LV15146A

LV15146A - N-acyl-diarylsulfonamide derivatives as aminiacyl-t-rna synthetase inhibitors

Info

Publication number: LV15146A
Application number: LVP-15-14A
Authority: LV
Inventors: Aigars Jirgensons; Einārs Loža; Paul William Finn; Michael Charlton; De Pouplana Lluis Ribas; Adēlaide SAINT-LĒGER
Original assignee: Latvijas Organiskās Sintēzes Institūts
Priority date: 2015-02-13
Filing date: 2015-02-13
Publication date: 2016-08-20
Also published as: LV15146B

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

IZGUDROJUMA APRAKSTSDESCRIPTION OF THE INVENTION

Izgudrojuma jomaField of Invention

Izgudrojums attiecas uz medicīnisko preparātu izveidošanu, galvenokārt uz bakteriālo aminoacil-f-RNS sintetāžu inhibitoriem bakteriālo infekciju ārstēšanai. It īpaši izgudrojums attiecas uz jauniem N-acil-diarilsulfonamīdiem, to farmaceitiskām kompozīcijām un to izmantošanu par aminoacil-r-RNS sintāžu inhibitoriem.The invention relates to the preparation of medical preparations, in particular to inhibitors of bacterial aminoacyl-f-RNA synthetics for the treatment of bacterial infections. In particular, the invention relates to novel N-acyl-diarylsulfonamides, their pharmaceutical compositions, and their use as inhibitors of aminoacyl-r-RNA synthases.

Izgudrojuma pamatojumusJustification of the invention

Rezistences veidošanās pret pašlaik izmantotajiem antibakteriāliem medikamentiem ir aktivizējusi jaunu ķīmijterapijas līdzekļu meklējumus, pret kuriem rezistence attīstās lēni vai tās izveidošanās ir pilnībā bloķēta. To varētu panākt, iedarbojoties uz tādiem funkcionālo baktēriju proteīniem, kuru mutāciju rezultātā notiek baktēriju fitnesa samazināšanās. Par šādiem molekulāriem mērķiem jaunu zāļvielu izveidei ir atzīti baktēriju enzūni, kurus sauc par aminoacil-t-RNS sintetāzēm (aaRS) (Gadakh, B. Van Aerschot, A. Aminoacyl-tRNA synthetase inhibitors as antimicrobial aģents: a patent revievv no 2006 till present. Expert Opin. Ther. Patents 2012, 22,1453-1465. Vondenhoff, G.H.M.; Van Aerschot A. Aminoacyl-ί-RNA synthetase inhibitors as potential antibiotics. Eur. J. Med. Chem. 2011,46 5227-5236. Pham, J.S.; Dawson, K. L.; Jackson, K.E.; Lim, E. E.; Pasaje, C. F. A.; Tumer, K.E.C.; Ralph. S. A. Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasties. Int. J. Parasitol. Drugs Drug Resist. 2014, 4, 41-13.) Izoleicil-i-RNS sintetāzes (IleRS) inhibitors Mupirocīns ir klīniski apstiprināta zāļviela plaša spektra grampozitīvo baktēriju izraisīto infekciju ārstēšanai. Ir izveidota rinda inhibitoru citu baktēriālo ί-RNS sintetāžu inhibēšanai, taču līdz šim neviens no tiem nav apstiprināts un izmantots zāļvielu klīnikā.The development of resistance to antibacterial drugs currently in use has triggered the search for new chemotherapeutic agents against which resistance develops slowly or is completely blocked. This could be achieved by acting on functional bacterial proteins whose mutations result in a loss of bacterial fitness. For such molecular purposes, bacterial enzymes called aminoacyl-t-RNA synthetases (aaRS) (Gadakh, B. Van Aerschot, A. Aminoacyl-tRNA synthetase inhibitor antimicrobial agent: a patent revievv from 2006 till present) are recognized for the development of new herbs. Expert Opin Ther. Patents 2012, 22, 1453-1465, Vondenhoff, GHM; Van Aerschot A. Aminoacyl-RNA synthetase inhibitor and potential antibiotics Eur. J. Med. Chem. 2011,46 5227-5236. , JS; Dawson, KL; Jackson, KE; Lim, EE; Pasaje, CFA; Tumer, KEC; Ralph. SA Aminoacyl-tRNA synthetases as drug targets in eukaryotic routine. Int. J. Parasitol. Drugs Drug Resist., 2014, 4 , 41-13.) Isoleucil-i-RNA Synthase (IleRS) Inhibitor Mupirocin is a clinically approved drug for the treatment of infections caused by a wide spectrum of Gram-positive bacteria. A series of inhibitors have been developed to inhibit other bacterial ß-RNA synthetics, but so far none of them has been approved and used in the drug clinic.

Izgudrojuma kopsavilkumsSummary of Invention

Izgudrojums piedāvā metodi bakteriālu infekciju ārstēšanai cilvēkiem vai dzīvniekiem, ievadot terapeitiski efektīvu savienojuma daudzumu. Šis savienojums ir aminoacil-f-RNS sintetāzes inhibitors, un šo savienojumu var ievadīt zāļvielas prekursora, farmaceitiski pieņemama sāls, hidrāta vai solvāta veidā, kā arī jebkura tā polimorfa veidā.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 inhibitor of aminoacyl-f-RNA synthetase and can be administered in the form of a drug precursor, a pharmaceutically acceptable salt, a hydrate or a solvate, as well as any polymorph thereof.

Citā aspektā izgudrojums piedāvā farmaceitisku kompozīciju bakteriālo infekciju ārstēšanai, kas satur terapeitiski efektīvu daudzumu kompozīcijas, kuras sastāvā ietilpst (i) zāļviela, vai zāļvielas prekursors vai tās farmaceitiski pieņemama sāls, hidrāts, solvāts vai zāļvielas polimorfs; (ii) farmaceitiski pieņemams nesējs, kur zāļviela ir aminoacil-i-RNS sintetāzes inhibitors.In another aspect, the invention provides a pharmaceutical composition for treating bacterial infections comprising a therapeutically effective amount of a composition comprising (i) a drug, or a drug precursor, or a pharmaceutically acceptable salt, hydrate, solvate, or drug polymorph thereof; (ii) a pharmaceutically acceptable carrier wherein the drug is an aminoacyl-i-RNA synthetase inhibitor.

Citā aspektā izgudrojums piedāvā medikamentu plašai izmantošanai bakteriālo infekciju ārstēšanai vai profilaksei, tai skaitā kompozīciju, kuras sastāvā ir zāļviela, tās prekursors, vai tās farmaceitiski pieņemama sāls, hidrāts, solvāts vai zāļvielas polimorfs, un kuras sastāvā ir aminoacil-/-RNS sintetāzes inhibitors.In another aspect, the invention provides a medicament for a wide range of uses for treating or preventing 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.

Citā aspektā izgudrojums piedāvā zāļvielu tās prekursoru, vai farmaceitiski pieņemamu sāli vai esteri, lai ārstētu vai novērstu bakteriālu infekciju, kur zāļviela ir aminoacil-t-RNS sintetāzes inhibitors.In another aspect, the invention provides a drug for its precursor, or a pharmaceutically acceptable salt or ester, for the treatment or prevention of a bacterial infection wherein the drug is an inhibitor of aminoacyl-t-RNA synthetase.

Vienā no izgudrojuma realizācijas variantiem aminoaciR-RNS sintetāzes inhibitors ir savienojums ar formulu I, kas šajā pieteikumā tiks saukts par N-acil-diarilsulfonamīda atvasinājumu:In one embodiment of the invention, the aminoacid-RNA synthetase inhibitor is a compound of formula I, which in this application will be referred to as the N-acyldiarylsulfonamide derivative:

Vispārīgā formula I:General formula I:

5 kurā: AI ir arilgrupa Q ir kovalentā saite vai linkeris; A2 ir arilgrupa, kas ir savienotājgrupa; R1 un R2 pēc izvēles ir metilēngrupas aizvietotāji; R3 un R4 pēc izvēles ir aminogrupas aizvietotāji; un šo atvasinājumu farmaceitiski pieņemami sāļi, solvāti, amīdi, esteri, ēteri, ķīmiski aizsargātas formas un zāļvielu prekursori.Wherein: A 1 is aryl Q is a covalent bond or linker; A2 is aryl which is a linker; R 1 and R 2 are optionally substituted with methylene; R3 and R4 are optionally substituted amino; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and drug precursors thereof.

Arilgrupa f AliAril Group A Ali

Arilgrupa (AI) ir pēc izvēles aizvietota Cs-2oarilgmpa......Aryl (AI) is optionally substituted Cs-2oarilgmpa ......

Vienā no variantiem, AI ir pēc izvēles aizvietota C5-2oheteroarilgrupa, vai AI ir pēc izvēles aizvietota monocikliska C5-2oheteroarilgrupa, vai AI ir pēc izvēles aizvietota C5-2okarboarilgrupa, vai AI ir pēc izvēles aizvietota monocikliska C5-2okarboarilgrupa, vai AI ir pēc izvēles aizvietota monocikliska Cs-ekarboarilgrupa, vai AI ir pēc izvēles aizvietota fenilgrupa, vai AI ir Cs-2oarilgrupa, kas atvasināta no viena no sekojošiem savienojumiem: pirimidīna, piridīna, triazīna, 9H-purina, furāna, imidazola, naftalīna, hinolīna, indola, benzimidazola, hinazolīna.In one embodiment, AI is optionally substituted C5-2oheteroaryl, or AI is optionally substituted monocyclic C5-2oheteroaryl, or AI is optionally substituted C5-2-carboaryl, or AI is optionally substituted monocyclic C5-2-carboaryl, or AI is optional substituted monocyclic C8-eco-aroyl or AI is optionally substituted phenyl, or Al is C2-aroyl derived from one of the following compounds: pyrimidine, pyridine, triazine, 9H-purine, furan, imidazole, naphthalene, quinoline, indole, benzimidazole , quinazoline.

Vienā no variantiem AI ir pēc izvēles aizvietota pirimidilgrupa ar formulu:In one of the variants AI is optionally substituted pyrimidyl having the formula:

9 kurā n ir skaitlis no 0 līdz 3, un katrs RA is savstarpēji nesaistīts aizvietotājs, tāds, kāds tas ir šeit definēts.9 wherein n is 0 to 3, and each R a is a non-linked substituent, as defined herein.

Vai arī, AI ir pēc izvēles aizvietota pirimidilgrupa, Q ir kovalentā saite vai linkeris; A2 ir arilgrupa, kas ir savienotāj grupa, R1 un R2 ir metilēngrupas aizvietotāji, R3 un R4 ir aminogrupas aizvietotāji un savienojumam ir sekojoša vispārīgā formula:Or, AI is optionally substituted pyrimidyl, Q is a covalent bond or linker; A2 is aryl, 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:

, kurā vienā no variantiem, n ir skaitlis no 0 līdz 3; vienā no variantiem, n ir skaitlis no Q līdz 2; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir skaitlis no 1 līdz 3; vienā no variantiem, n ir 1 vai 2; vienā no variantiem, n ir 3; vienā no variantiem, n ir 2; vienā no variantiem, n ir 1; vienā no variantiem, n ir 0.in one of the variants, n is 0 to 3; in one of the variants, n is a number from Q to 2; in one of the variants, n is 0 or 1; in one of the variants, n is a number from 1 to 3; in one of the variants, n is 1 or 2; in one of the variants, n is 3; in one of the variants, n is 2; in one of the variants, n is 1; in one of the variants, n is 0.

Ja pirmidilgrupa nav pilnībā aizvietota ar cikla aizvietotājiem RA, tie var tikt izkārtoti jebkurā kombinācijā. Piemēram, ja n ir 1, RA var būt 2'-, 4'-, vai 5'- pozīcijās. Līdzīgi, ja n ir 2, divas Ra grupas var būt, piemēram, 2',4'-, 2',5'-, vai 4',5'- pozīcijās.If the primidyl group is not completely substituted by the ring substitutes for RA, they can be arranged in any combination. For example, if n is 1, RA can be in the 2'-, 4'-, or 5'- positions. Similarly, if n is 2, the two Ra groups can be, for example, 2 ', 4'-, 2', 5'-, or 4 ', 5'-.

Vienā no variantiem, n ir 1, un RA grupa ir 2'-pozīcijā.In one of the variants, n is 1 and the RA group is in the 2'-position.

Vienā no variantiem, n ir 2, un viena RA grupa ir 4'-pozīcijā, un otra RA grupa ir 2'-pozīcijā. Katrs arilaizvietotājs RA ir tāds, kāds tas šeit definēts. Vēlamie cikla aizvietotāji RA ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, t-butil-, ciano-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, amido- (neaizvietotu, t.i., -CONH2), acetamido-, acetil-, nitro-, sulfonamido- (neaizvietotu, t.i., -SO2NH2), un fenilgrupu.In one of the variants, n is 2, and one RA group is in the 4'-position, and the other RA group is in the 2 'position. Each aryl substituent RA is as defined herein. Preferred Cycle Substitutes for RA include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy -, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido-, acetyl, nitro, sulfonamide (unsubstituted) , ie, -SO2NH2), and phenyl.

Viena no variantiem, AI ir pec izvēles aizvietota imidazopirimidilgrupa ar vispārīgo formulu:One of the variants of AI is optionally substituted imidazopyrimidyl with the general formula:

> kurā n ir skaitlis no 0 līdz 3, un katrs RA ir neatkarīgs aizvietotājs, tāds, kāds tas ir šeit definēts. Tā vienā no variantiem AI ir pēc izvēles aizvietota imidazopirimidilgrupa, Q ir kovalentā saite vai linkeris; A2 ir arilgrupa, kas ir savienotājgrupa; R1 un R2 ir metilēngrupas aizvietotāji; R3 un R4 ir aminogrupas aizvietotāji; un savienojumam ir sekojoša vispārīgā formula:> wherein n is 0 to 3, and each RA is an independent substituent, as defined herein. In one of its variants, AI is optionally substituted imidazopyrimidyl, Q is a covalent bond or linker; A2 is aryl which is a linker; R 1 and R 2 are methylene substituents; R3 and R4 are amino substituents; and the compound has the following general formula:

, kurā vienā no variantiem, n ir skaitlis no 0 līdz 3; vienā no variantiem, n ir skaitlis no 0 līdz 2; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir skaitlis no 1 līdz 3; vienā no variantiem, n ir 1 vai 2; vienā no variantiem, n ir 3; vienā no variantiem, n ir 2; vienā no variantiem, n ir 1; vienā no variantiem, n ir 0.in one of the variants, n is 0 to 3; in one of the embodiments, n is 0 to 2; in one of the variants, n is 0 or 1; in one of the variants, n is a number from 1 to 3; in one of the variants, n is 1 or 2; in one of the variants, n is 3; in one of the variants, n is 2; in one of the variants, n is 1; in one of the variants, n is 0.

Ja imidazogrupa nav pilnībā aizvietota ar cikla aizvietotājiem RA, tie var tikt izvietoti jebkurā pozīcijā. Piemēram, ja n ir 1, RA var būt 2'-, 7'-, vai 8'- pozīcijās. Līdzīgi, ja n ir 2, divas RA grupas var būt, piemēram, 2',7'-, 2',8'-, vai 7',8'- pozīcijās.If the imidazogroup is not completely substituted by a ring substitute for RA, they can be positioned at any position. For example, if n is 1, RA can be in the 2'-, 7'-, or 8'- position. Similarly, if n is 2, two RA groups can be, for example, 2 ', 7'-, 2', 8'-, or 7 ', 8'-.

Katrs arilaizvietotājs RA ir tāds, kāds tas ir šeit definēts.Each aryl substituent RA is as defined herein.

Piemēri vēlamajiem cikla aizvietotāji RA, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, r-butil-, ciano-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, amido- (neaizvietotu, t.i., -CONH2), acetamido-, acetil-, nitro-, sulfonamido- (neaizvietotu, t.i., -SO2NH2), un fenilgrupu.Examples of preferred cycle substitutes for RA include, but are not limited to, the following: fluoro, chloro, bromo, methyl, ethyl, isopropyl, r-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., -SO2NH2), and phenyl.

Vienā no variantiem, AI ir pēc izvēles aizvietota 4-piridilgrupa ar vispārīgo formulu:In one embodiment, the AI is optionally substituted 4-pyridyl with the general formula:

kurā n is skaitlis no 0 līdz 4 un katrs RA ir neatkarīgs aizvietotājs, tāds, kāds tas ir šeit definēts.wherein n is an integer from 0 to 4 and each RA is an independent substituent as defined herein.

Vienā no variantiem, AI ir pēc izvēles aizvietota 4-piridilgrupa, Q ir kovalentā saite vai linkeris, A2 ir arilgrupa, kas ir savienotāj grupa, R1 un R2 ir metilēngrupas aizvietotāji, R3 un R4 ir aminogrupas aizvietotāji un savienojumam ir sekojoša vispārīgā formula:In one embodiment, AI is optionally substituted 4-pyridyl, Q is a covalent bond or linker, A2 is aryl, is a linking group, R1 and R2 are methylene substituents, R3 and R4 are amino substituents, and the compound has the following general formula:

, kurā: vienā no variantiem, n ir skaitlis no 0 līdz 4; vienā no variantiem, n ir skaitlis no 0 līdz 3; vienā no variantiem, n ir skaitlis no 0 līdz 2; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir skaitlis no 1 līdz 4; vienā no variantiem, n ir skaitlis no 1 līdz 3; vienā no variantiem, n ir 1 vai 2; vienā no variantiem, n vai 4; vienā no variantiem, n vai 3; vienā no variantiem, n vai 2; vienā no variantiem, n vai 1; vienā no variantiem, n vai 0., wherein: in one of the variants, n is 0 to 4; in one of the embodiments, n is 0 to 3; in one of the embodiments, n is 0 to 2; in one of the variants, n is 0 or 1; in one of the variants, n is a number from 1 to 4; in one of the variants, n is a number from 1 to 3; in one of the variants, n is 1 or 2; one of the variants n or 4; one of the variants n or 3; one of the variants n or 2; one of the variants n or 1; in one of the variants, n or 0.

Ja piridīna grupa nav pilnībā aizvietota ar cikla aizvietotājiem RA, tie var tikt izvietoti jebkurā pozīcijā. Piemēram, ja n ir 1, RA var būt 2'-, 3'-, 5'- vai 6'- pozīcijās. Līdzīgi, ja n ir 2, divas RA grupas var būt, piemēram 2',3'-, 2',5'-, 2',6'-, vai 3',5'- pozīcijās.If the pyridine group is not completely replaced by a ring substitute for RA, they can be positioned at any position. For example, if n is 1, RA can be in the 2'-, 3'-, 5'- or 6'- positions. Similarly, if n is 2, two RA groups can be, for example, 2 ', 3', 2 ', 5', 2 ', 6'-, or 3', 5'-.

Vienā no variantiem, n ir 1, un viena RA grupa ir 2-pozīcijā.In one of the variants, n is 1 and one RA group is in the 2-position.

Katrs cikla aizvietotājs, RA, ir tāds, kāds tas ir šeit definēts.Each cycle substitute, RA, is as defined herein.

Piemēri vēlamajiem cikla aizvietotājiem RA, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, ί-butil-, ciano-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, amido- (neaizvietotu, t.i., -CONH2), acetamido-, acetil-, nitro-, sulfonamido- (neaizvietotu, t.i., -SO2NH2) un fenilgrupu.Examples of preferred cycle substitutes for RA include, but are not limited to, the following: fluoro, chloro, bromo, methyl, ethyl, isopropyl, ß-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., -SO2NH2) and phenyl.

Viena no variantiem, AI ir pēc izvēles aizvietota 2-piridilgrupa ar sekojošu vispārīgo formula:One of the variants, AI is optionally substituted 2-pyridyl with the following general formula:

> kurā n ir skaitlis no 0 līdz 4, un katrs RA ir neatkarīgs aizvietotājs, tāds, kāds tas ir definēts šeit.> wherein n is 0 to 4, and each RA is an independent substituent, as defined herein.

Vienā no variantiem, AI ir pēc izvēles aizvietota 2-piridilgrupa, Q ir kovalentā saite vai linkeris, A2 ir arilgrupa, kas ir savienotājgrupa, R1 un R2 ir metilēngrupas aizvietotāji, R3 un R4 ir aminogrupas aizvietotāji un savienojumam ir sekojoša vispārīgā formula:In one embodiment, A 1 is optionally substituted 2-pyridyl, Q is a covalent bond or linker, A 2 is aryl, 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:

kurā vienā no variantiem, n ir skaitlis no 0 līdz 4; vienā no variantiem, n ir skaitlis no 0 līdz 3; vienā no variantiem, n ir skaitlis no 0 līdz 2; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir skaitlis no 0 līdz 4; vienā no variantiem, n ir skaitlis no 0 līdz 3; vienā no variantiem, n ir skaitlis no 0 līdz 2; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir skaitlis no 1 līdz 4; vienā no variantiem, n ir skaitlis no 1 līdz 3; vienā no variantiem, n ir 1 vai 2; vienā no variantiem, n ir 4; vienā no variantiem, n ir 3; vienā no variantiem, n ir 2; vienā no variantiem, n ir 1; vienā no variantiem, n ir 0.in one of the variants, n is 0 to 4; in one of the embodiments, n is 0 to 3; in one of the embodiments, n is 0 to 2; in one of the variants, n is 0 or 1; in one of the embodiments, n is 0 to 4; in one of the embodiments, n is 0 to 3; in one of the embodiments, n is 0 to 2; in one of the variants, n is 0 or 1; in one of the variants, n is a number from 1 to 4; in one of the variants, n is a number from 1 to 3; in one of the variants, n is 1 or 2; in one of the variants, n is 4; in one of the variants, n is 3; in one of the variants, n is 2; in one of the variants, n is 1; in one of the variants, n is 0.

Ja piridmgrupa nav pilnībā aizvietota ar cikla aizvietotājiem RA, tad tie var būt izvietoti jebkurā pozīcijā. Piemēram, ja n ir 1, RA var būt 3'-, 4’-, 5'- vai 6'- pozīcijās. Līdzīgi, ja n ir 2, divas Ra grupas var būt, piemēram, 3',4'-, 3',5'-, 3',6'-, 4',5'-, 4',6'- vai 5',6'- pozīcijās.If the pyridine group is not completely replaced by a ring substitute for RA, then they can be positioned at any position. For example, if n is 1, RA can be in the 3'-, 4'-, 5'- or 6'- positions. Similarly, if n is 2, the two Ra groups can be, for example, 3 ', 4', 3 ', 5', 3 ', 6', 4 ', 5', 4 ', 6' - or 5 ', 6'-positions.

Vienā no variantiem, n ir 0.In one of the variants, n is 0.

Vienā no variantiem, n ir 1, un viena RA grupa ir 6'-pozīcijā.In one of the variants, n is 1 and one RA group is in the 6'-position.

Katrs cikla aizvietotājs RA ir tāds, kāds tas ir definēts šeit.Each cycle substitute RA is as defined here.

Piemēri vēlamajiem cikla aizvietotājiem, RA, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, t-butil-, ciano-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, amido- (neaizvietotu, t.i., -CONH2), acetamido-, acetil-, nitro-, sulfonamido- (neaizvietotu, t.i., -SO2NH2) un fenilgrupu.Examples of preferred cycle substitutes, RA, include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, isopropyl, t-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., -SO2NH2) and phenyl.

Vienā no variantiem, AI ir pēc izvēles aizvietota 1,3,5-triazinilgrupa ar sekojošu vispārīgo formula:In one embodiment, AI is optionally substituted 1,3,5-triazinyl with the following general formula:

, kurā: n ir skaitlis no 0 līdz 2 un katrs RA ir neatkarīgs aizvietotājs, tāds, kāds tas ir šeit definēts. Vienā no variantiem, AI ir pēc izvēles aizvietota 1,3,5-triazinilgrupa, Q ir kovalentā saite vai linkeris, A2 ir arilgrupa, kas ir savienotājgrupa, R1 un R2 ir metilēngrupas aizvietotāji, R3 un R4 ir aminogrupas aizvietotāji un savienojumam ir sekojoša vispārīgā formula:, wherein: n is 0 to 2 and each RA is an independent substituent as defined herein. In one embodiment, AI is optionally substituted 1,3,5-triazinyl, Q is a covalent bond or linker, A2 is aryl, is a linker, R1 and R2 are methylene substituents, R3 and R4 are amino substituents, and the compound has the following general formula: formula:

, kurā: vienā no variantiem, n ir skaitlis no 0 līdz 2; vienā no variantiem, n ir skaitlis no 0 līdz 1; vienā no variantiem, n ir 0 vai 1; vienā no variantiem, n ir 1 vai 2; vienā no variantiem, n ir 2; vienā no variantiem, n ir 1; vienā no variantiem, n ir 0., wherein: in one of the variants, n is 0 to 2; in one of the embodiments, n is 0 to 1; in one of the variants, n is 0 or 1; in one of the variants, n is 1 or 2; in one of the variants, n is 2; in one of the variants, n is 1; in one of the variants, n is 0.

Ja triazīna grupa nav pilnībā aizvietota ar cikla aizvietotājiem RA, tie var tikt izvietoti jebkurā pozīcijā. Piemēram, ja n ir 1, RA var būt 3'-, 4’-, 5'- vai 6'- pozīcijās. Līdzīgi, ja n ir 2, divas Ra grupas var būt, piemēram, 3',4'-, 3',5'-, 3',6'-, 4',5'-, 4',6'- vai 5',6'- pozīcijās.If the triazine group is not completely replaced by ring substitutes for RA, they can be positioned in any position. For example, if n is 1, RA can be in the 3'-, 4'-, 5'- or 6'- positions. Similarly, if n is 2, the two Ra groups can be, for example, 3 ', 4', 3 ', 5', 3 ', 6', 4 ', 5', 4 ', 6' - or 5 ', 6'-positions.

Vienā no variantiem, n ir 0.In one of the variants, n is 0.

Vienā no variantiem, n ir 1, un viena Ra grupa ir 6'-pozīcijā.In one of the embodiments, n is 1 and one Ra is in the 6'-position.

Katrs cikla aizvietotājs, RA, ir tāds, kāds tas ir definēts šeit.Each cycle substitute, RA, is as defined here.

Piemēri vēlamajiem cikla aizvietotājiem RA, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, t-butil-, ciano-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, amido- (neaizvietotu, t.i., -CONH2), acetamido-, acetil-, nitro-, sulfonamido- (neaizvietotu, t.i., -SO2NH2) un fenilgmpu.Examples of preferred cycle substitutes for RA include, but are not limited to, the following: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, and the like. , isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido, acetyl, nitro, sulfonamide (unsubstituted, i.e., -SO2NH2) and phenylgmp.

Linkeris (Ό) Kā minēts augstāk, vairākos variantos Q ir kovalentā saite vai linkeris; vairākos variantos Q ir kovalentā saite; vairākos variantos Q ir linkeris.Linker (Ό) As mentioned above, in several variants Q is a covalent bond or linker; in several variants Q is a covalent bond; in several variants Q is a linker.

Vienā no variantiem, Q ir kovalentā saite.In one of the variants, Q is a covalent bond.

Vienā no variantiem, Q ir pēc izvēles aizvietota Ci-4alkilēngrupa.In one embodiment, Q is optionally substituted C 1-4 alkylene.

Vienā no variantiem, Q ir pēc izvēles aizvietota metilēngrupa.In one embodiment, Q is optionally substituted methylene.

Arilgrupa, kas ir savienotāj grupa (A2)Aryl, a linking group (A2)

Arilgrupa, kas ir savienotāj grupa (A2) ir pēc izvēles aizvietota C5-2oarilēngrupa.The aryl group which is the linking group (A2) is optionally substituted with C5-2oarylene.

Vienā no variantiem, A2 ir pēc izvēles aizvietota C5-2oheteroarilēngrupa. Vienā no variantiem, A2 ir monocikliska un pēc izvēles aizvietota Cs-2oheteroarilēngrupa. Vienā no variantiem, A2 ir monocikliska un pēc izvēles aizvietota C5-6heteroarilēngrupa.In one of the embodiments, A2 is optionally substituted with C5-2heteroarylene. In one embodiment, A2 is monocyclic and optionally substituted C 2 -C 2 heteroarylene. In one embodiment, A2 is a monocyclic and optionally substituted C5-6 heteroarylene group.

Vienā no variantiem, A2 ir pēc izvēles aizvietota C5-2okarboarilēngrupa. Vienā no variantiem, A2 ir monocikliska un pēc izvēles aizvietota C5-2okarboarilēngrupa. Vienā no variantiem, A2 ir monocikliska un pēc izvēles aizvietota C5-6karboarilēngrupa. Vienā no variantiem, A2 ir pēc izvēles aizvietota fenilēngrupa.In one embodiment, A2 is optionally substituted with C5-Carboarylene. In one embodiment, A 2 is a monocyclic and optionally substituted C 5 -C 2 carboarylene. In one embodiment, A2 is monocyclic and optionally substituted C5-6carboarylene. In one embodiment, A2 is optionally substituted phenylene.

Fenilēngrupa, kas ir savienotāj grupa var būt orto-, meta-, vai /?am-pozīcijā, fenilēngrupa, kas ir pēc izvēles aizvietota ar aril-aizvietotājiem RB:Phenylene, which is a linking group, may be in the ortho-, meta-, or? -Amino position, phenylene optionally substituted with aryl substituents RB:

Vienā no variantiem, fenilēngrupa, kas ir savienotāj grupa, ir ffieta-fenilēngrupa vai para-fenilēngrupa. Vienā no variantiem, fenilēngrupa, kas ir savienotāj grupa, ir para-fenilēngrupa. Vienā no variantiem, fenilēngrupa, kas ir savienotāj grupa, ir meta-fenilēngrapa.In one embodiment, the phenylene group which is a linking group is phenya-phenylene or para-phenylene. In one embodiment, the phenylene group which is a linking group is para-phenylene. In one of the embodiments, the phenylene group which is a linking group is meta-phenylenraprap.

Vienā no variantiem, m ir skaitlis no 0 līdz 4.In one of the variants, m is a number from 0 to 4.

Vienā no variantiem, m ir skaitlis no 0 līdz 3.In one of the variants, m is a number from 0 to 3.

Vienā no variantiem, m ir skaitlis no 0 līdz 2.In one of the variants, m is a number from 0 to 2.

Vienā no variantiem, m ir 0 vai 1.In one of the variants, m is 0 or 1.

Vienā no variantiem, m ir skaitlis no 1 līdz 4.In one of the variants, m is a number from 1 to 4.

Vienā no variantiem, m ir skaitlis no 1 līdz 3.In one of the variants, m is a number from 1 to 3.

Vienā no variantiem, m ir 1 vai 2.In one of the variants, m is 1 or 2.

Vienā no variantiem, m ir 4.In one of the variants, m is 4.

Vienā no variantiem, m ir 3.In one of the variants, m is 3.

Vienā no variantiem, m ir 2.In one of the variants, m is 2.

Vienā no variantiem, m ir 1.In one of the variants, m is 1.

Vienā no variantiem, m ir 0.In one of the variants, m is 0.

Katrs arilaizvietotājs RB, ir tāds, kāds tas ir šeit definēts.Each aryl substituent RB is as defined herein.

Piemēri vēlamajiem arilaizvietotājiem RB, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, ί-butil-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, acetamido-, nitro- un fenilgrupu.Examples of preferred aryl substituents RB include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, and the like. trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl.

Kad Q ir kovalentā saite vai linkeris, A2 ir meta-fenilēngrupa, tad savienojumam ir sekojoša vispārīgā formula:When Q is a covalent bond or a linker, A2 is a meta-phenylene, then the compound has the following general formula:

kad Q ir kovalentā saite, A2 ir meta-fenilēngrupa, tad savienojumam ir sekojoša vispārīgā formula:when Q is a covalent bond, A2 is a meta-phenylene, then the compound has the following general formula:

Katrs alkil- un amino- aizvietotājs, Rl, R2, R3 un R4, ir tāds, kāds tas ir šeit definēts.Each alkyl and amino substituent, R 1, R 2, R 3 and R 4, is as defined herein.

Piemēri vēlamajiem aizvietotājiem, R1-R4, ietver, bet neaprobežojas ar sekojošiem: fluor-, hlor-, brom-, metil-, etil-, izopropil-, i-butil-, trifluormetil-, hidroksi-, metoksi-, etoksi-, izopropoksi-, trifluormetoksi-, metiltio-, trifluormetiltio-, hidroksimetil-, amino-, dimetilamino-, dietilamino-, morfolino-, acetamido-, nitro- un fenilgrupu.Examples of preferred substituents, R 1 -R 4, include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, isopropyl, i-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, and the like. isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, acetamido-, nitro and phenyl.

StereoķīmiiaStereochemistry

Vairākām no šeit parādītajām struktūrām ir attēlota to specifiskā stereoķīmiskā konfigurācija. Tāpat, vairākām no šeit parādītajām struktūrām nav attēlota to specifiskā stereoķīmiskā konfigurācija. Līdzīgi, daudzām ķīmiskām struktūrām parādītas stereoķīmiskās konfigurācijas vienā vai vairākās pozīcijās, savukārt citām pozīcijām, konfigurācija nav attēlota. Ja ķīmiskajai struktūrai stereoķīmiskā konfigurācija nav attēlota, tad jāuzskata, ka struktūra ietver visus iespējamos stereoizomērus, gan individuāli, gan kā stereoizomēru maisījumu.Several of the structures shown here show their specific stereochemical configuration. Similarly, several of the structures shown here do not display their specific stereochemical configuration. Similarly, many chemical structures show stereochemical configurations in one or more positions, while other positions have no configuration. If the chemical structure is not depicted in the stereochemical configuration, it should be considered that the structure includes all possible stereoisomers, both individually and as a mixture of stereoisomers.

AizvietotājiSubstitutes

Cs-ioaril: Šeit lietotatais apzīmējums "C5-2oaril," nozīmē monovalentu grupu, ko iegūst, ja C5-2oaromātiskam savienojumam atņem vienu ūdeņraža atomu, un šis savienojums sastāv no viena, diviem vai vairākiem cikliem (piemēram, kondesētiem cikliem) un sastāv no 5 līdz 20 atomiem, un, kur vismaz viens no cikliem ir aromātikais gredzens. Vēlams, ka katrā no cikliem ir 5 līdz 7 atomi. Šajā kontekstā priedēkļi (piemēram: C3-20, C5-7, C5-6, utt.) apzīmē cikla atomu skaitu vai cikla atomu skaita diapazonu, gan oglekļa atomiem, gan heteroatomiem. Piemēram, šeit lietotais apzīmējums "C5-6aril," norāda uz arilgrupu, kas sastāv no 5 vai 6 cikla atomiem. Arilgrupu piemēri ietver C3-2oaril, Cs^aril, Cs^aril.Cs-ioaril: The designation "C5-2oaril," as used herein, means a monovalent group obtained when one hydrogen atom is deprived of a C5-2oaromatic compound and the compound consists of one, two or more cycles (e.g., condensed cycles) and consists of 5 to 20 atoms, and wherein at least one of the rings is an aromatic ring. Preferably, each cycle has 5 to 7 atoms. In this context, prefixes (for example: C3-20, C5-7, C5-6, etc.) denote the number of cyclic atoms or the range of atomic cycles, both carbon atoms and heteroatoms. For example, the term "C5-6aril" as used herein refers to an aryl group consisting of 5 or 6 ring atoms. Examples of aryl groups include C 3-20 aryl, C 1-4 aryl, C 1-4 aryl.

Cikla atomi visi var būt oglekļa atomi, kā tas ir "karboarilgrupās" (piemēram, C5-2okarboaril). Karboarilgrupu piemēri ietver, bet neaprobežojas ar tādiem, kas atvasināti no benzola (t.i., fenil-) (C6), naftalīna (CIO), azulēna (CIO), antracēna (C14), fenantrēna (C14), naftacēna (C18) un pirēna (C16).Cyclic atoms can all be carbon atoms, as is "carboaryl" (e.g., C5-Carboaryl). Examples of carboaryl groups include, but are not limited to, those derived from benzene (ie, phenyl) (C6), naphthalene (CIO), azulene (CIO), anthracene (C14), phenanthrene (C14), naphthacene (C18) and pyrene ( C16).

Piemēri arilgrupām, kuras sastāda kondensētie cikli, no kuriem vismaz viens ir aromātisks, ietver, bet neaprobežojas ar grupām, kuras ir atvasinātas no indēna (C9), izoindēna (C9) un fluorēna (C13).Examples of aryl groups consisting of condensed cycles of which at least one is aromatic include, but are not limited to, indene (C9), isoindene (C9) and fluorene (C13) groups.

Alternatīvi, cikla atomi var būt viens vai vairāki heteroatomi, ietverot, bet neaprobežojoties ar skābekli, slāpekli vai sēru kā tas ir “heteroarilgrupās”. Šajā gadījumā grupu var saukt kā C5-2oheteroarilgrupu, kur "C5-20" norāda un cikla atomu skaitu, kas var būt gan oglekļa atomi, gan heteroatomi. Vēlams, lai katrā ciklā ir no 5 līdz 7 cikla atomiem, no kuriem 0 līdz 4 ir cikla heteroatomi.Alternatively, the ring atoms may be one or more heteroatoms, including but not limited to oxygen, nitrogen or sulfur as it is in "heteroaryl". In this case, the group can be called C5-2oheteroaryl, where "C5-20" denotes the number of ring atoms that can be both carbon and heteroatoms. Preferably, each cycle has 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.

Monociklisko heteroarilgrupu piemēri ietver, bet neaprobežojas ar tādiem, kas atvasināti no: N1: pirola (azola) (C5), piridīna (azīna) (C6); 01: furāna (oksola) (C5); S1: tiofena (tiola) (C5); N101: oksazola (C5), izoksazola (C5), izoksazīna (C6); N201: oksadiazola (furazāna) (C5); N301: oksatriazola (C5); N1S1: tiazola (C5), izotiazola (C5); N2: imidazola (1,3 diazola) (C5), pirazola (1,2 diazola) (C5), piridazīna (1,2 diazīna) (C6), pirimidīna (1,3 diazīna) (C6) (e.g., citozīna, timīna, uracilā), pirazīna (1,4 diazīna) (C6); N3: triazola (C5), triazīna (C6); un N4: tetrazola (C5).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); S1: thiophene (thiol) (C5); N101: oxazole (C5), isoxazole (C5), isoxazine (C6); N2 O1: oxadiazole (furazan) (C5); N301: oxatriazole (C5); N 1 S 1: thiazole (C 5), isothiazole (C 5); 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).

Kombinācijas Šeit ir nepārprotami uzrādīta katra un ikviena ar augstāk aprakstīto variantu saderīga kombinācija, tā it kā katra un ikviena kombinācija būtu individāli un tieši uzskaitīta.Combinations Here is a clear combination of each and every variant described above, as if each and every combination were individually and directly listed.

Specifiski variantu piemēriSpecific examples of variants

Sekojošie piemēri papildus ilustrē izgudrojumu, taču šo ilustrāciju nekādā veidā nevar interpretēt kā izgudrojuma pielietojuma ierobežojumu. Kā dotā izgudrojuma piemēri ir uzrādīti sekojoši N-acil-diarilsulfonamīdu atvasinājumi 8.1-8.18:The following examples further illustrate the invention, but cannot be interpreted in any way as a limitation of the use of the invention. As examples of the present invention, the following N-acyl-diarylsulfonamide derivatives are shown 8.1-8.18:

Vispārīgs sintēzēs apraksts 1. ShēmaGeneral Synthesis Description 1. Scheme

Starpproduktu 2 sintēze, vispārīgā metode A Demonstrēta uz savienojuma 2.1 sintēzes piemēra: 3-Brombenzosulfonamīds (2.1)Synthesis of Intermediate 2, General Method A Example of Compound 2.1 Synthesis: 3-Bromobenzenesulfonamide (2.1)

3-Brombenzo-l-sulfonilhlorīda (1.1) (4,073 g, 15,94 mmol) šķīdumam DCM (67 ml), kas atdzesēts ledus vannā pievieno 25 % NH4OH šķīdumu ūdenī (3,7 ml, 57,15 mmol). Reakcijas masu maisa dzesējot 0,5 h, pēc tam maisa 6 h istabas temperatūrā. Izveidojas nogulsnes, kuras nofiltrē, mazgā ar ūdeni un žāvē vākumā virs P2O5. Iegūst 3-brombenzosulfonamīdu (2.1) (3,270 g, 87 %) ka bezkrāsainu kristālisku vielu. 'H NMR (DMSO-cfe) δ: 7,97 (t, /=1,9 Hz, 1H), 7,84-7,80 (m, 2H), 7,54 (t, /=7,9 Hz, 1H), 7,50 (b s, 2H). LCMS (ESI) m/z: 235,98 [ΜΗ]*. Pēc metodes, kas analoģiska metodei A, iegūti sekojoši savienojumi:To a solution of 3-Bromobenzo-1-sulfonyl chloride (1.1) (4.073 g, 15.94 mmol) in DCM (67 mL) in a cooled ice bath add 25% NH 4 OH in water (3.7 mL, 57.15 mmol). The reaction mass was stirred under cooling for 0.5 h then stirred for 6 h at room temperature. A precipitate is formed which is filtered off, washed with water and dried in a cover over P2O5. Obtained 3-bromobenzenesulfonamide (2.1) (3.270 g, 87%) as a colorless crystalline substance. 1 H NMR (DMSO-d 6) δ: 7.97 (t, δ = 1.9 Hz, 1H), 7.84-7.80 (m, 2H), 7.54 (t, / 7.9) Hz, 1H), 7.50 (bs, 2H). LCMS (ESI) m / z 235.98 [ΜΗ] *. By the method analogous to Method A, the following compounds were obtained:

Starpproduktu 3 sintēze, vispārīgā metode B Demonstrēta uz savienojuma 3.1 sintēzes piemēra: (S)-terc-butil (l-(3-bromfenilsulfonamido)-4-metil-l-oksopentan-2-il)karbamāts (3.1)Synthesis of Intermediate 3, General Method B Demonstrated on the synthesis of compound 3.1: (S) -tert-butyl (1- (3-bromophenylsulfonamido) -4-methyl-1-oxopentan-2-yl) carbamate (3.1)

BOC-L-leicīna monohidrāta (0,592 g, 2,37 mmol) šķīdumam DMF (5 ml) secīgi pievieno 3-brombenzosulfonamīdu (0,561 g, 2,37 mmol), HBTU (0,900 g, 2,37 mmol), TEA (0,66 ml, 4,75 mmol), un katalītisku daudzumu DMAP (0,029 g, 0,237 mmol). Reakcijas masu maisa 24 h un izlej ūdenī (70 ml). Maisījumu ekstrahē ar EtOAc (3 x 75 ml), apvienotos organiskos ekstraktus mazgā ar 1N aq. HC1 (20 ml), ūdeni (2 * 100 ml), pies. aq. NaCl (100 ml), un žāvē virs (Na2SC>4). Šķīdinātājus ietvaicē un atlikumu (0,988 g) attīra ar Biotage attīrīšanas sistēmu (C18HS 40+M kolona, eluents: ūdens-metanols, gradients no 1:1 līdz 0:100). Iegūst 0,660 g (61,8 %) ((5)-terc-butil (l-(3-bromfenilsulfonamido)-4-metil-l-oksopentan-2-il)karbamātu (3.1) kā putas. *H NMR (CDC13) 5: 9,57 (b s, 1H), 8,16 (t, /=l,8z, 1H), 8,00 (d, /=7,9 Hz, 1H), 7,75 (ddd, /= 7,9;1,8;1,0 Hz, 1H), 7,40 (t, /=7,9 Hz, 1H), 4,70 (neatrisināts d, /=6,4 Hz, 1H), 4,06-3,92 (m, 1H), 1,70-1,52 (m, 3H), 1,44 (s, 9H), 0,91 (d, /=6,3 Hz, 3H), 0,87 (d, /=6,3 Hz, 3H). LCMS (ESI) m/z: 449,2 [M-H]'.To a solution of BOC-L-leucine monohydrate (0.592 g, 2.37 mmol) in DMF (5 mL) was successively added 3-bromobenzenesulfonamide (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), the combined organic extracts are washed with 1N aq. HCl (20 mL), water (2 * 100 mL), pies. aq. NaCl (100 mL) and dried over (Na 2 SO 4). The solvents are evaporated and the residue (0.988 g) purified by Biotage purification system (C18HS 40 + M column, eluent: water-methanol, gradient 1: 1 to 0: 100). 0.660 g (61.8%) of ((5) -tert-butyl (1- (3-bromophenylsulfonamido) -4-methyl-1-oxopentan-2-yl) carbamate (3.1) is obtained as a foam. ) 5: 9.57 (bs, 1H), 8.16 (t, / = 1.8z, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.75 (ddd, / = 7.9, 1.8, 1.0 Hz, 1H), 7.40 (t, J = 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, 6.3 Hz, 3H) , 0.87 (d, J = 6.3 Hz, 3H) LCMS (ESI) m / z: 449.2 [MH] '.

Pec metodes, kas analoģiska metodei B, iegūti sekojoši savienojumi:Following the method analogous to Method B, the following compounds were obtained:

Starpproduktu 4 sintēze, vispārīgā metode C Demonstrēta uz savienojuma 4.1 sintēzes piemēra: (S)-ierc-butil (4-metil-l-okso-l-(3-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)fenilsulfon-amido)pentan-2-il)karbamāts (4.1)Synthesis of Intermediate 4, General Method C: Example 4: Synthesis of Compound 4.1: (S) -Sert-Butyl (4-methyl-1-oxo-1- (3- (4,4,5,5-tetramethyl-1,3, 3)) 2-Dioxaborolan-2-yl) phenylsulfonamido) pentan-2-yl) carbamate (4.1)

Caur ((S)-terc-butil (l-(3-bromfenilsulfonamido)-4-metil-l-oksopentan-2-il)karbamātu (3.1), (1,000 g, 2,23 mmol), KOAc (0,874 g, 8,9 mmol) un PdCl2(dppf)2 (0,18 g, 0,22 mmol) masījumu dioksānā (40 ml) barbotē argonu 10 min. Pie reakcijas maisījuma pievieno £zs(pinakolāta)diborānu (0,85 g, 3,35 mmol). Reakcijas trauku noslēdz un karsē pie 110 °C 17 h. Maisījumu atdzesē līdz istabas temperatūrai un nofiltrē caur celītu. Filtrātu ietvaicē un tumšo eļļveidīgo atlikumu (3,0 g) attīra hromatogrāfiski uz silikagela kolonas (eluents: petrolēteris-etilacetāts, gradients no 4:1 līdz 1:1). Iegūst 1,281 g (5)-īerc-butil 4-metil-l-okso-1 -(3 -(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenilsulfonamido)pentan-2-il)karbamāta (4.1) un (5)-(3-(īV-(2-((ferc-butoksikarboniI)amino)-4-metilpentanoil)sulfamoil)-fenil)borskābes maisījumu (4.1a) kā stiklveida materiālu. Iegūto maisījumu izmanto nākošajā stadijā bez papildu attīrīšanas. LCMS (ESI) m/z: 495,28 [M-H]' (4.1, aiztures laiks 3,939 min.) un 413,22 [M-H]‘ (4.1a, aiztures laiks 2,750).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 a mass of dioxane (40 mL) are bubbled with argon for 10 min. 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) Obtain 1.281 g of (5) -ert-butyl 4-methyl-1-oxo-1- (3- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) phenylsulfonamido) pentan-2-yl) carbamate (4.1) and (5) - (3- (N- (2 - ((tert-butoxycarbonyl) amino) -4-methylpentanoyl) sulfamoyl) - phenyl) boric acid mixture (4.1a) as glassy material. The resulting mixture is used in the next step without further purification. LCMS (ESI) m / z 495.28 [M-H] - (4.1, retention time 3.939 min.) And 413.22 [M-H] '(4.1a, retention time 2.750).

Pec metodes, kas analoģiska metodei C, iegūti sekojoši savienojumi:Following the method analogous to Method C, the following compounds were obtained:

Starpproduktu 5 sintēze, vispārīgā metode D Demonstrēta uz savienojuma 5.1 sintēzes piemēra: 3-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)benzosulfonamīds (5.1)Synthesis of Intermediate 5, General Method D Example of Compound 5.1 Synthesis: 3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzosulfonamide (5.1)

Caur 3-brombenzosulfonamīda (2.1) (0,620 g, 2,63 mmol), KOAc (1,032 g, 10,52 mmol), un PdCl2(dppf)2 (0,100 g, 0,137 mmol) maisījumu dioksānā (20 ml) barbotē argonu 10 min, pie rekcijas masījuma pievieno 6w(pinakolāto)diborānu (1,000 g, 3,94 mmol), reakcijas trauku noslēdz un reakcijas maisījumu karsē pie 110 °C 24 h. Maisījumu atdzesē līdz istabas temperatūrai un filtrē caur celītu. Filtrātu koncentrē un atlikumu attīra hromatogrāfiski uz silikagela kolonas (eluents petrolēteris-etilacetāts, gradients no 4:1 līdz 1:1). Iegūst 0,663 g (89 %) 3-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)benzosulfonamīdu (5.1) kā bezkrāsainu cietu vielu. Ή NMR (DMSO-de, 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, J=l,2; 7,4 Hz, 1H), 7,59 (ddd, /=7,9; 7,4; 0,5 Hz, 1H), 1,32 (s, 12H), LCMS (ESI) m/z: 284,0 [M+H]+. Pēc metodes, kas analoģiska metodei D, iegūti sekojoši savienojumi:A mixture of 3-bromobenzenesulfonamide (2.1) (0.620 g, 2.63 mmol), KOAc (1.032 g, 10.52 mmol), and PdCl 2 (dppf) 2 (0.100 g, 0.137 mmol) in dioxane is bubbled with argon 10 min, add 6w (pinacolate) diborane (1.000 g, 3.94 mmol) to the reflux, close the reaction vessel and heat the reaction mixture at 110 ° C for 24 h. The mixture is cooled to room temperature and filtered through celite. The filtrate is concentrated and the residue is purified by chromatography on a silica gel column (eluent petroleum ether-ethyl acetate, gradient from 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. NMR (DMSO-d6, 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, J = 1.2, 7.4 Hz, 1H), 7.59 (ddd, J = 7.9, 7.4, 0.5 Hz, 1H), 1.32 (s, 12H), LCMS (ESI) m / z: 284.0 [M + H] +. By the method analogous to Method D, the following compounds were obtained:

Starpproduktu 6 sintēze, vispārīgā metode E Demonstrēta uz savienojuma 6.1 sintēzes piemēra: (3-(2-amino-6-metilpirimidin-4-il)benzosulfonamIds (6.1)Synthesis of Intermediate 6, General Method E Example: Synthesis of Compound 6.1: (3- (2-Amino-6-methylpyrimidin-4-yl) benzosulfonamide (6.1))

Pie 3-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)benzosulfonamīda (5.1) (0,030 g, 0,106 mmol) šķīduma dioksānā (3 ml) secīgi pievieno 2-amino-4-hlor-6-metilpirimidīnu (0,015 g, 0,105 mmol), Na2CC>3 (0,034 g, 0,321 mmol) un ūdeni (0,15 ml). Caur iegūto maisījumu barbotē argonu 10 min, tad maisījumam pievieno PdCh(dppf)2 (0,004 g, 0,005 mmol). Reakcijas trauku noslēdz un maisījumu karsē pie 100 °C 16 h. Maisījumu atdzesē līdz istabas temperatūrai un filtrē caur celītu. Filtrātu koncentrē un atlikumu attīra hromatogrāfiski uz silikagela kolonas (eluents: hloroforms-metanols, gradients no 100:5 līdz 90:10). Iegūst 0,014 g (50 %) of 3-(2-amino-6-metilpirimidin-4-il)benzosulfonamīdu (6.1). ’H NMR (DMSO-d6, 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, /=7,8; 1,7; 1,1 Hz, 1H), 7,69 (t, /=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]+. Pēc metodes, kas analoģiska metodei E, iegūti sekojoši savienojumi:2-amino-4 is added sequentially 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). Chlor-6-methylpyrimidine (0.015 g, 0.105 mmol), Na 2 CO 3 (0.034 g, 0.321 mmol) and water (0.15 mL). Argon is bubbled through the resulting mixture for 10 min, then PdCh (dppf) 2 (0.004 g, 0.005 mmol) is added to the mixture. The reaction vessel is sealed and the mixture heated at 100 ° C for 16 h. The mixture is cooled to room temperature and filtered through celite. The filtrate is concentrated and the residue is purified by chromatography on a silica gel column (eluent: chloroform-methanol, gradient from 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, / = 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 the method analogous to Method E, the following compounds were obtained:

Starpproduktu 7 sintēze:Synthesis of Intermediates 7:

a) Vispārīgā metode Fa) General method F

Demonstrēta uz savienojuma 7.1 sintēzes piemēra: (S)-ferr-butil (1 -(3 -(2-amino-6-metilpirimidin-4-il)fenilsulfamido)-4-metil-1 -oksopentan-2- il)karbamāts (7.1)An example of the synthesis of compound 7.1 has been shown: (S) -fert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate ( 7.1)

Iepriekšējā stadijā iegūto (<S)-terc-butil (4-metil-l-okso-l-(3-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)fenilsulfamido)pentan-2-il)karbamāta un (4.1) un (<S)-(3 -(N-(2-((terc-butoksikarbonil)amino)-4-metilpentanoil)sulfamoil)fenil)borskābes (4.1a) (0,600 g) maisījumu izšķīdina dioksānā (34 ml). Maisījumam pievieno 2-amino-4-hlor-6-metilpirimidīnu (0,174 g, 1,21 mmol), Na2C03 (0,385 g, 3,63 mmol), un ūdeni (1,7 ml). Caur iegūto maisījumu barbotē argonu 10 min un pievieno PdCk(dppf)2 (0,045 g, 0,061 mmol). Reakcijas trauku noslēdz un saturu karsē pie 110 °C 18 h. Maisījumu atdzesē līdz istabas temperatūrai un filtrē caur celītu. Filtrātu koncentrē un atlikumu (0,76 g) attīra hromatogrāfiski uz silikagela kolonas (eluents: hloroforms-metanols, gradients no 100:1 līdz 100:2). Iegūst 0,246 g (49,4 %, aprēķināts, izejot no 3.1) (S)-te/r-butil (l-(3-(2-amino-6-metilpirimidin-4-il)fenilsulfamido)-4-metil-l-oksopentan-2-il)karbamāta (7.1). !H NMR (DMSO-de) 5: 12,33 (b s, 1H), 8,58 (s, 1H), 8,31 (d, /=7,9 Hz, 1H), 7,97 (d, /=7,9 Hz, 1H), 7,71 (t, /=7,9 Hz, 1H), 7,08 (s, 1H), 7,01 (b s, 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, /=6,7 Hz, 3H), 0,78 (d, /=6,7 Hz, 3H). LCMS (ESI) m/z: 478,36 [M+H]+. Pēc metodes, kas analoģiska metodei F, iegūti sekojoši savienojumi:(<S) -tert-butyl (4-methyl-1-oxo-1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylphenamide) obtained in the previous step) pentan-2-yl) carbamate and (4.1) and (<S) - (3 - (N- (2 - ((tert-butoxycarbonyl) amino) -4-methylpentanoyl) sulfamoyl) phenyl) boric acid (4.1a) g) dissolving the mixture in dioxane (34 mL). To the mixture was added 2-amino-4-chloro-6-methylpyrimidine (0.174 g, 1.21 mmol), Na 2 CO 3 (0.385 g, 3.63 mmol), and water (1.7 mL). The resulting mixture is bubbled with argon for 10 min and PdCk (dppf) 2 (0.045 g, 0.061 mmol) is added. The reaction vessel is sealed and the contents heated at 110 ° C for 18 h. The mixture is cooled to room temperature and filtered through celite. The filtrate is concentrated and the residue (0.76 g) purified by chromatography on a silica gel column (eluent: chloroform-methanol, gradient from 100: 1 to 100: 2). Obtain 0.246 g (49.4%, calculated from 3.1) of (S) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl 1-Oxopentan-2-yl) carbamate (7.1). 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, (= 7.9 Hz, 1H), 7.71 (t, J = 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] +. Following the method analogous to Method F, the following compounds were obtained:

b) Vispārīgā metode Gb) General method G

Demonstrēta uz savienojuma 7.1 sintēzes piemēra: (S)-tert-butil (1 -(3-(2-amino-6-metilpirimidin-4-il)fenilsulfamido)-4-metil-1 -oksopentan-2- il)karbamāts (7.1)An example of the synthesis of compound 7.1 is shown: (S) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate ( 7.1)

Pie BOC-Z-leicīna monohidrāta (0,085 g, 0,34 mmol) šķīduma DMF (3,5 ml) istabas temperatūrā secīgi pievieno 3-(2-amino-6-metilpirimidin-4-il)benzosulfonamīdu (6.1) (0,090 g, 0,34 mmol), HBTU (0,129 g, 0,34 mmol), TEA (0,10 ml, 0,72 mmol) un katalītisku DMAP (0,004 g, 0,033 mmol) daudzumu. Reakcijas masu maisa istabas temperatūrā 72 h un ietvaicē vakuumā. Atlikumu (0,378 g) attīra hromatogrāfiski uz silikagela kolonas (eluents hloroforms-metanols, gradients no 100:2 līdz 90:10). Iegūst 0,100 g (61 %) (S)-terc-butil (1-(3-(2-amino-6-metilpirimidin-4-il)fenilsulfamido)-4-metil-l-oksopentan-2-il)karbamātu (7.1). Ή NMR (DMSO-de) δ: 12,33 (b s, 1H), 8,58 (s, 1H), 8,31 (d, /=7,9 Hz, 1H), 7,97 (d, /=7,9 Hz, 1H), 7,71 (t, /=7,9 Hz, 1H), 7,08 (s, 1H), 7,01 (b s, 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, /=6,7 Hz, 3H), 0,78 (d, /=6,7 Hz, 3H). LCMS (ESI) m/z: 478,36 [M+H]+. *H NMR (CDCb) δ: 9,57 (b s, 1H), 8,16 (t, /=l,8z, 1H), 8,00 (d, /=7,9 Hz, 1H), 7,75 (ddd, /=7,9; 1,8; 1,0 Hz, 1H), 7,40 (t, /=7,9 Hz, 1H), 4,70 (neatrisināts d, /=6,4 Hz, 1H), 4,06-3,92 (m, 1H), 1,70-1,52 (m, 3H), 1,44 (s, 9H), 0,91 (d, /=6,3 Hz, 3H), 0,87 (d, /=6,3 Hz, 3H). LCMS (ESI) m/z: 449,2 [M-H]’. Pēc metodes, kas analoģiska metodei F, iegūti sekojoši savienojumi:To a solution of BOC-Z-leucine monohydrate (0.085 g, 0.34 mmol) in DMF (3.5 mL) at room temperature was added 3- (2-amino-6-methylpyrimidin-4-yl) benzosulfonamide (6.1) successively (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 was stirred at room temperature for 72 h and evaporated in vacuo. The residue (0.378 g) is purified by chromatography on a silica gel column (eluent chloroform-methanol, gradient from 100: 2 to 90:10). Obtain 0.100 g (61%) of (S) -tert-butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate ( 7.1). 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, / = 7.9 Hz, 1H), 7.71 (t, J = 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, δ = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: 478.36 [M + H] +. 1 H NMR (CDCl 3) δ: 9.57 (bs, 1H), 8.16 (t, / = 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, / = 6.4 Hz, 1H), 4.06-3.92 (m, 1H), 1.70-1.52 (m, 3H), 1.44 (s, 9H), 0.91 (d, / = 6, 3 Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H). LCMS (ESI) m / z: 449.2 [M-H] -. Following the method analogous to Method F, the following compounds were obtained:

c) Starpprodukta OSVferc-butil (\-(3-( 2-hidroksipirimidin-4-illfenilsulfamido)-4-metil-1 -oksopentan-2-iDkarbamāta (7.161 sintēze(c) Intermediate OSVferc-butyl (- (3- (2-Hydroxypyrimidin-4-ylphenylsulfamido) -4-methyl-1-oxopentan-2-ylcarbamate (Synthesis of 7.161)

(S)-ter c-butil (1 -(3 -(2-hlorpirimidin-4-il)fenilsulfamido)-4-metil-1 -oksopentan-2-il)karba- māta (7.15) (0,189 g, 0,39 mmol) šķīdumam THF (2 ml) pievieno 1 N aq. NaOH (22 ml) un iegūto emulsiju maisa 55 °C 1,5 h. Maisījumu atdzesē līdz 0 °C un paskābina līdz pH 3-4, pievienojot aukstu 2 N aq. HC1 (11 ml). Nogulsnes filtrē, filtrātu ekstrahē ar (3 x 25 ml), un ekstraktu žāvē (N2SO4). Šķīdinātājus ietvaicē un atlikumu apvieno ar nogulsnēm un attīra hromatogrāfiski uz silikagela kolonas (eluents: hloroforms-metanols, 10:3). Iegūst 0,110 g (60,5 %) (<S)-ferc-butil (l-(3-(2-hidroksipirimidin-4-il)fenilsulfamido)-4-metil-l-oksopentan-2-il)karbamātu (7.16) kā putas. JH NMR (DMSO-de, HMDSO) δ: 12,38 (b s, 1H), 12,05 (s, 1H), 8,63 un 8,58 (s un s, kopā 1H), 8,40-8,28 (m, 1H), 8,10 (d, 7=6,3 Hz, 1H), 8,03 (d, 7=7,5 Hz, 1H), 7,71 (t, 7=7,7 Hz, 1H), 7,01 (d, 7=6,3 Hz, 1H), 6,85 un 6,53 (b s un b s, kopā 1H), 3,94-3,85 un 3,84-3,73 (m un m, kopā 1H), 1,66-1,18 (m, 3H), 1,28 (s, 9H), 0,80 (d, 7=6,2 Hz, 3H), 0,78 (d, 7=6,2 Hz, 3H). LCMS (ESI) m/z: 465.4 [M+H]+.(S) -ter c-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 were stirred at 55 ° C for 1.5 h. The mixture is cooled to 0 ° C and acidified to pH 3-4 with cold 2N aq. HCl (11 mL). The precipitate is filtered off, the filtrate is extracted with (3 x 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). Obtain 0.110 g (60.5%) of (β) -fert-butyl (1- (3- (2-hydroxypyrimidin-4-yl) phenylsulfamido) -4-methyl-1-oxopentan-2-yl) carbamate (7.16). ) as a foam. 1 H NMR (DMSO-d 6, HMDSO) δ: 12.38 (bs, 1H), 12.05 (s, 1H), 8.63 and 8.58 (s and s, total 1H), 8.40-8 , 28 (m, 1H), 8.10 (d, 7 = 6.3 Hz, 1H), 8.03 (d, 7 = 7.5 Hz, 1H), 7.71 (t, 7 = 7, 7 Hz, 1H), 7.01 (d, 7 = 6.3 Hz, 1H), 6.85 and 6.53 (bs and bs, total 1H), 3.94-3.85 and 3.84- 3.73 (m and m, total 1H), 1.66-1.18 (m, 3H), 1.28 (s, 9H), 0.80 (d, 7 = 6.2 Hz, 3H), 0.78 (d, J = 6.2 Hz, 3H). LCMS (ESI) m / z: 465.4 [M + H] +.

Produktu 8 sintēze, vispārīgā metode H Demonstrēta uz savienojuma 8.1 sintēzes piemēra: (S)-2-amino-N-((3-(2-amino-6-metilpirimidin-4-il)fenil)sulfonil)-4-metilpentānamīds (8.1)Synthesis of products 8, general method H Demonstrated on the synthesis of compound 8.1: (S) -2-Amino-N - ((3- (2-amino-6-methylpyrimidin-4-yl) phenyl) sulfonyl) -4-methylpentanamide ( 8.1)

(5)-ier/-butil (l-(3-(2-amino-6-metilpirimidin-4-il)fenilsulfaxnido)-4-metil-l-oksopentan-2-il)karbamātu (7.1) (0,246 g, 0,515 mmol) izšķīdina dihlormetānā, kas satur 5 % TFE (12 ml) un iegūto šķīdumu maisa istabas temperatūrā 2 h. Reakcijas maisījumu koncentrē vakuumā un eļļveidīgo brūno atlikumu (0,396 g) attīra, izmantojot Biotage purifikācijas sistēmu (CisHS 40+M kolona, eluents: ūdens - acetonitrils, gradients no 95:5 līdz 60:40). Iegūst 0,162 g (83 %) (1S)-2-amino-N-((3-(2-amino-6-metilpirimidin-4-il)fenil)sulfonil)-4-metilpentānamīdu (8.1) kā bezrāsainu kristālisku vielu, k.t. 241-242 °C (sad.). (DMSO-d6, HMDSO) δ: 8,50 (t, /=1,7 Hz, 1H), 8,05 (ddd, /= 7,8; 1,7; 1,2 Hz, 1H), 7,88 (ddd, .7=7,8; 1,7; 1,2 Hz, 1H), 7,67 (b s, 3H), 7,50 (t, /=7,8 Hz, 1H), 7,01 (s, 1H), 6,63 (s, 2H), 3,37-3,30 (m, 1H, pārklājas ar ūdeni), 2,31 (s, 3H), 1,73-1,60 (m, 1H), 1,58 (ddd, /=13,7; 8,4; 5,6 Hz, 1H), 1,38 (ddd, /=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]+. Elementanalīze: aprēķināts: C17H23N5O3S χ 0,09 CF3COOH (2,5 %) χ 1,12 H20 (4,9 %): C 50,59; H 6,26; N 17,17. Atrasts: C 50,59; H 6,32; N 17,23. Pēc metodes, kas analoģiska metodei H, iegūti sekojoši savienojumi:(5) - tert -Butyl (1- (3- (2-amino-6-methylpyrimidin-4-yl) phenylsulfaxido) -4-methyl-1-oxopentan-2-yl) carbamate (7.14) (0.246 g, 0.515 mmol) is dissolved in dichloromethane containing 5% TFE (12 mL) and the resulting solution is 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, gradient 95: 5 to 60:40). 0.162 g (83%) of (1S) -2-amino-N - ((3- (2-amino-6-methylpyrimidin-4-yl) phenyl) sulfonyl) -4-methylpentanamide (8.1) is obtained as a colorless crystalline substance. others 241-242 ° C (dec.). (DMSO-d6, HMDSO) δ: 8.50 (t, J = 1.7 Hz, 1H), 8.05 (ddd, δ = 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, 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, δ = 13.7; 8.4; 5.6 Hz, 1H), 1.38 (ddd, δ = 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: C 17 H 23 N 5 O 3 S χ 0.09 CF 3 COOH (2.5%) χ 1.12 H 2 O (4.9%): C 50.59; H, 6.26; N, 17.17. Found: C, 50.59; H, 6.32; N, 17.23. By the method analogous to method H, the following compounds were obtained:

Visi savienojumi raksturoti ar: a) 'H-KMR un atsevišķos gadījumos ar 13C-KMR spektru datiem. KMR veikta, izmantojot Varian Mercury spektrometru (400 MHz) ķīmiskās nobīdes (δ) dotas ppm (miļjonām daļām) pret iekšējo stanartu; b) ar LC/MS analīzēm, kas veiktas, izmantojot tandēma LC/MS spektrometru Water Acquity UPLC ar SQ masas-selektīvo detektoru; c) ar elementanalīzem; d) atsevišķos gadījumos ar kušanas temperatūrām.All compounds are characterized by: a) H-NMR and, in some cases, 13C-NMR spectra. The NMR was performed using the chemical shifts (δ) of the Varian Mercury spectrometer (400 MHz) given in ppm (parts per million) to the internal standard; b) LC / MS analysis performed using a tandem LC / MS Water Acquity UPLC with SQ-selective detector; c) by elemental analysis; d) in some cases with melting temperatures.

Savienojumu 8 fizikāli ķīmiskais raksturojumsPhysico-chemical characteristics of compounds 8

In vitro testiIn vitro test

Savienojumu antibakteriālā aktvitāte pārbaudīta in vitro kā to spēja inhibēt aminoacil-t-RNS sintetāzes (aaRS) atbilstoši sekojošai procedūrai.The antibacterial activity of the compounds was tested in vitro for their ability to inhibit aminoacyl-t-RNA synthetase (aaRS) according to the following procedure.

Izmantotās aaRSsUsed aaRSs

Leicil-, valil- un izoleicil-i-RNS sintetāzes (LRS, VRS un IRS, atbilstoši) no Escherichia coli (Eco) un Staphylococcus aureus (Sau).Leicyl, valyl and isoleicyl-i-RNA synthetases (LRS, VRS and IRS, respectively) from Escherichia coli (Eco) and Staphylococcus aureus (Sau).

Proteīnu ekspresija un attīrīšanaProtein expression and purification

Escherichia coli Ml 5 šūnas, kas transformētas ar plasmīdu pQE-60, vai pQE-70, un kas satur izvēlētās aaRS open-reading frame sekvenci, inducē ar 1 mM IPTG (izopropil /?-D-l-tiogalaktopiranozīdu) 3 h pie 37 °C. Bakteriālās šūnas savāc un lizē ar 20 mM NaH2P04 (pH 8.0) , 200 mM NaCl, 10 mM imidazola un proteāzes inhbitora kokteili (Roche). Patogēnās aaRS attīra ar niķeļa afinitātes standarta hromatogrāfiju. Proteīna koncentrāciju nosaka spektrofotometriski.Escherichia coli M1 cells transformed with plasmid pQE-60 or pQE-70 and containing the selected aaRS open-reading frame sequence are induced by 1 mM IPTG (isopropyl / D-thiogalactopyranoside) for 3 h at 37 ° C . Bacterial cells are harvested and lysed with 20 mM NaH 2 PO 4 (pH 8.0), 200 mM NaCl, 10 mM imidazole and protease inhibitor cocktail (Roche). Pathogenic aaRS is purified by standard nickel affinity chromatography. Protein concentration is determined spectrophotometrically.

In vitro f-RNS transkripcijaIn vitro f-RNA transcription

i-RNSLeu, /-RNSVal un f-RNSIle no E. coli un S. aureus transkripciju in vitro veic 4 h pie 37 °C, izmantojot T7 RNA polimerāzi. Transcripcijas reakcijai izmanto 40 mM Tra-HCl (pH 8.0) , 22 mM MgC12, 1 mM spermidīnu, 5 mM DTT, 0,01 % Tritonu Χ-100, 4 mM GTP, 4 mM ATP, 4 mM UTP, 4 mM CTP, 16 mM GMP, 250 μΜ T7 RNS polimerāzi un ar 150 pg BstNI apstrādātu plasmīdu. Pēc reakcijas beigām, maisījumu uznes uz 6 % poliakrilamīda 8 M unnvielas denaturējoša gela, lai attīrītu transkribēto f-RNS un aizvāktu piemaisījumus. Attīrīto ί-RNS kvanitificē ar Nanodrop 2000 (Thermo Scientifič). ICso noteikšanaIn-vitro transcription of i-RNALeu, / -RNAVal and f-RNSIle from E. coli and S. aureus is carried out for 4 h at 37 ° C using T7 RNA polymerase. 40 mM Tra-HCl (pH 8.0), 22 mM MgCl 2, 1 mM spermidine, 5 mM DTT, 0.01% Triton 100-100, 4 mM GTP, 4 mM ATP, 4 mM UTP, 4 mM CTP are used for the transcription reaction. 16 mM GMP, 250 µΜ T7 RNA polymerase and 150 µg BstNI treated plasmid. After completion of the reaction, the mixture is applied to a 6% polyacrylamide 8 M denaturing gel to purify transcribed f-RNA and remove impurities. The purified ί-RNA is quantified by Nanodrop 2000 (Thermo Scientifič). Determination of IC50

Aminoacil-t-RNS sintetāzes (aaRS) katalizētā reakcija notiek divās stadijās. Pirmajā stadijā aaRS aktivē tai atbilstošo aminoskābi ar ATP; un otrajā stadijā aktivētā aminoskābe tiek konjugēta ar t-RNA. So reakciju var aprakstīt sekojoši: [1] ARS + aa + ATP = ARS-aa-AMP + PPiThe aminoacyl-t-RNA synthetase (aaRS) catalyzed reaction occurs in two stages. In the first stage, the aaRS activates the corresponding amino acid with ATP; and in the second stage, the activated amino acid is conjugated to t-RNA. This reaction can be described as follows: [1] ARS + aa + ATP = ARS-aa-AMP + PPi

[2] ARS-aa-AMP + tRNS = aa-f-RNS + AMP + ARS (ARS, aminoacil-/-RNS sintetāze; aa, aminoskābe; ARS-aa-AMP, enzīms, kas saistīts ar aminoaciladenilātu; aa-t-RNS, aminoacil-t-RN S).[2] ARS-aa-AMP + tRNA = aa-f-RNA + AMP + ARS (ARS, aminoacyl - / - RNA synthetase; aa, amino acid; ARS-aa-AMP, enzyme linked to aminoacyladenylate; aa-t -RNA, aminoacyl-t-RN S).

Patogēnās aaRS aktivitāti monitorē, mērot ATP patērēšanas ātrumu, jo tas ir tieši proporcionāls aaRS aktvitātei. Ja pētāmais savienojums, pie 50 pM koncentrācijas inhibē aminoacilēšanas reakciju, samazinās ATP patēriņa ātrums, salīdzinājumā ar kontroles reakciju bez inhbitora pievienošanas. Tas ļauj noteikt inhibīcijas procentuālo īpatsvaru. Ja savienojuma procentuālais īpatsvars ir virs 80 %, tad nosaka IC50, izmantojot to pašu enzimātisko testu (komerciāls testa komplekts Kinase RR no BioThema AB, Sweden) pie dažādām inhibitora koncentrācijām. Zināmos LRS, VRS vai IRS inhibitorus izmanto kā testa pozitīvos standartus. IC50 aprēķinam izmanto nelineāro regresijas analīzi.Pathogenic aaRS activity is monitored by measuring ATP consumption rate as it is directly proportional to aaRS activity. If the test compound inhibits the aminoacylation reaction at a concentration of 50 pM, the rate of ATP consumption decreases compared to the control response without the addition of the inhaler. This allows to determine the percentage of inhibition. If the percentage of the compound is above 80%, the IC50 is determined using the same enzymatic assay (commercial test kit Kinase RR from BioThema AB, Sweden) at different inhibitor concentrations. Known LRS, VRS or IRS inhibitors are used as test positive standards. Non-linear regression analysis is used for IC50 calculation.

Dažu izvēlēto aminoacil t-RNS inhibitom IC50 vērtībasSome selected aminoacyl t-RNA inhibit IC50 values

i.a. - neaKtivs virs du μΜ Konceniracija; n.a.i.a. - eiKtivs above two μΜ Concession; n.a.

- nav noteiKts.- not specified.

Claims

1. A compound of the general formula I:

wherein A 1 is aryl; Q is a covalent bond or linker; A2 is aryl which is a linker; R1 and R2 are optionally substituted methylene; R3 and R4 are optionally substituted amino; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms and drug precursors.

A compound according to claim 1, wherein the aryl A 1 is any of the following substituents: A 1 is optionally substituted C 5-20 aryl; or AI is optionally substituted C5-2-heteroaryl; or AI is optionally substituted monocyclic C5-2-heteroaryl; or A 1 is optionally substituted C 2 -C 2 carboaryl; or AI is optionally substituted monocyclic C5-2-carboaryl; or AI is optionally substituted monocyclic C5-6 carboaryl; or AI is optionally substituted phenyl; or Al is C5-2oaryl derived from one of the following compounds: pyrimidine, pyridine, triazine, 9H-purine, furan, imidazole, naphthalene, quinoline, indole, benzimidazole, quinazoline.

A compound according to claim 1 or 2, wherein the AI is optionally substituted pyrimidyl having the formula:

> wherein: n is 0 to 3, and each RA is an independent substituent; or AI is optionally substituted pyrimidyl; Q is a covalent bond or linker; A2 is aryl which is a linker; R 1 and R 2 are methylene substituents; R3 and R4 are amino substituents and the following general formula is used for the compound:

wherein: n is 0 to 3; or n is 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 by a ring substituent, then it is arranged at any position; or n is 1 and the Ra group is in the 2'-position; or n is 2, one RA group is in the 4'-position, and the other RA group is in the 2'-position.

A compound according to claim 3 or 4, wherein the ring substituents RA include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, ß-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido, acetyl, nitro, sulfonamido- (unsubstituted, i.e., -SO2NH2), and phenyl.

A compound according to claim 1 or 2, wherein A 1 is optionally substituted imidazopyrimidyl of the general formula:

> wherein n is 0 to 3, and each RA is an independent substituent.

A compound according to claim 6, wherein A 1 is optionally substituted imidazopyrimidyl, Q is a covalent bond or linker; A2 is aryl which is a linking group; R 1 and R 2 are methylene substituents; R3 and R4 are amino substituents; and the connection has the following general font:

The compound of claim 7, wherein the ring substituents RA include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido, acetyl, nitro, sulfonamido- (unsubstituted, i.e., -SO 2 NH 2), and phenyl.

A compound according to claim 1 or 2, wherein: Al is optionally substituted 4-pyridyl with the general formula:

) wherein n is 0 to 4, and each RA is an independent substituent.

The compound of claim 9, wherein A 1 is optionally substituted 4-pyridyl, Q is a covalent bond or linker, A 2 is aryl, is a linking group, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino substituents, and for the compound has the following general formula:

Wherein: n is 0 to 4; or n is 0 to 3; or n is 0 to 2; justirOvail; 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 by a ring substituent, then they are positioned at any position; in one of the variants, n is 1 and one RA group is in the 2'-position; preferred cyclic substituents for RA include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy , methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido-, acetyl, nitro, sulfonamide (unsubstituted, ie SO2NH2) and phenyl.

The compound of claim 1 or 2, wherein A 1 is optionally substituted 2-pyridyl having the following general formula:

wherein n is 0 to 4, and each RA is an independent substituent.

A compound according to claim 12, wherein in one of the variants AI is optionally substituted 2-pyridyl, Q is a covalent bond or linker, A2 is aryl, which is a linking group, R1 and R2 are methylene substituents, R3 and R4 are amino groups substitutes and the compound has the following general formula:

wherein: n is 0 to 4; or n is 0 to 3; or n is 0 to 2; or n is 0 or 1; or n is 0 to 4; or n is 0 to 3; or n is 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 by a ring substituent R a, they are positioned at any position; one of the variants n is 0; or n is 1 and one RA group is in the 6'-position; or cyclic substituents, RA, include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, ß-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy -, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido- (unsubstituted, ie -CONH2), acetamido-, acetyl, nitro, sulfonamide (unsubstituted, ie -SO2NH2) and phenyl.

A compound according to claim 1 or 2, wherein A 1 is optionally substituted 1,3,5-triazinyl having the following general formula:

I wherein n is 0 to 2, and each RA is an independent substituent.

A compound according to claim 15, wherein A 1 is optionally substituted 1,3,5-triazinyl, Q is a covalent bond or linker, A 2 is aryl which is a linking group, R 1 and R 2 are methylene substituents, R 3 and R 4 are amino group substituents and the compound has the following general formula:

wherein: n is 0 to 2; or n is 0 to 1; justirOvail; 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 by a ring substituent R a, they are positioned at any position; or n is 0; or n is 1 and one RA group is in the 6'-position; cycle substitutes RA 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, ie -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 optionally substituted methylene.

A compound according to claims 1 to 17, wherein: A 2 is an aryl group which is a linking group, preferably optionally substituted with C 5-20 arylene; or A 2 is Optionally substituted C 1-6 heteroaryl orene: or A 2 is optionally substituted monocyclic C 1-10 heteroarylene; or A2 is optionally substituted monocyclic Cs-eheteroarylene; or A2 is optionally substituted C5-2 carboarylene; or A2 is optionally substituted monocyclic C5-2-carboarylene; or A2 is optionally substituted monocyclic C5-6carboarylene; or A2 is optionally substituted phenylene.

A compound according to claim 1 or claim 2, wherein: the phenylene group which is a linking group is in the ortho, meta, or paired position, optionally substituted with aryl substituents RB:

The compound of claim 20, wherein: Phenylene is meta-phenylene or para-phenylene; or phenylene is para-phenylene; or phenylene is meta-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; or m is 3; or m is 2; or m is 1; or m is 0.

The compound of claim 20 or 21, wherein the aryl substituents RB include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, ß-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 linker and A2 is a me-a-phenyleng group, the compound has the following general formula:

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

wherein the substituents R1-R4 include: fluoro, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, 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 the manufacture of a medicament or medical component for treating bacterial infections.