥΥΎΥΥ NHBoc ' 3.6 В 2.1 NHBoc

Synthesis of Intermediates 4, General Method C

Demonstrated on the synthesis example of compound 4.1:

(S) -tert-butyl (4-methyl-1-oxo-1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylsulfonamide) pentane-2- (il) carbamate (4.1)

3.1 4.1 4.1a

Through ((S) -tert-butyl (1- (3-bromophenylsulfonamido) -4-methyl-1-oxopentan-2-yl) carbamate (3.1), (1.000 g, 2.23 mmol), KOAc (0.874 g, 8 , 9 mmol) and PdCl 2 (dppf) 2 (0.18 g, 0.22 mmol) in dioxane (40 mL) is bubbled with argon for 10 min Add 0z5 (pinacolate) diborane (0.85 g, 3.35) to the reaction mixture The reaction vessel is sealed and heated at 110 ° C for 17 h The mixture is cooled to room temperature and filtered through celite, the filtrate is evaporated and the dark oily residue (3.0 g) is purified by chromatography on a silica gel column (eluent: petroleum ether-ethyl acetate, gradient). from 4: 1 to 1: 1), yields 1.281 g of (S) -Z-butyl 4-methyl-oxo-1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane). 2-yl) phenylsulfonamido) pentan-2-yl) carbamate (4.1) and (S) - (3- (V- (2 - ((tert-butoxycarbonyl) amino) -4-methylpentanoyl) sulfamoyl) phenyl) boronic acid (4.1a) ) as a glass material The resulting mixture is used in the next step without further purification LCMS (ESI) m / z: 495.28 [MH] '(4.1, retention time 3.939 min) and 413.22 [M-H] '(4.1a, retention time 2.750).

By a method analogous to Method C, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 4.1 C 3.1 O O 0 NHBoc * 4.6 C 3.6 NHBoc

Synthesis of Intermediates 5, General Method D

Demonstrated on Example 5.1 Synthesis of Connection:

3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzosulfonamide (5.1)

Argon is bubbled through dioxane (20 mL) through a mixture of 3-bromobenzosulfonamide (2.1) (0.620 g, 2.63 mmol), KO Ac (1.032 g, 10.52 mmol), and PdCl 2 (0.100 g, 0.137 mmol). 10 min add & N (pinacolate) diborane (1,000 g, 3.94 mmol) to the reaction mixture, seal the reaction vessel, and heat the reaction mixture at 110 ° C for 24 h. Cool the mixture to room temperature and filter through celite. Concentrate the filtrate and purify the residue by chromatography on a silica gel column (petroleum ether - ethyl acetate gradient 4: 1 to 1: 1). 0.663 g (89%) of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzosulfonamide (5.1) is obtained as a colorless solid. 1 H NMR (DMSO-d 6, HMDSO) δ: 8.14 (ddd, ^J = 2.0; 1.1; 0.5 Hz, 1H), 7.93 (ddd, ^J = 7.9, 2, 0; 1.3 Hz, 1H), 7.85 (td, 7 = 1.2, 7.4 Hz, 1H), 7.59 (ddd, 7 = 7.9, 7.4, 0.5 Hz) , 1H), 1.32 (s, 12H), LCMS (ESI) m / z: 284.0 [M + H] ⁺ .

By a method analogous to Method D, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 5.1 D 2.1 >_<Ό ^NHz

Synthesis of Intermediates 6, General Method E

Demonstrated on Example 6.1 Synthesis of Connection:

(3- (2-Amino-6-methylpyrimidin-4-yl) benzosulfonamide (6.1)

To a solution of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzosulfonamide (5.1) (0.030 g, 0.106 mmol) in dioxane (3 mL) is added sequentially 2-amino-4 -chloro-6-methylpyrimidine (0.015 g, 0.105 mmol), Log (0.034 g, 0.321 mmol) and water (0.15 mL). Argon is bubbled through the resulting mixture for 10 min, then PdCl 2 (0.004 g, 0.005 mmol) is added. The reaction vessel is sealed and the mixture is heated at 100 ° C for 16 h. Cool the mixture to room temperature and filter through celite. The filtrate is concentrated and the residue is purified by chromatography on a silica gel column (eluent: chloroform-methanol gradient 100: 5 to 90:10). 0.014 g (50%) of 3- (2-amino-6-methylpyrimidin-4-yl) benzosulfonamide (6.1) is obtained.

1 H NMR (DMSO-d ₆ , HMDSO) δ: 8.54 (t, J = 1.6 Hz, 1H), 8.23 (ddd, J = 7.8, 1.5, 1.1 Hz , 1H),

7.92 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.42 (s, 2H) , 7.09 (s, 1H), 6.67 (s, 2H), 2.32 (s, 3H), LCMS (ESI) m / z: 265.1 [M + H] ⁺ .

By a method analogous to Method E, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 6.1 E 5.1 TTX 'nh ₂

Synthesis of Intermediates 7:

(a) General method

Demonstrated on Example 7.1 of Synthesis of Connection:

(S) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.1)

4.1а

(S) -tert-Butyl (4-methyl-1-oxo-1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylsulfamide) pentane-2 from the preceding step -yl) carbamate and (S) - (3- (2V- (2 - ((tert-butoxycarbonyl) amino) -4-methylpentanoyl) sulfamoyl) phenyl) boronic acid (4.1a) (0.600 g) are dissolved in dioxane ( 34 ml). To the mixture was added 2-amino-4-chloro-6-methylpyrimidine (0.174 g, 1.21 mmol), Hagozoic (0.385 g, 3.63 mmol), and water (1.7 mL). The resulting mixture is bubbled with argon for 10 min and PdCl 2 (dppf) 2 (0.045 g, 0.061 mmol) is added. Stopper the reaction vessel and heat the contents at 110 ° C for 18 h. Cool the mixture to room temperature and filter through celite. The filtrate is concentrated and the residue (0.76 g) is purified by chromatography on a silica gel column (eluent: chloroform-methanol gradient 100: 1 to 100: 2). 0.246 g (49.4%, calculated from 3.1) of (5) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentane are obtained. 2-yl) carbamate (7.1).

Δ NMR (DMSO-d6) δ: 12.33 (bs, 1H), 8.58 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.97 (d, J3). Δ = 7.9 Hz, 1H), 7.71 (t, δ = 7.9 Hz, 1H), 7.08 (s, 1H), 7.01 (bs, 1H), 6.70 (s, 2H), 4.00-3.90 (m, 1H), 2.32 (s, 3H), 1.63-1.19 (m, 3H), 1.28 (s, 9H), 0.80 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: 478.36 [M + H] ⁺ .

By a method analogous to Method F, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 7.1 F 4.1 N Al. .о о she JL v I / LA ЙНВос ' 7.2 F 4.2 Л nA о, .0 о Il JVI / H ₂ nAAV LA NHBoc ' 7.3 F 4.3 she JL V A / ΑνΎΥΥΥΥ LA NHBoc '

7.4 F 4.4 N == \ / NH N ^ V 0 .0 0 jh \ V Λ / hAnAA / ^ H ^ Af NHBoc 1 7.5 F 4.5 N A 0. .0 0 π J V A NHBoc ' 7.6 F 4.6 N A 0 .0 0 I АрЛА ЙНВос 7.7 F 4.7 N A 0. .0 0 she J V A /. / Y-J Jinov 7.8 F 4.8 N ^ A Cl · .0 0 ii J V A / ^^ YAi NHBoc ' 7.9 F 4.9 A V1 / Η, Ν ^ Αργ ^ 'VY NHBoc' 7.10 F 4.10 <λ .0 0 V A / hAnAA / qY ^ Yl ЙНВос ' 7.11 F 4.11 nh ₂ nA 0. .0 о ji J v A / ΙχΥ NHBoc ' 7.12 F 4.12 nh ₂ nA Cl · о о ьА VA / iTy hA ^ a ЙНВос ' 7.13 F 4.13 N ^ Y 0. .0 о ji zA VA / h ₂ n ^A nAv ^S + AA NHBoc ' 7.14 F 4.14 n ^ + n 0. .0 0 she л Y A / NHBoc 1

7.15 F 4.15 νΆ, O. .0 0 11 1 V А / х. / • χ ^ NHBoJ 7.17 F 4.17 0 О .0 О il J _л V А Ιχ ^ NHBoc ' 7.18 F 4.18 α. О. .0 О 11 Д V А ^ Х / * Х ^ ДНВос '

(b) General method

Demonstrated on Example 7.1 of Synthesis of Connection:

(S) - tert -Butyl (1- (3- (2-amino-6-methylpmmidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.1)

To a solution of BOC-Z-leucine monohydrate (0.085 g, 0.34 mmol) in DMF (3.5 mL) at room temperature is added sequentially 3- (2-amino-6-methylpyrimidin-4-yl) benzosulfonamide (6.1) (0.090 g) , 0.34 mmol), HBTU (0.129 g, 0.34 mmol), TEA (0.10 mL, 0.72 mmol) and catalytic DMAP (0.004 g, 0.033 mmol). The reaction mass is stirred at room temperature for 72 h and evaporated in vacuo. The residue (0.378 g) was purified by chromatography on a silica gel column (eluent chloroform-methanol gradient 100: 2 to 90:10). 0.100 g (61%) of (S) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamide) -4-methyl-1-oxopentan-2-yl) carbamate (7.1) are obtained. ). 1 H NMR (DMSO-d 6) δ: 12.33 (bs, 1H), 8.58 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.97 (d, Δ = 7.9 Hz, 1H), 7.71 (t, δ = 7.9 Hz, 1H), 7.08 (s, 1H), 7.01 (bs, 1H), 6.70 (s, 2H), 4.00-3.90 (m, 1H), 2.32 (s, 3H), 1.63-1.19 (m, 3H), 1.28 (s, 9H), 0.80 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: 478.36 [M + H] ⁺ . NMR (CDCl ₃ ) δ: 9.57 (bs, 1H), 8.16 (t, J = 1.8z, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.75 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 4.70 (unresolved d, J = 6.4 Hz) , 1H), 4.06-3.92 (m, 1H), 1.70-1.52 (m, 3H), 1.44 (s, 9H), 0.91 (d, J = 6.3) Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H). LCMS (ESI) m / z: 449.2 [MH] +.

By a method analogous to Method F, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 7.1 G 6.1 o ₄ .0 0 11 JV Ā ĀHBocJ

c) Synthesis of intermediate (NHert-butyl (1- (3- (2-hydroxypyrimidin-4-yl) phenylsulfamido) -4-methyl-oxopentan-2-yl) carbamate (7.16))

7.15 7.16 (S) -tert-butyl (1- (3- (2-chloropyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.15) (0.189 g, 0, To a solution of 39 mmol) in THF (2 mL) was added 1 N aq. NaOH (22 mL) and the resulting emulsion was stirred at 55 ° C for 1.5 h. The mixture is cooled to 0 ° C and acidified to pH 3-4 by the addition of cold 2 N aq. HCl (11 mL). The precipitate is filtered off, the filtrate is extracted with (3 * 25 ml) and the extract is dried (N2SO4). The solvents are evaporated and the residue is combined with the precipitate and purified by chromatography on a silica gel column (eluent: chloroform-methanol, 10: 3). 0.110 g (60.5%) of (S) -tert-butyl (1- (3- (2-hydroxypyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.16) is obtained as a foam. .

Ή NMR (DMSO-d6, HMDSO) δ: 12.38 (bs, 1H), 12.05 (s, 1H), 8.63 and 8.58 (s and s, 1H total), 8.40-8 , 28 (m, 1H), 8.10 (d, J = 6.3 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 1, 1 Hz, 1H), 7.01 (d, 7 = 6.3 Hz, 1H), 6.85 and 6.53 (bs and bs, 1H total), 3.94-3.85 and 3.84- 3.73 (m and m, 1H total), 1.66-1.18 (m, 3H), 1.28 (s, 9H), 0.80 (d, J = 6.2 Hz, 3H), 0.78 (d, J = 6.2 Hz, 3H). LCMS (ESI) m / z: 465.4 [M + H] ⁺ .

Synthesis of Products 8, Comprehensive Method

Demonstrated on Example 8.1 of Synthesis of the Coupling:

(S) -2-Amino-N - ((3- (2-amino-6-methylpyrimidin-4-yl) phenyl) sulfonyl) -4-methylpentanamide (8.1)

TFA

NHBoc

7.1

8.1 (S) -tertbutyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.1) (0.246 g, 0.515 mmol) is dissolved in dichloromethane containing 5% TFE (12 mL) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture is concentrated in vacuo and the oily brown residue (0.396 g) is purified using a Biotage purification system (CisHS 40 + M column, eluent: water-acetonitrile, 95: 5 to 60:40 gradient). 0.162 g (83%) of (S) -2-amino-N - ((3- (2-amino-6-methylpyrimidin-4-yl) phenyl) sulfonyl) -4-methylpentanamide (8.1) is obtained as a colorless crystalline solid, m.p. mp 241-242 ° C (sat). (DMSO-d _6, HMDS) δ: 8.50 (t, 7 = 1.7 Hz, 1H), 8.05 (ddd, 7 = 7.8, 1.7, 1.2 Hz, 1H) 7.88 (ddd, 7 = 7.8; 1.7; 1.2 Hz, 1H); 7.67 (bs, 3H); 7.50 (t, 7 = 7.8 Hz, 1H), 7 , 01 (s, 1H), 6.63 (s, 2H), 3.37-3.30 (m, 1H, overlapping with water), 2.31 (s, 3H), 1.73-1.60 (m, 1H), 1.58 (ddd, J = 13.7, 8.4, 5.6 Hz, 1H), 1.38 (ddd, J = 13.7, 8.3, 5.8 Hz) , 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.3 Hz, 3H). LCMS (ESI) m / z:

378.2 [M + H] ⁺ . Elemental Analysis: Calculated: C17H23N5O3S x 0.09 CF3COOH (2.5%) x 1.12 H2O (4.9%): C, 50.59; H, 6.26; N, 17.17. Found: C, 50.59; H, 6.32; N, 17.23.

By a method analogous to Method H, the following compounds were obtained:

Connection No. Procedure Precursor Substrate 8.1 H 7.1 O. .0 0 II JV Ā / ΑνΑΑ ЧА ЙН ₂ 1 8.2 H 7.2 nA О. / ° и ii J v А / нААУууУ ЧА nh ₂ · 8.3 H 7.3 N ^ 4 О .0 о IJV А / кА nh ₂ 1 8.4 H 7.4 Ν = ξ / ΝΗ О. , О О 1 zl _л V А / нААрг 'ίττγ чА ΝΗ ₂ ¹ 8.5 H 7.5 nA 0. .о о | v V / /А йи ₂ I 8.6 H 7.6 О .0 о. ДаА КА нн ₂

8.7 Η 7.7 nAj, 0. .0 θ JI 1 / ч VA XX / χ <Α Jin ₂ ¹ 8.8 Η 7.8 0. .0 0 π J _ V Α / «А нн ₂ 1 8.9 Η 7.9 N ^ 4 0, .0 0 IjJ V А Αχ <ζ \ AA / AiA ^ \ χ ^ζ ^ Ανχ ^ζ ^ Η2Ν ^^ γ · γ N γγ ΥΥ νη ₂ ¹ 8.10 Η 7.10 ΥΑ ° Λ 1 νη ₂ ¹ 8.11 Η 7.11 νη ₂ nA 0. .0 θ 11 1 _Λ V 1 _ ΝΗ ₂ ¹ 8.12 Η 7.12 νη ₂ nA ° ч / ° и η JL ν Д / * χ ^ νη ₂ I 8.13 Η 7.13 νΑχ Cl · .0 θ 11 1 V А / X / η ₂ ν ^λ Α ^ /; ^ν ΛΑ йн ₂ ¹ 8.14 Η 7.14 Ν ^ Ν 0., 0 θ Ji л V Α / χ / hAVAyY ΝΗ ₂ I 8.15 Η 7.15 I 1 Н ^Ξ 1 νη ₂ ¹ 8.16 Η 7.16 Ν ^ Α 0, .Ο Ο л / А VA / s. / ноААаААА ЧА νη ₂ 1 8.17 Η 7.17 А nA _ο о 0 ιι Α V / h ₂ n ^A nAV ^ч йА <ЧА ЙН ₂ 1

All compounds are characterized by: a) 1 H-NMR and in some cases ¹³ C-NMR spectral data. NMR performed on a Varian Mercury spectrometer (400 MHz) with chemical shifts (δ) given in ppm (parts per million) against internal standard; (b) LC / MS analyzes using a Water Acquity UPLC tandem LC / MS spectrometer with a SQ mass-selective detector; (c) elemental analyzes; (d) in individual cases with melting points.

Physico-chemical characterization of compounds 8

Connection №. physico-chemical profile 8.1 mp 241-242 ° C (sat). ^! 1 H NMR (DMSO-cL, HMDSO) δ: 8.50 (t,> 1.7 Hz, 1H), 8.05 (ddd,>7.8;1.7; 1.2 Hz, 1H), δ , 88 (ddd,>7.8;1.7; 1.2 Hz, 1H); 7.67 (bs, 3H); 7.50 (t, > 7.8 Hz, 1H); 7.01 ( s, 1H), 6.63 (s, 2H), 3.37-3.30 (m, 1H, overlapping with water), 2.31 (s, 3H), 1.73-1.60 (m, 1H), 1.58 (ddd, &gt;13.7;8.4; 5.6 Hz, 1H), 1.38 (ddd, &gt;13.7;8.3; 5.8 Hz, 1H), 0 , 83 (d, > 6.3 Hz, 3H), 0.81 (d, > 6.3 Hz, 3H). LCMS (ESI) m / z: 378.2 [M + H] ⁺ . Elemental Analysis: Calculated for C 17 H 23 N 5 O 3 S x 0.09 CF 3 COOH (2.5%) χ 1.12 H2O (4.9%): C, 50.59; H, 6.26; N, 17.17. Found: C, 50.59; H, 6.32; N17.23. 8.2 mp 87-88 ° C (sat). Ή NMR (DMSO-d ₆₎ δ: 8.60 (1H, br s), 8.40 to 7.90 (5H, br m), 7.73 (1H, unresolved t,> 7.5 Hz) 7.506.75 (2H, m), 6.66 (1H, br s), 3.89 (3H, br s), 3.78 (1H, br s), 1.68-1.40 (3H, m) ), 0.93-0.71 (6H, br s). ¹³ C NMR (DMSO-d 6) δ: 171.4; 169.7; 163.0; 158.5; 158.2; 140.3; 137.2; 131.6; 129.6; 129.3; 125.9; 92.7; 53.5; 51.7; 23.4; 22.6; 21.3. LCMS (ESI) m / z: 394.2 [M + H] ⁺ . Elemental Analysis: Calculated for C 17 H ₂₃ N ₅ O ₄ S 2.6 CF 3 COOH (42.7%) 0.25 H ₂ O (0.6%): C 38.40; H, 3.79; N, 10.09. Found: C, 38.42; H, 4.16; N, 9.70.

8.3 mp 224-226 ° C (sat). Ή NMR (DMSO-d _6, HMDS) δ: 0.81 (3H, d,> 6.5 Hz), 0.83 (3H, d,> 6.5 Hz), 1.38 (1H, ddd, >5.8;8.3; 13.7 Hz), 1.58 (1H, ddd,> 5.6, 8.3, 13.7 Hz), 1.67 (1H, m), 3.32 (1H , dd,>5.6; 8.3 Hz, water overlap), 6.75 (2H, s), 7.09 (1H, d, > 5.2 Hz), 7.52 (1H, t, > 7.8 Hz), 7.67 (3H, bs), 7.89 (1H, ddd,> 0.9, 1.6, 7.8 Hz), 8.06 (1H, ddd,> 0, 9; 1.6; 7.8 Hz), 8.33 (1H, d, > 5.2 Hz), 8.53 (1H, t, > 1.6 Hz). ¹³ C NMR (DMSOd 6) δ: 21.8; 22.7; 23.7; 40.5; 53.4; 105.8; 125.3; 125.4; 128.3; 128.9; 136.6; 146.0; 159.3; 163.0; 163.9; 172.7. LCMS (ESI) m / z: 364.1 [M + H] ⁺ . Elemental Analysis: Calculated for C16H21N5O3S x 0.05 CF3COOH (1.5%) x 0.85 H2O (4.0%): C, 50.30; H, 5.96; N, 18.22. Found: C, 50.31; H, 5.98; N, 18.17. 8.4 mp 117 ° C (sat). Ή NMR (DMSO-d ₆₎ δ: 9.32 (1H, s), 9.03 (1H, d,> 7.6 Hz), 8.25 (1H, s), 8.16 (3H, bs ), 8.10 (1H, d, > 7.6 Hz), 7.83 (1H, t, > 7.6 Hz), 6.8-3.4 (broad water signal), 3.82 (1H, bs), 1.64-1.42 (3H, m), 0.84-0.76 (6H, bm). ¹³ C NMR (DMSO-d ₆ ) δ: 169.4; 160.0; 156.0; 150.5; 142.0; 139.5; 136.7; 134.0; 129.5; 129.4; 128.1; 123.6; 51.6; 23.4; 22.6; 21.3. LCMS (ESI) m / z: 404.2 [M + H] ⁺ . Elemental Analysis: Calculated for C17H21N7O3S x 2.65 CF3COOH (42.6%) x 0.2 H2O (0.5%): C, 37.77; H, 3.42; N, 13.82; S, 4.52. Found: C, 37.87; H, 3.46; N, 13.76; S, 4.00. 8.5 mp 246 ° C. 1 H NMR (DMSO-d 6, HMDSO) δ: 9.11 (d,> 1.1 Hz, 1H), 8.61 (t,> 1.6 Hz, 1H), 8.21 (ddd,> 7) , Δ; 1.6; 1.1 Hz, 1H); 7.98 (s, 1H); 7.94 (ddd,>7.8;1.5; 1.1 Hz, 1H); 7.67 (bs, 3H), 7.58 (t, > 7.8 Hz, 1H), 3.36-3.34 (m, 1H, overlap with water), 2.55 (s, 3H), 1.67 (nonet, > 6.6 Hz, 1H), 1.59 (ddd, &gt;13.7;8.1; 5.7 Hz, 1H), 1.38 (ddd, &gt;13.7;8.1; 5.9 Hz, 1H), 0.83 (d, > 6.6 Hz, 3H), 0.81 (d, > 6.6 Hz, 3H). ¹³ C NMR (DMSO-d ₆ ) δ: 173.2; 168.4; 162.1; 158.8; 146.8; 136.1; 129.8; 128.9; 128.9; 126.0; 116.8; 53.8; 41.0; 24.2; 24.1; 23.1; 22.2. LCMS (ESI) m / z: 363.1 [M + H] ⁺ . Elemental Analysis: Calculated for C17H22N4O3S χ0.3 H2O (1.5%): С 55.51; N, 6.19; N, 15.23. Found: С 55.51; N, 6.25; N, 15.19. 8.6 incl. 97 ° C. 1 H NMR (DMSO-d6, HMDSO) δ: 8.67 (t,> 1.7 Hz, 1H), 8.32 (d,> 7.8 Hz, 1H), 8.04 (ddd,> 7.8, 1.7, 1.0 Hz, 1H),

7.95 (bs, 3H), 7.73 (t, 7 = 7.8 Hz, 1H), 7.24 (s, 1H), 7.20 (bs, 3H), 3.76-3.68 (m, 1H), 2.38 (s, 3H), 1.86-1.75 (m, 1H), 1.25-1.14 (m, 1H), 1.09-0.96 (m , 1H), 0.79 (d, J = 7.0 Hz, 3H), 0.73 (t, J = 7.4 Hz, 3H). LCMS (ESI) m / z: 378.2 [M + H] ⁺ . Elemental: calculated C17H23N5O3S χ 2.56 CF ₃ COOH (43.1%) χ 0.4 H ₂ O (1.1%) С 39,27; Η 3.93; N, 10.35. Found: С 39,28; Η 3.91; N, 10.44. 8.7 mp 186-188 ° C (dec). 1 H NMR (DMSO-d ₆ , HMDSO) δ: 8.76 (s, 1H), 8.54-8.48 (m, 1H), 8.25-8.19 (m, 2H), δ 08-7.94 (m, 4H), 7.79-7.72 (m, 2H), 7.57-7.52 (m, 3H), 6.91 (bs, 2H), 3.76-. 3.65 (m, 1H, overlapping with water), 1.65-1.42 (m, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.2 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 169.6; 165.3; 163.9; 163.1; 158.5; 158.1; 138.1; 136.9; 132.1; 130.8; 129.6; 129.4; 128.7; 127.0; 126.0; 102.1; 51.6; 23.4; 22.6; 21.3. LCMS (ESI) m / z: 440.3 [M + H] ⁺ . Elemental Analysis: Calculated for C22H25N5O3S x 2.1 CF3COOH (34.3%) χ 1.05 Н2О (2.7%): С 45.09; Η 4.22; N, 10.03. Found: С 45.05; Η 4.26; N, 9.83. 8.8 mp 151 ° C (dec). 1 H NMR (DMSO-d ₆ , HMDSO) δ: 9.01 (bs, 2H), 8.49 (bs, 3H), 8.44 (s, 1H), 8.39 (bs, 2H), δ 33 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.4 Hz, 1H), -9.4 -7.2 (bs, 1H), 3.93 (bs, 1H), 1.68-1.51 (m, 3H), 0.83 (d, J = 5.7 Hz, 3H), 0, 82 (d, J = 6.0 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 169.9; 153.2; 143.7; 140.9; 136.2; 133.6; 131.1; 130.3; 127.2; 124.7; 51.8; 23.9; 22.9; 22.2. LCMS (ESI) m / z: 348.2 [M + H] ⁺ . Elemental Analysis: Calculated for C17H21N3O3S χ 2 HCl (15.9%) χ 2.1 H2O (8.3%): С 44.56; 5 5.98; N, 9.17. Found: С 44,54; N, 5.57; N, 9.06. 8.9 mp 141 ° C (dec). Ή NMR (DMSO-d6, HMDSO) δ: 13.86 (bs, 1H), 8.36-8.02 (m, 9H), 7.80 (t, J = 7.3 Hz, 1H), δ , 36-7.31 (m, 1H), 7.22 (dd, J = 6.7, 1.6 Hz, 1H), 8.36-7.10 (bs, 1H), 3.74 (m , overlap with water, 1H), 1.67-1.43 (m, 3H), 0.82 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H). ¹³ C NMR (DMSO-d ₆ ) δ: 170.0; 154.4; 152.2; 141.1; 136.7; 136.1; 131.9; 130.4; 129.4; 125.9; 110.4; 110.2; 51.7; 23.4; 22.5; 21.7. LCMS (ESI) m / z: 363.2 [M + H] ⁺ . Elemental analysis: Calculated for C17H22N4O3S χ 3 HCl (22.0

%) χ 1.45 H ₂ O (5.2%): С 41.01; Η 5.65; N, 11.25. Found: С 41.01; Η 5.62; N11.20. 8.10 mp 148 ° C (dec). 1 H NMR (DMSO-d ₆ , HMDSO) δ: 8.42 (t, J = 1.7 Hz, 1H), 7.96 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.77 (ddd, 7.7; 1.7; 1.1 Hz, 1H), 7.65 (bs, 3H), 7.47 (dd, 7 = 8.1; 7.5 Hz) , 1H), 7.43 (t, 7 = 7.7 Hz, 1H), 7.01 (dd, 7 = 7.5; 0.7 Hz, 1H), 6.43 (dd, 7 = 8, 1; 0.7 Hz, 1H), 6.05 (bs, 2H), 3.35-3.29 (m, water, 1H), 1.75-1.61 (m, 1H), 1 , 59 (ddd, J = 13.8, 8.4, 5.4 Hz, 1H), 1.38 (ddd, J = 13.8, 8.5, 5.8 Hz, 1H), 0.83 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H). ¹³ C NMR (DMSO-d ₆ ) δ: 172.6; 159.6; 153.7; 146.7; 138.9; 138.0; 127.7; 127.7; 126.8; 125.0; 108.3; 107.3; 53.4; 40.6; 23.7; 22.7; 21.8. LCMS (ESI) m / z: 363.2 [M + H] ⁺ . Elemental Analysis: Calculated for C 17 H 22 N 4 O 3 S χ 0.36 HCl (3.5%): C, 54.37; Η 6.00; N, 14.92. Found: С 54,39; Η 6.10; N, 14.82. 8.11 mp 234 ° C (dec). Ή NMR (DMSO-d _6, HMDS) δ: 13.11 (bs, 1H), 8.51 (bs, 1H), 8.31 (bs, 3H), 8.28 (s, 1H), 8, 22 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 8.70- 7.50 (bs, 4H), 6.53 (s, 1H), 3.87 (bs, 1H), 1.69-1.49 (m, 3H), 0.85 (d, 7 = 6, 0 Hz, 3H), 0.84 (d, J = 6.1 Hz, 3H). LCMS (ESI) m / z: 379.2 [M + H] ⁺ . Elemental analysis: calculated for C16H22N6O3S χ 3 HCl (20.4%) χ 2.7 Н ₂ О (9.1%): С 35.82; Η 5.71; N, 15.67. Found: С 35.78; Η 5.62; N, 15.22. 8.12 Ή NMR (DMSO-d _6, HMDS) δ: 8.71 (unresolved d, 7 = 0.7 Hz, 1H), 8.63 (bs, 2H), 8.44 (t, 7 = 1.8 Hz , 1H), 8.29 (bs, 3H), 8.23 (ddd, J = 8.0; 1.8; 1.0 Hz, 1H), 8.15 (ddd, J = 8.0; 1 , Δ; 1.0 Hz, 1H), 7.85 (t, 7 = 8.0 Hz, 1H), 7.14 (d, 7 = 0.7 Hz, 1H), -9.5-7, 0 (bs, 1H), 3.84 (bs, 1H, overlapping with water), 1.68-1.47 (m, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0 , 83 (d, J = 6.3 Hz, 3H). LCMS (ESI) m / z: 364.2 [M + H] ⁺ . Elemental Analysis: Calculated for C 16 H ₂₁ N ₅ O 3 S • 3 HCl (22.0%) · 1.3 H ₂ O (4.7%): C, 38.73; H, 5.40; N, 14.11. Found: C, 39.07; H, 5.28; N, 13.64. 8.13 Ή NMR (DMSO-d6, HMDSO) δ: 8.50 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.67 (b s, 3H), 7.50 (t, J = 7.7 Hz, 1H), 7.00 (s, 1H), -9.0-6.9 (b s, 1H), 6.64 (s, 2H), 3.45-3.25 (m,

1N, overlapped with water), 2.59 (q, 7 = 7.6 Hz, 2H), 1.77-1.52 (m, 2H), 1.44-1.33 (m, 1H), 1 , 22 (t, J = 7.6 Hz, 3H), 0.85-0.79 (m, 6H). ¹³ C NMR (DMSO-d 6) δ: 173.2; 172.7; 163.8; 163.1; 146.0; 136.9; 128.7; 128.3; 128.0; 125.3; 104.0; 53.4; 40.5; 30.3; 23.7; 22.7; 21.8; 12.8. LCMS (ESI) m / z: 392.2 [M + H] ⁺ . 8.14 Ή NMR (DMSO-d _6, HMDS) δ: 8.91 (t, 7 = 1.8 Hz, 1H), 8.66 (s, 1H), 8.62 (ddd, 7 = 7.9, 1 , 6; 1.1 Hz, 1H), 8.39 (unresolved d, 7-5.9 Hz, 3H), 8.16 (ddd, 7 = 7.9, 2.0, 1.1 Hz, 1H) ), 7.93 (bs, 1H), 7.88 (bs, 1H), 7.82 (t, J = 7.9 Hz, 1H), -9.5-7.0 (bs, 1H), 3.91 (m, 1H, overlap with water), 1.63-1.49 (m, 3H), 0.81 (d, J = 6.1 Hz, 3H), 0.81 (d, J = 6.1 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 169.1; 168.1; 166.5; 166.4; 139.3; 136.6; 133.0; 131.1; 129.9; 127.3; 51.3; 23.4; 22.5; 21.7. LCMS (ESI) m / z: 365.2 [M + H] ⁺ . Elemental: calculated C15H20N6O3S * 3 HC1 (20.6%) χ 0,3 Et2O (4.2%) χ 0.4 C ₄ H ₈ O ₂ (6.6%) С 40.24; Η 5.54; N, 15.82. Found: С 40.64; Η 5.63; N, 15.99. 8.15 mp 231-238 ° C (dec). Ή NMR (DMSO-d _6, HMDS) δ: 8.93 (d, 7 = 5.2 Hz, 1H), 8,73 (t, 7 = 1.8 Hz, 1H), 8.52 (ddd, Δ = 7.9; 1.7; 1.0 Hz, 1H); 8.34 (bs, 3H); 8.27 (d, δ = 5.2 Hz, 1H); 8.17 (ddd, 7 = 7.9; 1.9; 1.0 Hz, 1H), 7.86 (t, 7 = 7.9 Hz, 1H), 3.91-3.80 (m, 1H), 1.651.47 ( m, 3H), 0.83 (d, J = 6.1 Hz, 6H). ¹³ C NMR (DMSO-d 6) δ: 169.5; 164.3; 161.9; 160.6; 140.4; 135.4; 132.5; 130.8; 130.3; 126.2; 116.6; 66.3; 51.5; 23.4; 22.5; 21.6. LCMS (ESI) m / z: 383.2 [M + H] ⁺ . Elemental analysis: calculated for C16H19CIN4O3S ^χ HC1 (8.6%) χ 0.3 H2O (1.3%): С 45.25; Η 4.89; N, 13.19. Found: С 45.48; Η 4.72; N12.73. 8.16 mp 191-221 ° C (dec). 1 H NMR (DMSO-d 6, HMDSO) δ: 8.65 (unresolved t, 7 = 1.7 Hz, 1H), 8.49-8.38 (m, 4H), 8.21 (d, 7 = 6.3 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 6, 3 Hz, 1H), -8.8-7.0 (bs, 1H), 3.95-3.86 (m, 1H), 1.66-1.50 (m, 3H), 0.81 ( d, J = 5.9 Hz, 1H), 0.81 (d, J = 5.9 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 169.2; 168.6; 155.7; 149.7; 139.5; 136.3; 133.1; 130.7; 130.1; 126.7; 100.7; 51.3; 23.4; 22.5; 21.7. LCMS (ESI) m / z: 365.2 [M + H] ⁺ . Elemental analysis: calculated for C 16 H 20 N 4 O 4 S 2

HCl (15.2%) X 1.5 H ₂ O (5.6%) x 0.2 Et ₂ O (3.1%): C 42.11; H, 5.68; N, 11.69. Found: C, 41.93; H, 5.21; N, 11.23. 8.17 1 H NMR (DMSO-d 6) δ: 8.48 (t, J = 1.7 Hz, 1H), 8.00 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.85 (ddd, 7 = 7.8; 1.6; 1.0 Hz, 1H); 7.60 (bs, 3H); 7.46 (t, 7 = 7.8 Hz, 1H); , 66 (bs, 2H), 6.45 (s, 1H), 5.31 (septet, J = 6.2 Hz, 1H), 3.40-3.27 (m, 1H, water overlap), 1.74-1.61 (m, 1H), 1.58 (ddd, J = 13.7, 8.3, 5.5 Hz, 1H), 1.38 (ddd, J = 13.7, 8). , 3; 5.9 Hz, 1H), 1.29 (d, J = 6.2 Hz, 6H), 0.83 (d, J = 6.5 Hz, 3H), 0.82 (d, 7 = 6.5 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 172.9; 170.2; 164.2; 163.6; 145.8; 136.8; 128.5; 128.1; 127.9; 125.3; 92.4; 67.6; 53.4; 40.7; 23.7; 22.7; 21.9; 21.8. LCMS (ESI) m / z: 422.2 [M + H] ⁺ . Elemental Analysis: Calculated for C 19 H 21 N 5 O 4 S x 0.4 HCl (3.3%): C, 52.33; H, 6.33; N, 16.06. Found: C, 52.56; H, 6.41; N, 15.99. 8.18 1 H NMR (DMSO-d 6, HMDSO) δ: 8.63 (t, ^J = 1.6 Hz, 1H), 8.36 (ddd, ^J = 8.1, 1.6, 1.0 Hz, 1H ), 8.32 (bs, 3H), 8.10 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H) , 7.46 (distorted t, 7 = 7.8 Hz, 2H), 7.27 (distorted t, 7 = 7.4 Hz, 1H), (distorted d, J = 1.6 Hz, 2H), 6 , 89 (s, 1H), 3.94-3.82 (m, 1H, overlapping with water), 3.83.2 (2H, overlapping with water), 1.67-1.47 (m, 3H) , 0.83 (d, J = 5.7 Hz, 3H), 0.83 (d, J = 5.7 Hz, 3H). ¹³ C NMR (DMSO-d 6) δ: 171.4; 169.3; 161.6; 161.0; 152.2; 139.7; 135.4; 132.4; 130.1; 130.1; 129.9; 126.2; 125.7; 121.7; 94.2; 66.4; 51.4; 23.4; 22.6; 21.6. LCMS (ESI) m / z: 456.3 [M + H] ⁺ . Elemental Analysis: Calculated for C ₂₂ H ₂₅ N ₅ O ₄ S x 2 HCl (12.9%) x 2 H ₂ O (6.4%): C, 46.81; H, 5.54; N, 12.41. Found: C, 46.89; H, 5.36; N, 12.01.

In vitro test

The compounds were tested for their antibacterial activity in vitro as their ability to inhibit aminoacyl - / - RNA synthetase (aaRS) according to the following procedure.

Used aaRSs

Leicyl-, valyl- and isoleicyl-i-RNA synthetases (LRS, VRS and IRS, respectively) from Escherichia coli (Eco) and Staphylococcus aureus (Sau).

Protein expression and purification

Escherichia coli M1 5 cells transformed with plasmid pQE-60 or pQE-70 containing the selected aaRS open-reading frame sequence are induced with 1 mM IPTG (isopropyl / 7-D-l-thiogalactopyranoside) for 3 h at 37 ° C. . Bacterial cells are harvested and lysed with a cocktail of 20 mM NaEhPCk (pH 8.0), 200 mM NaCl, 10 mM imidazole and protease inhibitor (Roche). Pathogenic aaRS is purified by standard nickel affinity chromatography. Protein concentration is determined spectrophotometrically.

In vitro transcription of t-RNA

Z-RNA ^Leu , Z-RNA ^Val and t-RNA ^Ile from E. coli and 5 aureus are transcribed in vitro for 4 h at 37 ° C using T7 RNA polymerase. The transcription reaction uses 40 mM Zrfr-HCl (pH 8.0), 22 mM MgCl 2, 1 mM spermidine, 5 mM DTT, 0.01% Triton X-100, 4 mM GTP, 4 mM ATP, 4 mM UTP, 4 mM CTP, 16 mM GMP, 250 μΜ T7 RNA polymerase, and 150 pg BstNI-treated plasmid. After the reaction is complete, the mixture is applied to a 6% polyacrylamide 8 M urea denaturing gel to purify the transcribed t-RNA and remove impurities. Purified ί-RNA is quantified by Nanodrop 2000 (Thermo Scientific).

Determination of IC50

The catalyzed reaction of aminoacyl-t-RNA synthetase (aaRS) occurs in two steps. In the first step, aaRS activates its corresponding amino acid with ATP; and in a second step, the activated amino acid is conjugated to i-RNA. This reaction can be described as follows:

[1] ARS + aa + ATP = ARS-aa-AMP + PPi [2] ARS-aa-AMP + tRNA = aa-t-RNA + AMP + ARS (ARS, aminoacyl-t-RNA synthetase; aa, amino acid; ARS-aa-AMP, an enzyme linked to aminoacyladenylate; aa-t-RNA, aminoacyl-i-RNA).

The activity of pathogenic aaRS is monitored by measuring the rate of ATP uptake as it is directly proportional to aaRS activity. When the test compound inhibits the aminoacylation reaction at 50 41M, the rate of ATP uptake is reduced compared to the control reaction without addition of an inhibitor. This allows you to determine the percentage inhibition. If the percentage of the compound is above 80%, determine the IC50 using the same enzymatic assay (commercial assay kit Kinase RR from BioThema AB, Sweden) at different inhibitor concentrations. Known inhibitors of LRS, VRS or IRS are used as test positive standards. Non-linear regression analysis is used to calculate the IC50.

IC50 values for selected aminoacyl ARNS inhibitors

Sav. No. ID IC50 EcoLRS (μΜ) IC50 EcoIRS (μΜ) IC50 EcoVR S (μΜ) IC50 SauLRS (μΜ) IC50 Jan. (μΜ) IC50 JanVRS (μΜ) IK-580 8.1 0.014 n.d. i.a. 4.34 i.a. i.a. IK-617 8.2 0.012 n.d. i.a. 3 i.a. i.a. IK-587 8.3 0.054 n.d. i.a. 2.18 i.a. i.a. K-615 8.4 0.084 n.d. i.a. 1.11 i.a. i.a. IK-621 8.5 0.045 n.d. i.a. 2 i.a. i.a. BM-13 8.6 21.8 n.d. i.a. i.a. 103 @ 50 μΜ i.a. IK-625 8.7 0.22 n.d. i.a. 3 i.a. i.a. IK-636 8.8 0.013 n.d. i.a. 0.81 i.a. i.a. IK-634 8.9 0.002 n.d. i.a. 0.33 i.a. i.a. IK-635 8.10 0.006 n.d. i.a. 1.64 i.a. i.a. IK-627 8.11 0.02 n.d. i.a. 0.72 i.a. i.a.

DG- 435 8.12 0.01 n.d. i.a. 1.3 i.a. i.a. DG- 437 8.13 0.011 n.d. how to. 2.15 i.a. i.a. DG- 440 8.14 0.0034 n.d. i.a. 0.53 i.a. i.a. DG- 444 8.15 0.064 n.d. i.a. 6.23 i.a. i.a. DG- 445 8.16 0.063 n.d. i.a. 13.9 i.a. i.a. DG- 455 8.17 102% @ 50 μΜ n.d. n.d. n.d. n.d. n.d. DG- 453 8.18 104% @ 50 μΜ n.d. n.d. n.d. n.d. n.d.

i.a. - inactive at concentrations above 50 μΜ; n.d. - not specified.

Claims (23)

1. Compound of general formula I: A1 Formula I in which: AI is aryl; Q is a covalent bond or linker; A2 is an aryl group which is a linking group; R1 and R2 are optional substituents on the methylene group; R3 and R4 are optional amino substituents; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms and drug precursors thereof. A compound according to claim 1, wherein the aryl group AI is any of the following: AI is an optionally substituted C 5-20 aryl group; or AI is optionally substituted C5-2oheteroaryl; or AI is an optionally substituted C 8-2 monocyclic group; or AI is optionally substituted C5-2carboaryl; or AI is optionally substituted C5-2carboaryl monocyclic; or AI is optionally substituted C5-6carboaryl monocyclic; or AI is optionally substituted phenyl; or AI is a C5-20 aryl group derived from one of the following compounds: pyrimidine, pyridine, triazine, 9H-purine, pyran, imidazole, naphthalene, quinoline, indole, benzimidazole, quinazoline. A compound according to claim 1 or 2, wherein AI is an optionally substituted pyrimidyl group of the formula: 4 'where: n is a number from 0 to 3, and each R ^A is an independent substituent; or AI is optionally substituted pyrimidyl; Q is a covalent bond or linker; A2 is an aryl group which is a linking group; R1 and R2 are methylene substituents; R3 and R4 are amino substituents, and the compound has the following general formula: n is a number from 0 to 3; or n is a number from 0 to 2; or n is 0 or 1; or n is a number from 1 to 3; or n is 1 or 2; or n is 3; or n is 2; or n is 1; or n is 0. A compound according to claim 3, wherein if the pyrimidyl group is not completely substituted with the ring substituents R ^A , they are arranged at any position; or n is 1 and R ^a is at the 2 'position; or n is 2, one R ^A group is at the 4 'position and the other R ^a group is at the 2' position. A compound according to claim 3 or 4, wherein the ring substituents R ^A include: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e. -CONH 2), acetamido, acetyl, nitro, sulfonamido (unsubstituted, i.e. -SO 2 NH 2), and phenyl. A compound according to claim 1 or 2, wherein AI is an optionally substituted imidazopyrimidyl group of the general formula: 8 ', where n is a number from 0 to 3, and each R ^A is an independent substituent. The compound of claim 6, wherein Al is an optionally substituted imidazopyrimidyl group, Q is a covalent bond or a linker; A2 is an aryl group which is a linking group; R1 and R2 are methylene substituents; R3 and R4 are amino substituents; and the connection has the following general form: in which: n is a number from 0 to 3; or n is a number from 0 to 2; or n is 0 or 1; or n is a number from 1 to 3; or n is 1 or 2; or n is 3; or n is 2; or n is 1; or n is 0. The compound of claim 7, wherein the ring substituents R ^A include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy -, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, ie -CONH2), acetamido, acetyl, nitro, sulfonamide - (unsubstituted, i.e. -SO 2 NH 2), and phenyl. A compound according to claim 1 or 2, wherein: AI is an optionally substituted 4-pyridyl group of the general formula: 6 ' 3 'where n is a number from 0 to 4 and each R ^A is an independent substituent. The compound of claim 9, wherein A 1 is an optionally substituted 4-pyridyl group, Q is a covalent bond or linker, A 2 is an aryl group which is a linker, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino substituents and is the following general form: wherein: n is a number from 0 to 4; or n is a number from 0 to 3; or n is a number from 0 to 2; or n is 0 or 1; or n is a number from 1 to 4; or n is a number from 1 to 3; or n is 1 or 2; or n is 4; or n is 3; or n is 2; or n is 1; or n is 0. A compound according to claim 9 or 10, wherein if the pyridine group is not completely substituted with ring substituents R ^A , they are located at any position; in one embodiment, n is 1 and one R ^A group is at the 2 'position; preferred ring substituents R ^A include: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, i-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy -, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amide (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido (unsubstituted, - SO2NH2) and phenyl. A compound according to claim 1 or 2, wherein A 1 is optionally substituted 2-pyridyl having the following general formula: 4 'where n is a number from 0 to 4 and each R ^A is an independent substituent. The compound of claim 12, wherein in one embodiment, A 1 is an optionally substituted 2-pyridyl group, Q is a covalent bond or a linker, A 2 is an aryl group which is a linker, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino groups. and the compound has the following general formula: n is a number from 0 to 4; or n is a number from 0 to 3; or n is a number from 0 to 2; or n is 0 or 1; or n is a number from 0 to 4; or n is a number from 0 to 3; or n is a number from 0 to 2; or n is 0 or 1; or n is a number from 1 to 4; or n is a number from 1 to 3; or n is 1 or 2; or n is 4; or n is 3; or n is 2; or n is 1; or n is 0. A compound according to claim 12 or 13, wherein if the pyridine group is not completely substituted with ring substituents R ^A , they are located at any position; in one embodiment, n is 0; or n is 1 and one R ^A group is at the 6 'position; or ring substituents, R ^A , include: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido (unsubstituted, ie. -SO2NH2) and phenyl. A compound according to claim 1 or 2, wherein Al is an optionally substituted 1,3,5-triazinyl group having the following general formula: 4 'where n is a number from 0 to 2 and each R ^A is an independent substituent. The compound of claim 15, wherein A 1 is optionally substituted 1,3,5-triazinyl, Q is a covalent bond or linker, A 2 is an aryl group which is a linker, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino substituents. and the compound has the following general formula: n is a number from 0 to 2; or n is a number from 0 to 1; or n is 0 or 1; or n is 1 or 2; or n is 2; or n is 1; or n is 0. A compound according to claim 15 or 16, wherein if the triazine group is not completely substituted with ring substituents R ^A , they are located at any position; or n is 0; or n is 1 and one R ^A group is at the 6 'position; ring substituents R ^A include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, abutyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio -, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido (unsubstituted, i.e., -CONH2), acetamido, acetyl, nitro, sulfonamido (unsubstituted, i.e., -SO2NH2) and phenyl. The compound of claims 1 to 17, wherein: Q is a covalent bond; or Q is optionally substituted C 1-4 alkylene; or Q is an optionally substituted methylene group. The compound of claims 1 to 17, wherein: A2 is aryl, which is a linking, preferably an optionally substituted C5- oarilēngrupa _2; or A2 is optionally substituted C5-2oheteroarylene; or A2 is an optionally substituted C5-2ohetereroarylene monocyclic group; or A2 is an optionally substituted C 8 -Chheteroarylene monocyclic group; or A2 is optionally substituted Cs-2carboarylene; or A2 is an optionally substituted C5-2carboarylene monocyclic group; or A2 is an optionally substituted C5-6carboarylene monocyclic group; or A2 is optionally substituted phenylene. A compound according to claim 1 or 2, wherein: the phenylene group which is a linking group is in the ortho, meta or para position, optionally substituted with aryl substituents R ^B : meta-paraorto- The compound of claim 20, wherein: phenylene is zzzeta-phenylene or para-phenylene; or the phenylene group is a γ-phenylene group; or the phenylene group is meZa-phenylene; or m is a number from 0 to 4; or m is a number from 0 to 3; or m is a number from 0 to 2; or m is 0 or 1; or m is a number from 1 to 4; or m is a number from 1 to 3; or m is 1 or 2; or m is 4; vaimir3; or m is 2; or m is 1; or m is 0. A compound according to claim 20 or 21 wherein the aryl substituents R ^B include: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl; when Q is a covalent bond or a linker and A2 is a / ε / a-phenylene group, the compound has the following general formula: when Q is a covalent bond and A2 is a meta-phenylene group, the compound has the following general formula: wherein the substituents R1-R4 include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, ributyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl. A compound for use according to any one of claims 1 to 22, for use as a medicament or medical component in the treatment of bacterial infections.