Macrolide derivatives, preparation thereof and therapeutic use thereof

The present invention relates to macrolide derivatives, and to the preparation and therapeutic use thereof. The compounds according to the present invention have substantial antimicrobial activity, mainly on gram-positive microorganisms, and also on mycobacteria, especially in the treatment of tuberculosis.

Due to the appearance of resistance, the development of novel antibacterial agents is necessary to make it possible to kill or to prevent the growth of mycobacteria, especially those which induce tuberculosis.

Tuberculosis is a disease which, at the present time, is still a worldwide health threat. Globally, a third of the human population is infected with Mycobacterium tuberculosis. Despite the fact that treatments exist and that the disease is curable, tuberculosis killed approximately 1 .82 million people in 2008, and its global incidence increases by 1 % per year, with an estimation in 2008 of 9.4 million annual new cases of declared disease. Added to this are the difficulties of correct prescription and of adherence to the treatment protocols, and also the emergence of multi-resistant strains of M. tuberculosis. Drug-drug interactions also interfere with the optimum treatment of AIDS and tuberculosis in the case of co-infected patients.

The common treatment protocols for combating sensitive strains of M. tuberculosis are mainly based on a combination of three or, more frequently, of four molecules: isoniazide (I NH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB). These drugs constitute the "first-line" treatment.

In recent decades, tuberculosis has become resistant to each of these molecules.

Strains that are resistant at least to isoniazide and to rifampicin are referred to as "multi-resistant" (MDR-TB). Recently, novel strains have appeared which are resistant to a larger number of molecules: those that are resistant to isoniazide, to rifampicin, to fluoroquinolones and to at least one injectable second-line drug are defined as being "ultra-resistant" (XDR-TB).

According to an estimation made by the WHO in 2009, there were 0.5 million cases of MDR-TB in 2007. Other evaluations report a relative incidence of about 1 1 % of multi-resistant strains among all new cases of tuberculosis.

Another therapeutic drawback in the treatment of tuberculosis is the interaction of rifampicin with treatments for combating HIV (human immunodeficiency virus), which represents an obstacle in the treatment of patients co-infected with tuberculosis and HIV. The current anti-HIV therapeutic recommendations favour, as a first-line treatment, an anti-retroviral triple therapy combining a protease inhibitor (PI ) or a non-nucleoside

reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors (NRTI). PI and NNRTI are metabolized by CYP3A4. Metabolic interactions between anti-retrovirals (ATRV) and certain combined drugs have been demonstrated. Thus, rifampicin, which is a powerful inducer of intestinal and hepatic CYP3A4, reduces the concentrations of ATRV.

There is an urgent need to develop improved therapies for combating tuberculosis. These novel anti-tuberculosis treatments should be capable of satisfying one or more of the following criteria:

• shorten the treatment time to improve the adherence to the treatment protocols and reduce the appearance of resistant bacteria,

• be well tolerated, acting via novel mechanisms of action and thus effective against multi-resistant and/or ultra-resistant strains,

• be active against tuberculosis.

• have a shortened latent tuberculosis (asymptomatic first infection) treatment time, so as to address the problem of the biological reservoir of M. tuberculosis.

FR 2 126 108 and Arnoux et al. (Journal of the American Chemical Society 102(10), 1980, 3605) describe sequanamycin (A), having the following formula:

(3S,4S,5R,7S,9S,10S,11 ,12S,13R)-12-[(4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-7-hydroxy-2-{1-[(5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]propan-2-yl}-10-[(3-hydroxy-6-methyl-4-oxotetrahydro-2 -/-pyran-2-yl)oxy]-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl) 3-methylbutanoate.

This compound is described therein as an antimicrobial agent and especially enables the treatment of tuberculosis. However, this compound may show instability, in particular in acidic or basic aqueous medium, and/or may also show metabolic instability, which makes it difficult to use as a drug.

It is therefore necessary to develop compounds with improved and/or more active pharmacokinetic properties, so as to enable their use as medicaments.

A subject of the present invention is in particular macrolide derivatives, which have bacteriostatic and/or bactericidal action, mainly on gram-positive microorganisms, and also on mycobacteria, especially against strains of sensitive Mycobacterium or Corynebacterium that are resistant to the first-line antibiotics, and the preparation and therapeutic uses thereof.

[COMPOUNDS]

The present invention relates to compounds corresponding to formula (I):

in which:

- Y represents a hydrogen atom, a group -(C=0)-NR2R3 or a group -(C=0)-0-Ri8;

- Z represents:

• a hydrogen atom,

• a group -C1-6-alkyl, which is unsubstituted or substituted with one or more groups R4,

· a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -NH- (C=0)-Ri 9 or with a group -NH-SO2-R20.

• a group -Cs-e-heterocycloalkyl,

• a group -NH-(C=0)-R5;

Ri represents a hydrogen atom, a group -C2-6-alkenyl, a group -C2-6-alkynyl or a group -C-j-6-alkyl which is unsubstituted or substituted with a group -C-|-4-fluoroalkyl or with a heteroaryl group which is unsubstituted or substituted with a group 3-(3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5-ylmethyl;

R2 represents a hydrogen atom or a group -Ci_6-alkyl;

R3 represents:

• a group -C3_7-cycloalkyl, which is unsubstituted or substituted with a group -C-i-3-alkyl substituted with a group -NH-SO2-R21 ,

• a heteroaryl group,

• a linear or branched group -Ci_6-alkyl, which is unsubstituted or substituted with a group chosen from:

• a group -NH-Re,

• a group -NH-SO2-R7,

• a group -NH-(C=0)-Rs,

• a group -C3_7-cycloalkyl, which is unsubstituted or substituted with a group -C3.6-heterocycloalkyl,

• a group -C3_6-heterocycloalkyl,

• an aryl group, which is unsubstituted or substituted with one or more groups chosen independently from a halogen atom and a group -C-|-4- fluoroalkyl,

• a heteroaryl group, which is unsubstituted or substituted with a group -C-i-3-alkyl, a group -C-|_4-alkoxy, a group -C-j-4-fluoroalkyl or a group

-C3-6-heterocycloalkyl,

• or alternatively with one or more groups -Ci-4-alkoxy;

or alternatively R2 and R3, together with the nitrogen atom to which they are attached, constitute a group -C3-6-heterocycloalkyl chosen from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; the said heterocycloalkyl group being unsubstituted or substituted with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group

-C-i-4-fluoroalkyl;

R4 independently represents a group chosen from:

a hydroxyl group,

a deuterium,

a halogen atom,

a group -Cs-z-cycloalkyl,

an aryl group, which is unsubstituted or substituted with one or more groups

-R9,

a heteroaryl group,

a group -C3..6-heterocycloalkyl,

a group -Ci -4-alkoxy,

a group -(C=O)-NH-R10,

a group -NH-R-n ,

a group -NH-(C=0)-R-|2,

or a group -N H(S02)- i 3;

R5 represents a heteroaryl group;

Re represents a heteroaryl group, which is unsubstituted or substituted with one or more halogen atoms;

R7 represents a group -Ci-4-fluoroalkyl, an aryl group or a heteroaryl group, the said aryl and heteroaryl groups being unsubstituted or substituted with one or more groups Ry;

RQ represents a heteroaryl group, which is unsubstituted or substituted with one or more groups R?;

Rg represents a halogen atom, a group -Ci -4-alkoxy, a formyl group (CHO) or a group -C-i- -alkyl, which is unsubstituted or substituted with a hydroxyl group; R-i o represents a heteroaryl group, which is unsubstituted or substituted with a group -C-i-3-alkyl;

R-1 1 represents:

• a group -C3_i o-heterocycloalkyl, which is unsubstituted or substituted with one or more oxide groups,

• a heteroaryl group or an aryl-Ci_4-alkyl group, the said heteroaryl or aryl groups being unsubstituted or substituted with one or more groups independently chosen from a halogen atom, a hydroxyl group, a nitro group and a group -C-i-3-alkyl;

- -12 represents:

• a group -Ci -4-alkoxy,

• a group -Ci -4-alkyl, which is unsubstituted or substituted with a group -NR-14R-15 or with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group -C-i-3-alkyl,

· a heteroaryl group, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a group -Ci-3-alkyl;

- R-13 represents:

• a group -Ci -4-alkyl,

• a group -Ci -4-fluoroalkyl,

· an aryl group, which is unsubstituted or substituted with a nitro group,

• or a heteroaryl group, which is unsubstituted or substituted with a group

-N R16R1 7;

- R-14, R-15, R-I 6 and R-| 7 each independently represent:

• a hydrogen atom,

· or a group -Ci-4-alkyl;

R-I 3 represents a group -C-| 4-alkyl or a benzyl group;

R-I 9 represents an aryl group or a heteroaryl group;

- R20 represents a group -Ci -4-alkyl or an aryl group;

- R21 represents an aryl group;

- Ry represents:

• a halogen atom,

• a group -Ci -4-alkoxy,

• a group -C-| .4-fluoroalkyl,

• a group -OCF3,

• a nitro group,

• a group -NH2,

• a group -NHCH3;

- F¾' represents:

· a hydroxyl group,

• a group -Ci-6-alkyl.

The compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or acid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids, for example for purifying or isolating the compounds of general formula (I), also form part of the invention.

The compounds of formula (I) according to the present invention also comprise those in which one or more hydrogen, carbon or halogen atoms, especially chlorine or fluorine atoms, have been replaced with their radioactive isotopes, for example deuterium or tritium to replace hydrogen or carbon-14 to replace carbon-12. Such labelled compounds are useful in research, metabolism or pharmacokinetic studies, and also in biological and pharmacological tests as tools.

In the context of the present invention:

• a Iky I represents a saturated, linear or branched aliphatic group; for example, a group

C-i-3-alkyl represents a linear or branched carbon-based chain of 1 to 3 carbon atoms, especially a methyl, ethyl, propyl or isopropyl. Similarly, a group C- -alkyl represents a linear or branched carbon-based chain of 1 to 4 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or ferf-butyl. Similarly, a group Chalky! represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, pentyl, isopentyl, neopentyl, ferf-pentyl, hexyl or isohexyl.

alkenyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a double bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned include the vinyl and allyl groups. alkynyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a triple bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned include the ethynyl and 2-propynyl groups.

cycloalkyl represents a saturated cyclic aliphatic group comprising from 3 to 7 carbon atoms. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

halogen represents a fluorine, chlorine, bromine or iodine atom.

fluoroalkyi represents an a Iky I group comprising from 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced with a fluorine atom. Examples of fluoroalkyi groups that may be mentioned include trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,3,3-tetrafluoropropyl, 1 , 1 -difluoroethyl and 3,3,3-trifluoro-2-(trifluoromethyl)propyl.

heterocycloalkyl represents a saturated or partially saturated, monocyclic or polycyclic, optionally substituted 3- to 9-membered ring including one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. The sulfur atoms may be in the form of sulfoxide or sulfone. By way of example, a heterocycloalkyl may be a pyrrolidine, a morpholine, a piperazine, a diazetidine, a dihydropyrrolidine, a piperidine, an azepane, an imidazolidine, a thiomorpholine, a tetrahydropyran, a tetrahydrothiophene, a tetrahydrothiopyran, a diazepane or an azabicyclooctane, a tropane, a 3,6-diazabicyclo[3.1 .0]hexane, a tetrahydrofuran, a 3,7-diazabicyclo[3.3.1 ]nonane or a tetrahydrothiophene 1 , 1 -dioxide.

aryl represents a monocyclic or polycyclic, optionally substituted aromatic system comprising from 6 to 14 carbon atoms. According to one embodiment of the invention, the aryl group comprises 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of aryl groups that may be mentioned include phenyl, naphthyl, indanyl, tetrahydronaphthyl, anthracenyl and azulenyl.

heteroaryl represents a monocyclic or polycyclic, optionally substituted 5- to 14-membered aromatic system. According to one embodiment of the invention, the heteroaryl is 5- to 10-membered and comprises one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of monocyclic heteroaryls that may be mentioned include

thiazole, thiadiazole, thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine. Examples of polycyclic heteroaryls that may be mentioned include indole, benzofuran, benzimidazole, benzothiophene, benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine, quinoxaline, naphthyridine,

2,3-dihydro-1 H-indole, 2 , 3-d i hyd robenzofu ra n , tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinazoline, furo[3,2-c]pyridine, 1 H-pyrrolo[2,3- b]pyridine or tetrahydroquinazoline.

• alkoxy represents a group O-alkyI containing a saturated, linear or branched aliphatic chain comprising 1 to 4 carbon atoms. Examples of alkoxy groups that may be mentioned include methoxy and ethoxy.

According to the present invention, distinguished compounds are those of formula (I) in which Y re resents a group -(C=0)- R2R3, of formula:

in which R-i , R2, R3 and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are also those of formula (I) in which Y represents a hydrogen atom, of formula:

in which and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a first variant of formula (IA), R2 represents a hydrogen atom and R3 represents a linear Ci 6-alkyl (Alk), which is unsubstituted or substituted with a group as defined for the compounds of formula (I), the compounds then having the formula (IC) below:

in which Ri and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

Within the compounds of formula (IC), distinguished compounds are those formula (I D) below in which Alk represents a methyl substituted with a phenyl group:

and Ri and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a second variant of formula (IA), distinguished compounds are those of formula (I E) in which R2 represents a hydrogen atom and R3 represents a branched Ci-6-alkyl (-C(CH3)2-Alk'), which is unsubstituted or substituted with a group as defined for the compounds

and Ri and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

Within the compounds of formula (I E), distinguished compounds are those of formula (IG) below in which Alk' represents a [(phenylsulfonyl)amino]methyl group:

and Ri and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

According to a third variant of formula (IA), R2 and R3 represent an unsubstituted group -Ci-6-alkyl (Alk), the compounds then having the formula (I F) below:

in which R-i and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a fourth variant of formula (IA), f¾ represents a hydrogen atom and

R3 represents an unsubstituted group -C3-7-cycloalkyl (cycloAlk), the compounds then having the form

in which Ri and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are also those of formula (I) in which Y represents a group -(C=0)-OR-i8, of formula:

in which R-| , R-| 8 and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are those of formula (I) in which:

- Y represents a hydrogen atom, a group -(C=0)-NR2R3 or a group -(OO)-OMe;

- Z represents:

• a hydrogen atom,

• a group -C-|_6-alkyl, which is unsubstituted or substituted with one or more groups R4,

• a cyclopropyl group, a cyclobutyl group, a 3-(benzoylamino)cyclobutyl group, a 3-[(pyrazin-2-ylcarbonyl)amino]cyclobutyl group, a 3-[(methylsulfonyl)amino] cyclobutyl group, a 3-[(phenylsulfonyl)amino]cyclobutyl group, a cyclopentyl group, a cyclohexyl group,

• a tetrahydro-2H-pyranyl group,

• a group -NH-(C=0)-R5;

Rl represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted with a 1 ,2,3-triazole group substituted with a 3-(3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5-ylmethyl group;

R2 represents a hydrogen atom or a methyl group;

R3 represents:

• a cyclohexyl group, a 1 -{[(phenylsulfonyl)amino]methyl}cyclohexyl group or a 1-{[(phenylsulfonyl)amino]methyl}cyclopentyl group,

• a 5,6,7,8-tetrahydroquinolin-5-yl group,

• or a linear or branched group C-i-4-alkyl, which is unsubstituted or substituted with a group chosen from:

-NH-Re,

• -NH-SO2-R7,

-NH-(C=0)-R8,

a 1 -morpholin-4-ylcyclopentyl group,

a tetrahydro-2H-pyranyl group, a tetrahydrofuranyl group or a morpholin-4-yl group,

• a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a chlorine atom and a group -CF3,

• a 1 H-pyrrolo[2,3-b]pyridinyl group, a 4-methyl-5, 6.7,8- tetrahydroquinazolin-2-yl group, a 6-methoxy-1 H-benzimidazol-2-yl group, a pyridinyl group, which is unsubstituted or substituted with a group -CF3 or with a morpholin-4-yl group,

• or alternatively with one or more methoxy groups;

or alternatively f¾ and R3, together with the nitrogen atom to which they are attached, constitute a -C3-6-heterocycloalkyl group chosen from: azetidine, morpholine, 4-[5-(trifluoromethyl)pyridin-2-yl]piperazine;

R4 independently represents a group chosen from:

• a hydroxyl group,

• a deuterium,

• a fluorine atom,

• a cyclopropyl group,

• a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a fluorine atom, a methoxy group, a -CH2OH group and a -CHO group,

• a pyridyl group,

• a morpholinyl group, a tetrahydro-2H-pyranyl group,

• a methoxy group,

• a group -(C=O)-NH-R10,

• a group -NH-R11 ,

• a group -NH-(C=0)-R-|2,

• or a group - H(S02)- i 3;

R5 represents a pyridyl group;

R6 represents a quinolyl group, the said quinolyl group being unsubstituted or substituted with a chlorine atom;

Rj represents a -CF3 group, a phenyl, pyridyl, pyrazolyl, 1 H-pyrrolo[2,3-b]pyridyl or indolyl group, the said phenyl, pyridyl, pyrazolyl, 1 H-pyrrolo[2,3-b]pyridyl or indolyl groups being unsubstituted or substituted with one or more groups Ry;

RQ represents a pyrazinyl group, the said pyrazinyl group being unsubstituted or substituted with one or more groups ?;

R-io represents a 1 ,8-naphthyridinyl group substituted with a methyl group;

- Ri i represents a tetrahydrothiophene-1 ,1 -dioxide, quinolyl, pyridyl or benzyl group, the said quinolyl, pyridyl or benzyl groups being unsubstituted or substituted with a chlorine atom, a hydroxyl group, a nitro group or a methyl group;

- Ri2 represents:

• a tert-butoxy group,

• a group -C-i-4-alkyl, which is unsubstituted or substituted with a group chosen from a group -NR14R15, pyridyl or pyrazolyl, the said pyridyl or pyrazolyl groups being unsubstituted or substituted with a methyl group,

· a pyrazinyl or pyridyl, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a methyl group;

- R-1 3 represents:

• a group -CF3,

• a phenyl group, which is unsubstituted or substituted with a nitro group, · or a pyridyl group, which is unsubstituted or substituted with a group -NR16 17;

- R-14, R-15, R-I 6 and R17 each independently represent:

• a hydrogen atom,

• a methyl group or an isopropyl group;

- Ry represents:

· a fluorine atom, a chlorine atom,

• a methoxy group,

• a group -CF3,

• a group -OCF3,

• a nitro group,

· a group -NH2,

• a group -NHCH3;

- R2' represents:

• a hydroxyl group,

• a methyl group;

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are those of formula (I) in which:

- Y represents a hydrogen atom or a group -(O0)-NR2R3;

- Z represents:

· a hydrogen atom,

• a methyl group, an isopropyl group, a 2,2-dimethylpropyl group,

• a group CD3,

• a 2-fluoroethyl group,

• a cyclopropylmethyl group,

· a 2-phenylethyl group,

• a [(7-methyl-1 ,8-naphthyridin-2-yl)amino]-4-oxobutyl group,

• a 2-{[(2-nitrophenyl)sulfonyl]amino}ethyl group,

• a cyclopropyl group,

• a tetrahydro-2H-pyranyl group;

- Ri represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group;

R2 represents a hydrogen atom or a methyl group;

- R3 represents:

• a methyl group,

· a 2-{[(2,6-difluorophenyl)sulfonyl]amino}-1 ,1-dimethylethyl group,

• a 1 ,1-dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl group,

• a 2-{[(2-fluorophenyl)sulfonyl]amino}-1 ,1 -dimethylethyl group,

• a 1 ,1-dimethyl-2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group,

• a 1 ,1-dimethyl-2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group, · a 2-methyl-1 -[(phenylsulfonyl)amino]propan-2-yl group,

• a 2-methyl-1 -{[(5-nitro-1 H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl group,

• a 2-methyl-1 -{[(trifluoromethyl)sulfonyl]amino}propan-2-yl group,

• a 2-methyl-1 -{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl group,

• a 1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl group, · a 1 ,1-dimethyl-2-morpholin-4-ylethyl group,

• a benzyl group,

• a 2-(4-pyridyl)ethyl group;

in the form of bases or of acid-addition salts.

Among the compounds according to the invention, mention may be made especially of the compounds below:

• (2R,3S,4R,5R,7S,9S,10S,11 !12S,13R)-7-[(benzylcarbamoyl)oxy]-2-(1 - {[(2R.3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy- -(methoxyimino)-6-methyltetrahydro- 2H-pyran-2-yl]oxy}-3,5!7,9,11 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5S,7R)-2!4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R!3S,4R!5R,7S,9S,10S!1 1 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-2- (1 {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yljoxyJpropan^-y -I O-l S^R^RJ-S-hydroxy^- methoxyimino^e-methyltetrahydro- 2H-pyran-2-yl]oxy}-3I5,7,9!11 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5R!7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S.4R,5R,7S,9S.10S,11 R,12S,13R)-12-{[(2S.7R)-4-cyclopropyl-2,5-dimethyl-1 ,4- oxazepan-7-yl]oxy}-2-(1 -{[(2R 3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1 -{[(5-hydroxypyrazin-2- yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-3,5,7,9,11 ,13-hexamethyl- 6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R!3S,4R!5R,7S!9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S!5R,7R)- 2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R!4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3.5J,9,11 ,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 RI12S,13R)-2-(1-{[(2RI3R,4R,5R!6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3RI6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-6,14-dioxo-7-({[2-(pyridin^ -yl)ethyl]carbamoyl}oxy)-12-{[(2S.5S,7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S.4R,5RJS,9S.10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7RH- cyciopropyl-2!5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R!4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R!3S,4R!5R,7S!9S, 10S,1 1 R,12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S!7R)-2!5-dimethyl-4-(2H3)methyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R.3R,4R!5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R!3S,4R,5R,7S,9S, 10S,1 1 R,12S! 13R)-7-[(dimethylcarbamoyl)oxy]-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R 3-hydroxy-4-(met oxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4l5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R!5R,7S,9S, 105,1 1 R,12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S!7R)-2,5-dimethyl-4-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S, 10S,1 1 R,12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-(2-fluoroethyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5RJS,9S, 10S,1 1 R,12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-{4-[(7-methyl-1 ,8-naphthyridin-2-yl)amino]-4-oxobutyl}-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S, 10S,1 1 R,12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5.7.9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S, 10S,1 1 R,12S, 13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-

methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyitetrahydro-2H-pyran-2-yl]oxy}-7-{[(1 -{[(5-hydroxypyrazin-2- yi)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-3,5,7,9,11 ,13-hexamethyl- 6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S.4R,5RJS,9S.10S,11 R,12S,13R)-2-(1-{[(2R,3R!4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methylteirahydro-2H-pyran-2-yl]oxy}-3, 5,7,9,11 ,13- hexamethyl-7-{[(2-methyl-1-{[(5-nitro-1 H-pyrazol-4-yl)sulfonyl]amino}propan-2- yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-hydroxy-2-(1-{[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}- 3,5J,9,1 1 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 ,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-7-{[(2-methyl-1-{[(trifluoromethyl)sulfonyl]amino}propan-2- yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)- 1 ,4-oxazepan-7-yl]oxy}-7-hydroxy-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy- 6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14- dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R!5R,7S!9S,10S,11 R!12S!13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2- yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5RJS,9S,10S,11 ,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5J,9,11 ,13-

hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2- yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yi]oxy}oxacyclotetradecan-4-yi 3-methylbutanoate;

• (2R!3S,4R,5R,7S,9S,10S!1 1 R!12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3!4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(mGihoxyimino)-6-methylieirahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamet yl-7-[({2-methyl-1-[(p enylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14- dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R!3S,4R,5R,7S,9S,10SI11 R,12S,13R)-2-(1-{[(2R,3R,4R!5R!6R)-5-hydroxy-3,4- dimethoxy-6-methyitetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-7 ({2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14- dioxo-12-{[(2S,5R,7R)-2,4,5-trimeihyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 ,1 -dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R.6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2S,7R)-4- isopropyl-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-3,5J,9,1 I J S-hexamethyl-e.H- dioxooxacyclotetradecan^-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,5R,7R)-4-(cyclopropylmethyl)-2,5- dimethyl-1 ,4-oxazepan-7-yl]oxy}-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R!5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,7R)-4-(cyclopropylmethyl)-2,5- dimethyl-1 ,4-oxazepan-7-yi]oxy}-7-[({1 ,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl} carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14- dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5RJS,9S,10S,11 ,12S,13R)-7-[({1 ,1 -dimethyl-2-[(phenylsulfonyl)amino] ethyl}carbamoyl)oxy]-12-{[(2SJR)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1 ,4- oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R!6R)-5-hydroxy-3,4-dimethoxy-6- methy!tetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4- (meihoxyimino)-6-methylteirahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14- dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S!11 R,12S,13R)-12-{[(2S!5S,7R)-4-(cyclopropylmethyl)-2,5- dimethyl-1 ,4-oxazepan-7-yl]oxy}-7-[({1 ,1-dimeihyl-2-[(phenylsulfonyl)arnino]ethyl} carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R!6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro -2H-pyran-2-yl]oxy}-1-meihylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro^H-pyran^-ylloxyi-S^J^J I JS-hexamethyl-e,^- dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S!11 R!12S,13R)-7-[({1 ,1 -dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,5R,7R)-4-(2,2-dimethylpropyl)- 2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R.3S.4R.5R,7S,9S.10S,11 R,12S,13R)-7-[({1.1 -dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5- dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R!6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3.5.7,9,11 .13-hexamethyl-6.14- dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-{[(1 ,1 -dimethyl-2-morpholin-4- ylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14- dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3- methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-{[(2-{[(2,6-difluorophenyl)sulfonyl]amino}- 1 ,1 -dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R!6R)-5-hydroxy-3,4-dimethoxy- 6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14- dioxo-12-{[(2S,7R)-2!4!5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3- methylbutanoate:

• (2R,3S R,5RJS,9S 10S,1 1 ,12S, 13R)-7-({[1 , 1 -dimethyl-2-({[4-(trif1uoromethyl) phenyl]sulfonyl}arnino)ethyl]carbamoyl}oxy)-2-(2-{[(2R!3R!4R!5R!6R)-5-hydroxy-3!4- dimethoxy-6-methylteirahydro-2H-pyran-2-yl]oxy}-1 -meihylethyl)-10-{[(2S,3R,6R)-3- hydroxy-4-(methoxyimino)-6-meihyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13- hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy} oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R!3S,4R!5R,7S!9S, 10S,1 1 R!12S, 13R)-7-{[(2-{[(2-fluorophenyl)sulfonyl]amino}-1 ,1 - dimeihylethyl)carbamoyl]oxy}-2-(2-{[(2R!3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-ylloxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4- (mGthoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3.5.7,9,1 1 , 13-hexamethyl-6,14- dioxo-12-{[(2S,7R)-2!4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3- methylbutanoate;

• (2R!3S,4R,5R,7S,9S, 10S!1 1 R!12S, 13R)-7-({[1 ,1 -dimethyl-2-({[2- (trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2- { R^R^R^R^RJ-S-hydroxy-S^-dimethoxy-e-methylteirahydro^H-pyran^-ylloxy}- 1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H- pyran-2-yl]oxy}-3, 5,7,9, 1 1 , 13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4- oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S, 10S,1 1 R,12S, 13R)-7-({[1 , 1 -dimethyl-2-({[4- (trifiuoromethoxy)phenyl]suifonyl}amino)ethyl]carbamoyl}oxy)-2-(2- {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}- 1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydrch2H^ pyran-2-yl]oxy}-3, 5,7,9, H . I S-hexamethyl-e.H-dioxo-^-i SJR^^.S-trimethyl-l ^- oxazepan-7-yi]oxy}oxacyciotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S, 105,1 1 R,12S, 13R)-7-[({1 , -dimethyi-2- [(phenylsuifonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)-10-({(2S,3R,6R)-3- hydroxy-6-methyl-4-[(2,2,2-trifiuoroethoxy)imino]tetrahydro-2H-pyran-2-yl}oxy)- 3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7- yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S,4R,5R,7S,9S, 10S,1 1 R,12S, 13R)-7-[({1 , 1 -dimethyi-2-[(phenylsulfonyl)amino] ethyl}carbamoyl)oxy]-10-{[(2S,3R,6R)-4-(ethoxyimino)-3-hydroxy-6-methyltetrahydro- 2H-pyran-2-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)-3,5,7,9,1 1 ,13-hexamethyl-6,14-

dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

in the form of bases or of acid-addition salts.

[PREPARATION]

[Nature of the strain]

The strain described in FR 2 126 108 deposited at the Northern Regional Research Laboratory (NRRL) under the number NRRL 3892 may be used.

The strain named Allokutzneria albata deposited at the Deutsche Sammlung Von Mikroorganismen und Zellkulturen GmbH (DSMZ) by the group Sanofi-Aventis (Sanofi Aventis Deutschland GmbH, Industriepark Hochst H831 , 65926 Frankfurt am Main) under the identification reference ST108942 may also be used.

[Fermentation and purification to isolate sequanamycin of formula (A)]

The fermentation and purification process described in FR 2 126 108 makes it possible to isolate sequanamycin of formula (A) from the strain Allokutzneria albata. This may be performed by application of the protocol below. This protocol is given as a non-limiting illustration: it may be adapted to other conditions.

Thus, the fermentation process described below was performed for 500 litres, but may be adapted for smaller or larger proportions.

The preculture medium (named "medium 5294") used is typically the following:

The pH of the medium before sterilization is 7.2.

The main culture medium (named "medium 5254-SeqOT) used is typically the following:

The fermentation process is typically as follows:

1 vial from the Banque de Cellules de Travail (BCT)

I

Step 1 : Preculture 1

500 μΙ_ of BCT were placed in a 300 ml conical flask comprising twice 100 ml of medium

5294. The mixture was stirred for 96 hours at 28 C.

I

Step 2: Preculture 2

25 ml of the culture medium from step 1 were placed in 4 times 500 ml of medium 5294 in a 2-litre conical flask, and the mixture was then stirred for 72 hours at 28 C.

I

Step 3: Preculture 3

1.5 L of the culture medium from step 2 were placed in 30 litres of medium 5294 in a 42-litre bioreactor, and the mixture was then stirred and aerated for 24 hours at 28 C, without monitoring the pH.

i

Step 4 (main culturing):

30 kg of the culture medium from step 3 were placed in 500 litres of medium 5294-Seq1 in an 800-litre bioreactor, and the mixture was then stirred and aerated for 96+5 hours at

28 C, without monitoring the pH.

I

Harvesting

The fermentation process described above was performed for 500 litres, but may be adapted for smaller or larger proportions. It was performed, for example, at a scale of 7000 litres as follows, using the same culture media:

Preculture 1 = 250 ml, inoculum: one vial of BCT.

Preculture 2 = 5 litres in flasks (2 * 2.5 litres), inoculum of 0.5% from preculture 1.

Preculture 3 = 400 litres of medium in a 600 litre bioreactor, seeding rate of 1.25% from preculture 2.

Main culture = 7000 litres of medium in a 10 000 litre bioreactor, seeding rate of 5.7% from preculture 3.

The fermentation process is followed by the purification process below (performed on the 500 litre fermentation broth described above).

Once the fermentation was complete, the fermentation broth was separated into culture supernatant and mycelium using a cylindrical seed grader. The separation led to about 440 litres of culture supernatant.

In separate batches, 100-120 litres of culture supernatant comprising, inter alia, the macrolide (sequanamycin (A)) were placed on a column filled with adsorption resin (glass column filled with styrene-divinyl benzene copolymer, inside diameter of 200, length of about 180 mm, flow rate of 250 ml/min). The resin was then washed with 30% 2-propanol.

The sequanamycin (A) was isolated by eluting the column with the following elution gradient: 30-70% B over 45 minutes, 70% B over 10 minutes, 100% B over 25 min; with A = H20, B = 2-propanol, modifier: 1 vol% NH4Ac 50 g/L adjusted to pH 7).

The fractions comprising the sequanamycin (A) were combined and the 2-propanol was evaporated off. The pH of the solution obtained was adjusted to above 7.5 and the solution was then extracted twice with EtOAc. The organic phases were combined and the solvents were evaporated off. The oil obtained (about 10 g per 100 litres of culture supernatant) was purified on silica gel (column of 40 mm x 260 mm), the column being eluted with an n-heptane to 30/70 n-heptane/EtOAc gradient over 45 minutes, followed by 30/70 n-heptane/EtOAc maintained for about 40 minutes (with a flow of 100 ml/minute). The monitoring of the purification may be performed by thin-layer chromatography, eluting with EtOAc and revealing the sequanamycins (in the form of blue spots) with a reagent such as vanillin.

According to the concentration of sequanamycin (A) in the individual 100 litre batches, about 2.5 to 3.5 g of sequanamycin (A) with a purity of 68-75% (determined by NMR) were obtained per batch.

If a higher purity is required, the sequanamycin (A) obtained may be repurified by reverse-phase chromatography on a WatersAtlantis machine with a 50x100 mm, 5 μ column. An elution gradient of H2O (A) and acetonitrile (B) and 1 vol% NH4Ac 50 g/L adjusted to pH 7 was used (40-60% B over 30 minutes, flow rate of 140 ml/min). The chromatography was monitored by a light-scattering electrical signal. The fractions comprising the sequanamycin (A) were combined and lyophilized after having evaporated off the acetonitrile. The sequanamycin (A) yield after this final purification step was 57%, with an 85% pure compound according to the NMR analyses.

The compounds of formula (I) according to the invention are prepared from sequanamycin of formula (A).

[Processes for preparing the compounds of formula (!) from sequanamycin of formula (A)]

In the steps described below, the usual organic chemistry reactions may be followed, especially those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Richard C. Larock, published by John Wiley & Sons Inc.

In the text hereinbelow, the term "protecting group PG" means a group that can, firstly, protect a reactive function such as a hydroxyl or an amine during the synthesis and, secondly, regenerate the intact reactive function at the end of the synthesis. Examples of protecting groups and also protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 4th Edition (John Wiley & Sons, Inc., New York), 2007.

In the text hereinbelow, the term "leaving group LG" means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and also references for their preparation are given in

Advanced Organic Chemistry, M.B. Smith and J. March. 6th Edition, Wiley Interscience, 2007, pp. 496-501 .

In accordance with the invention, the compounds of formula (I) in which Y represents a group -(C=0)-NR2R3 may be prepared according to the process characterized in that: a compound of formula (I), in which Y represents a hydrogen atom below:

and R1 and Z are as defined for the compounds of formula (I), is reacted with a compound of formula (I I) HN R2R3 in which R2 and R3 are as defined for the compounds of formula (I), in the presence of a carbonyl derivative and a base.

The introduction of a group Y representing a group -(C=0)-NR2R3 into the compounds of formula (I B) typically comprises the following four successive steps:

• a-1 ) protection of the hydroxyl functions of the compound of formula (I B),

• a-2) formation of a carbonyl intermediate from the hydroxyl function in position 7 of the macrocycle,

• a-3) reaction of the carbonyl intermediate with a compound of formula (II) HNR2R3,

• a-4) deprotection of the hydroxyl functions.

In step a-1 ), the hydroxyl functions of the compound of formula (I B) are protected to form a compound of formula (III) below, the hydroxyl function in position 7 of the macrocycle (onto which the group Y will be introduced) remaining free:

in which:

• Ri and Z are as defined for the compounds of formula (I);

• PGi and PG2 independently represent a hydroxyl-function protecting group.

In step a-2), the hydroxy I function in position 7 of the macrocycle of the compound of formula (II

· Ri and Z are as defined for the compounds of formula (I);

• LG represents a leaving group;

• PGi and PG2 independently represent a hydroxyl-function protecting group.

In step a-3), the carbonyl intermediate of formula (IV) is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I).

Step a-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), generally for 10 to 48 hours and at room temperature.

In step a-4), the hydroxy I functions of the compound obtained in step a-3) are deprotected.

Step a-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Plenum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.

As regards step a-1 ), the hydroxyl functions of compound (IB) are protected, for example, with acetate functions. This protection reaction may be performed by placing the compound of formula (I B) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at room temperature, the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (Il ia) below:

in which:

• R-i and Z are as defined for the compounds of formula (I).

In a first embodiment of step a-2), a compound of formula (I II) as defined above is reacted, for example, with 4-N,N-dimethylaminopyridine (DMAP) and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for example pyridine, in an a polar aprotic solvent, for example dichloromethane, at a temperature between -20 C and room temperature and for a time of between 5 and 30 hours, to form two carbon l intermediates of formulae (IVa) and (IVp) below:

in which:

• Ri and Z are as defined for the compounds of formula (I);

* PGi and PG2 independently represent a hydroxyl-function protecting group;

or

in which:

• Ri and Z are as defined for the compounds of formula (I);

• PGi and PG2 independently represent a hydroxyl-function protecting group, for example an acetate function.

In a second embodiment of step a-2), a compound of formula (III) is reacted, for example, with imidazole and diphosgene to form a carbonyl intermediate of formula (IVy) below:

in which:

• Ri and Z are as defined for the compounds of formula (I);

• PGi and PG2 independently represent a hydroxyl-f unction protecting group, for example an acetate function.

In a third embodiment of step a-2), a compound of formula (III) is reacted, for example, with diphosgene to form a carbonyl intermediate of formula (IV5) below:

in which:

• Ri and Z are as defined for the compounds of formula (I);

• PGi and PG2 independently represent a hydroxyl-f unction protecting group, for example an acetate function.

In particular, steps a-1 ), a-2), a-3) and a -4) may be performed simultaneously or in reverse order. Thus, for example:

a'-1 ) the hydroxyl functions of the compound of formula (IB) are protected, and a carbonyl intermediate is formed from the hydroxyl function in position 7 of the macrocycle by microwave heating of the compound of formula (IB) with, for example, Ν,Ν'-carbonyldiimidazole, in a solvent, for instance cyclohexane, and at a temperature of between 80 C and 100 C to obtain a compound of formula:

in which Z and Ri are as defined for a compound of formula (I);

a -2) the hydroxyl functions are deprotected by placing the compound of formula (XX) in contact with an acid, for instance hydrochloric acid, in a solvent, for instance tetrahydrofuran, to obtain a compound of formula:

(XXI)

in which Z and Ri are as defined for a compound of formula (I);

a'-3), the compound of formula (XXI) is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I).

Step a -3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), in the presence of a base, for instance 1 ,8-diazabicyclo[5.4.0]undec-7-ene, generally for 10 to 48 hours and at room temperature.

In accordance with the invention, the compounds of formula (I) in which Y represents a group -(C=0)-NR2R3 may also be prepared according to the process characterized in that:

in which:

• R-| , F¾ and R3 are as defined for the compounds of formula (I );

is reacted with an oxidizing agent to obtain a compound of formula (VI ):

in which:

R-i , R2 and R3 are as defined for the compounds of formula (I );

b-2) the compound of formula (VI ) thus obtained is reacted with a compound of formula (VI I):

ZN H2 (VI I)

in which Z is as defined for compound (I ), in the presence of a reducing agent, to obtain the expected compound of formula (I).

In step b-1 ), the oxidation of the compound of formula (V) is performed via the action of an oxidizing agent, for instance sodium penodate, in a polar solvent, for instance MeOH, and at a temperature of between 0 and 10 C.

In step b-2), the reaction of the compound of formula (VI ) with a compound of formula (VI I) takes place in the presence of a reducing agent, for instance sodium cyanoborohydride, in a slightly acidic medium, in a solvent such as MeOH .

In accordance with the invention, the compounds of formula (I) in which Y represents a hydrogen atom may be prepared according to the process characterized in that:

c-1 ) a compound of formula (VIII):

in which:

• Ri is as defined for the compounds of formula (I);

is reacted with an oxidizing agent to obtain a compound of formula (IX):

in which Ri is as defined for the compounds of formula (I);

c-2) the compound of formula (IX) thus obtained is reacted with a compound of formula (VII):

ZNH2 (VII)

in which Z is as defined for compound (I), in the presence of a reducing agent, to obtain the expected compound of formula (I).

Steps c-1 ) and c-2) are performed under the same operating conditions as those described in steps b-1 ) and b-2) above.

In accordance with the invention, the compounds of formula (I) in which Y represents a group -(C=0)-0-Ri8 may be prepared according to the process characterized in that:

a compou

(XXI)

in which Z and Ri are as defined for a compound of formula (I), is reacted with an alcohol of formula HO-R-is (XXII), in the presence of a base.

The reaction is performed in the presence of a mineral base, for instance potassium carbonate, at room temperature.

In particular, certain compounds of formula (I) may be prepared from other compounds of formula (I). Thus, for example, a compound of formula (I) in which Z = Me may be prepared from a compound of formula (I) in which Z = H , by reaction with formaldehyde in the presence of formic acid and in a solvent, for instance chloroform.

The compounds of formula (I) thus obtained may be subsequently separated from the reaction medium and purified according to standard methods, for example by crystallization or chromatography.

The compounds of formula (I) thus obtained are isolated in the form of the free base or of a salt, according to the standard techniques.

The compounds of formula (II) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (V) in which Y represents a group -(0=0)Ν[¾ί¾ are prepared by reacting a compound of formula (VIII):

in which Ri is as defined for the compounds of formula (I);

with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I), in the presence of a carbonyl derivative, according to the four steps below:

• d-1 ) protection of the hydroxyl functions of the compound of formula (VIII),

• d-2) formation of an activated intermediate by activation of the hydroxyl function in position 7 of the macrocycle,

• d-3) reaction of the activated intermediate with a compound of formula (II)

• d-4) optional deprotection of the hydroxyl functions.

In step d-1 ), the hydroxyl functions of the compound of formula (VIII) are protected to form a compound of formula (X) below (the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free):

in which:

• Ri is as defined for the compounds of formula (I);

• PG-i , PG2, PG3 and PG4 independently represent a hydroxyl-function protecting group.

In step d-2), a carbonyl intermediate is formed from the hydroxyl function in position 7 of the macrocycle of the compound of formula (X), especially one or more of the carbonyl intermediates of formula (XI) below:

in which:

• Ri is as defined for the compounds of formula (I);

• LG represents a leaving group;

• PGi , PG2PG3 and PG4 independently represent a hydroxyl-function protecting group.

In step d-3), the carbonyl intermediate obtained in step d-2) is reacted with a compound of formula (II) H N R2R3 in which R2 and R3 are as defined for the compounds of formula (I).

Step d-3) is typically performed in a polar solvent, for instance dimethylformamide

(DMF), generally for 10 to 48 hours and at room temperature.

In step d-4), the hydroxyl functions of the compound obtained in step d-3) are deprotected.

Step d-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Plenum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.

In a first embodiment of step d-1 ), the hydroxyl functions of compound (VIII) are protected, for example, with acetate functions. This protection reaction may be performed by placing the compound of formula (VII I) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at a temperature typically ranging from room temperature to 160 C, the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (Xa) below:

in which R-i is as defined for the compounds of formula (I).

In a second embodiment, step d-1 ) typically comprises the following three successive steps d-1-1 ), d-1-2) and d-1 -3):

- step d-1-1 ) the hydroxyl functions of the compound of formula (VIII) are protected with acyl imidazole functions to form a compound of formula (XII) by placing compound (VIII) in contact with 1 .Γ-carbonyldiimidazole in an a polar aprotic solvent, for example toluene, for a time from 10 minutes to 3 hours and at a temperature between room temperature and 80 C:

in which Ri is as defined for the compounds of formula (I).

The tertiary alcohol of mycarose reacts with the acylimidazole of the secondary alcohol at a to form the carbonate.

- step d-1 -2) the hydroxyl functions are deprotected by placing the compound of formula (XII) in contact with an acid, generally hydrochloric acid, in a polar aprotic solvent, for example tetrahydrofuran (THF), typically at room temperature and for a time from 2 to 24 hours, for example, to form the compound of formula (XIII) below:

in which R is as defined for the compounds of formula (I).

- step d-1 -3) the secondary hydroxyl functions of the compound of formula (XIII) are protected with acetate functions by placing the said compound in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, typically at room temperature and for a time from 5 to 48 hours, for example:

in which Ri is as defined for the compounds of formula (I).

In a first embodiment of step d-2), a compound of formula (Xa) as defined above is reacted with 4-N,N-dimethylaminopyridine (DMAP) and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for example pyridine, in an a polar aprotic solvent, for example dichloromethane, at a temperature between -20 C and 5 C for a time of between 30 minutes and 10 hours, and then at room

temperature for a time of between 5 and 30 hours, to form two carbonyl intermediates of formulae (XI a) and (ΧΙβ) below:

in which R-i is as defined for the compounds of formula (I).

In a second embodiment of step d-2), the compound of formula (XIV) is reacted, for example, with DMAP and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for example pyridine, to form two carbonyl intermediates of formulae (XV) and (XVI ) below:

and

in which Ri is as defined for the compounds of formula (I).

In a third embodiment of step d-2). a compound of formula (XIV) is reacted, for example, with 1 ,1 -carbonyldiimidazole to form a carbonyl intermediate of formula (XVII ) below:

(XVII)

in which R is as defined for the compounds of formula (I).

In a fourth embodiment of step d-2), a compound of formula (XIV) is reacted, for example, with diphosgene to form a carbonyl intermediate of formula (XVIII) below:

in which R-i is as defined for the compounds of formula (I).

The compounds of formula (VII) are commercially available, known or prepared according to methods known to those skilled in the art, and may be in salt form, such as the hydrochloride.

The compounds of formula (VIII) are prepared by reacting the sequanamycins (A) with a compound of formula (XIX) H2NOR1 in which Ri is as defined for the compounds of formula (I), in the presence of a base, for instance tnethylamine, if necessary. The reaction is performed in a solvent, for instance methanol.

The compounds of formula (XIX) are commercially available, known or prepared according to methods known to those skilled in the art, and may be in salt form, such as the hydrochloride.

The compounds of formula (XXI I) are commercially available, known or prepared according to methods known to those skilled in the art.

According to another of its aspects, a subject of the present invention is also the compounds of formulae (V) and (VIII). These compounds are useful as intermediates for synthesizing the compounds of formula (I).

Thus, a subject of the invention is compounds of formula (V):

in which:

• R-i , F¾ and F¾ are as defined for the compounds of formula (I).

A subject of the invention is also compounds of formula (VII I):

(VII I)

in which:

• F?i is as defined for the compounds of formula (I).

[Examples of preparation of the compounds of formula (I) from sequanamycin of formula (A)]

The following Examples describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention.

In the Preparations and in the Examples, the following abbreviations are used:

EtOAc: ethyl acetate

TLC: thin-layer chromatography

CHCI3: chloroform

DCM: dichloromethane

DMF: N,N-dimethylformamide

TEA: triethylamine

Nal04: sodium metaperiodate, sodium periodate

K2C03: potassium carbonate

MeOH: methanol

MgS04: magnesium sulfate

NaBH3CN: sodium cyanoborohydride

NaCI: sodium chloride

NaHC03: sodium bicarbonate

Na2S04: sodium sulfate

NH4CI: ammonium chloride

NH4Ac: ammonium acetate

THF: tetrahydrofuran

RT: room temperature

MATERIALS AND METHODS

The progress of the synthetic reactions is monitored by TLC. The plates are made of glass and are coated with Merck 60 F254 silica gel. After elution, the plates are observed under ultraviolet light at 254 nm and then revealed by spraying with a 5M sulfuric acid/water solution followed by heating.

The microwave reactions were performed using a Biotage Initiator 8 EXP microwave machine.

The products were purified, when necessary, on a Biotage SP-1 chromatograph or a Spot 2 chromatograph from Merck. The columns used are Merck 15-40 μηι silica columns (2.5 g to 400 g).

Analyses

Mass Spectrometry (MS):

Method a:

• The spectra were acquired on a Waters UPLC-SQD machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Chromatographic conditions:

• Column: Acquity BEH C18 - 1.7 pm - 2.1 x 50 mm.

• Solvents: A: H20 (0.1 % formic acid) B: CH3CN (0.1 % formic acid),

• Column temperature: 50 C,

• Flow rate: 1 ml/min,

• Gradient (2 min): from 5% to 50% B over 0.8 min; 1 .2 min: 100% B; 1 .85 min:

100% B; 1 .95: 5% B.

Method b:

• The spectra were acquired on a Waters UPLC-SQD machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Chromatographic conditions:

• Column: Acquity BEH C18 - 1.7 pm - 2.1 x 50 mm,

• Solvents: A: H20 (0.1 % formic acid) B: CH3CN (0.1 % formic acid),

• Column temperature: 50 C,

• Flow rate: 0.8 ml/min,

• Gradient (2.5 min): from 5% to 100% B over 1 .8 min; 2.40 min: 100% B; 2.45 min: 100% B; from 100% to 5% B over 0.05 min.

Method c:

• The spectra were acquired on a Waters ZQ machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Chromatographic conditions:

• Column: XBridge C18- 2.5 μνη - 3 x 50 mm,

• Solvents: A: H20 (0.1 % formic acid) B: CH3CN (0.1 % formic acid),

• Column temperature: 70 C,

• Flow rate: 0.9 ml/min,

• Gradient (7 min): from 5% to 100% B over 5.3 min; 5.5 min: 100% B; 6.3 min:

5% B.

Method d:

• The spectra were acquired on a Waters UPLC-SQD machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

· Chromatographic conditions:

• Column: Acquity BEH C18 - 1.7 pm - 2.1 x 50 mm,

• Solvents: A: H20 (0.1 % formic acid) B: CH3CN (0.1 % formic acid),

• Column temperature: 50°C,

• Flow rate: 1 ml/min,

· Gradient (5 min): from 5% to 100% B over 4.2 min; 4.6 min: 100% B: 4.8 min:

5% B.

Method e:

• The spectra were acquired on a Waters ZQ machine;

· Ionization: electrospray in positive and/or negative mode (ES+/-);

• Chromatographic conditions:

• Xselect C18 column 3.5 pm - 3 x 50 mm,

• Solvents: A: H20 (0.1 % formic acid) B: CH3CN (0.1 % formic acid),

• Column temperature: 60°C,

· Flow rate: 1 ml/min,

• Gradient (7 min): from 10% to 100% B over 4.5 min; 4.85 min: 100% B; 6.5 min: 10% B.

Method f:

· The spectra were acquired on an Agilent 6110 or Shimadzu 2010 machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Xtimate C18 column 2.1 X 30 mm, 3 μηι,

• Solvents: A: H20 (4L) + TFA ( .5 mL) B: CH3CN (4L) + TFA (0.75 ml_),

• Column temperature: 50°C,

• Flow rate: 1.2 ml/min,

• Gradient (2 min): from 10% to 80% B over 0.9 min; 1 .5 min: 80% B; 1.51 min:

10% B; 2 min: 10% B.

Method g:

• The spectra were acquired on a Shimadzu 2010 machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Merck RP-18e 2 X 25 mm column,

• Solvents: A: H20 (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 ml_), · Column temperature: 50 'C,

• Flow rate: 1.0 ml/min from 0 to 0.08 min; 1.5 ml from 0.08 to 1.50 min,

• Gradient (1 .50 min): from 0 to 0.08 min 5% B; from 5% to 95% B from 0.08 to 0.7 min; 1.10 min: 95% B; 1.11 : 5% B; 1 .5 min: 5% B.

Method h:

• The spectra were acquired on an Agilent 6110 or Shimadzu 2010 machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Xtimate C18 column 2.1 X 30 mm, 3 μηι,

• Solvents: A: H20 (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL), · Column temperature: 50 C,

• Flow rate: 1.2 ml/min,

• Gradient (2 min): from 30% to 90% B over 0.9 min; 1 .5 min: 90% B; 1.51 min:

30% B; 2 min: 30% B.

Method i:

• The spectra were acquired on an Agilent 6110 machine;

• Ionization: electrospray in positive and/or negative mode (ES+/-);

• Columns A: Durashell C18 2.1 X 30 mm, 3 μιτι; B: Xbrige RP18 2.1 X 50 mm, 5 pm,

· Solvents: A: H20 (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL),

• Column temperature: 50 C,

• Flow rate: 1.2 ml/min,

• Gradient (2 min): from 10% to 80% B over 0.9 min; 1 .5 min: 80% B; 1.51 min:

10% B; 2 min: 10% B.

1H Nuclear magnetic resonance (NMR)

The 1 H NMR spectra were recorded on a Bruker Avance spectrometer (300 MHz, 400 MHz, 500 MHz or 600 MHz) in deuterated DMSO. The chemical shifts are expressed in units δ (ppm) using tetramethylsilane (TMS) as internal reference. For the interpretation of the spectra, the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, dd = doubled doublet, ddd = doublet of doubled doublets, m = multiplet, ax. = axial, equat. = equatorial.

PREPARATION

Preparation of the intermediates for the examples described below:

Preparation 1 :

(2R,3S,4R,5R,7S,9S!10S,11 R,12S,13R)-12-{[(2R,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-7-hydroxy-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate.

12 g of sequanamycin (A) are placed in 175 ml of MeOH with stirring, and 5.3 ml of TEA, and 3 g of methylhydroxylamine hydrochloride are then added, in this order. The stirring is continued at RT for 20 hours and the MeOH is then evaporated off under vacuum. The crude reaction product is taken up in 150 ml of DCM and washed with 100 ml of water and then with 100 ml of saturated aqueous NaCI solution. The aqueous phases are extracted with 150 ml of DCM. The organic phases are combined, dried over MgS04, filtered and concentrated under vacuum. 12.7 g of the product obtained are suspended in 70 ml of a petroleum ether (40-60 C)/isopropanol mixture (2/1 ). The mixture is heated to 70 C, the insoluble matter is filtered off while hot and the product is then left to precipitate out at RT over 20 hours. It is filtered off by suction and rinsed with 20 ml of a petroleum ether (40-60 C)/isopropanol mixture (2/1 ). The precipitate is dried under vacuum at 35 C to give 10.62 g of expected product.

MS: method c

Retention time Tr (min) = 4.87; [M+Na]+: m/z 1014; [M-H+HC02H]-: m/z 1036. 1 H NMR spectrum (500 MHz, in ppm, DMSO-ds): 0.81 (d, J=6.8 Hz, 3 H); 0.93 to 1.01 (m, 15 H); 1.07 (d, J=7.0 Hz, 3 H); 1.09 to 1.13 (m, 9 H); 1.17 (d, J=6.0 Hz, 3 H);

1.18 (d. J=6.0 Hz, 3 H); 1 .24 (s, 3H); 1.44 (dd, J=10.8 and 14.4 Hz, 1 H); 1.68 to 1.76 (m. 2 H); 1 .81 (d, J=14.4 Hz, 1 H); 1.88 (dd, J=1 1.5 and 15.9 Hz, 1 H); 1.96 to 2.06 (m, 3 H); 2.07 to 2.20 (m, 4 H); 2.73 (quint, J=7.0 Hz, 1 H); 2.81 (t, J=9.0 Hz, 1 H); 2.89 to 2.97 (m, 2 H); 3.03 (ddd, J=2.5 and 7.3 and 9.5 Hz, 1 H); 3.18 (q, J =6.8 Hz, 1 H); 3.34 to 3.36 (m, 2 H); 3.37 (s, 3 H); 3.45 (s, 3 H); 3.52 (dq, J=6.2 and 9.4 Hz, 1 H); 3.60 (s, 1 H); 3.62 to 3.65 (m, 1 H); 3.66 (t, J=2.5 Hz, 1 H); 3.71 to 3.77 (m, 1 H); 3.78 (m, 1 H); 3.80 (s, 3 H); 3.81 to 3.84 (m, 1 H); 3.87 (m, 1 H); 4.39 to 4.46 (m, 3 H); 4.50 (s, 1 H); 4.72 (d, J = 8.3 Hz, 1 H); 4.78 (d, J=8.3 Hz, 1 H); 4.84 (d, J=7.3 Hz, 1 H); 4.87 (d. J=3.8 Hz, 1 H);

5.19 (d, J=4.4 Hz, 1 H).

Preparation 2: benzyl carbamate

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2R,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2/- -pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl

3-methylbutanoate.

Preparation 2.1 :

8.6 g of the compound obtained in Preparation 1 are placed in 86 ml of pyridine, and 8.27 ml of acetic anhydride are added. The mixture is stirred for 24 hours at room temperature, and the pyridine is then concentrated under vacuum. 150 ml of DCM are added and the resulting mixture is washed with 120 ml of 1 N HCI solution and then with 100 ml of saturated aqueous NaCI solution. The aqueous phases are extracted with 150 ml of DCM. The organic phases are combined, dried over Na2S04, filtered and then evaporated to dryness. 9.75 g of the expected product are obtained.

MS: method a

Retention time Tr (min) = 1 .27; [M+Na]+: m/z 1 140.

1 H NMR spectrum (400 MHz, in ppm, DMSO-d6): 0.81 (d, J=6.8 Hz, 3 H); 0.91 to 1.01 (m, 15 H); 1.02 (s, 3 H); 1.03 to 1.12 (m, 12 H); 1.21 (d. J=6.1 Hz, 3 H); 1.24 (s, 3 H); 1.50 (dd, J=10.5 and 14.5 Hz, 1 H); 1.72 to 1.94 (m, 6 H); 1.96 to 2.10 (m, 8 H); 2.12 to 2.18 (m, 3 H); 2.22 (s, 3 H); 2.77 (m, 1 H); 3.02 (dd, J=2.7 and 8.1 Hz, 1 H); 3.08 (m, 1 H);

3.16 (q, J=7.1 Hz, 1 H); 3.36 (m, 1 H); 3.39 (s, 3 H); 3.41 (s, 3H); 3.45 (m, 1 H); 3.63 to 3.72 (m, 2 H); 3.76 (broad s, 4 H); 3.80 (m, 1 H); 3.85 (t, J=2.7 Hz, 1 H); 4.1 1 (m, 1 H);

4.17 (s, 1 H); 4.35 (dd, J=2.7 and 10.3 Hz, 1 H); 4.42 (m, 2 H); 4.52 (d, J=8.1 Hz, 1 H); 4.63 (d, J=7.3 Hz, 1 H); 4.69 (d, J=9.0 Hz, 1 H); 4.75 (d, J=9.0 Hz, 1 H); 4.93 (d, J =

4.0 Hz, 1 H); 5.00 (d, J=7.3 Hz, 1 H).

Preparation 2.2:

1 g of the compound obtained in Preparation 2.1 are placed in 20 ml of pyridine in a microwave reactor, and 1 ml of acetic anhydride and 50 mg of 4-dimethylaminopyridine are added. The solution is heated for 2 hours at 155 C by microwave. The reaction medium is poured into 50 ml of DCM and washed with 30 ml of 1 N HCI solution and then with 30 ml of water. The aqueous phases are extracted with twice 50 ml of DCM. The organic phases are combined, dried over Na2S04, filtered and then evaporated to dryness under vacuum. The residue, 1.1 g of a brown foam, is purified by chromatography on a Merck cartridge (50 g of 15-40 μιη silica), eluting with a 40/60 EtOAc/heptane mixture. 0.69 g of the expected compound is obtained.

MS: method a

Retention time Tr (min) = 1 .29; [M+Na]+: m/z 1 182.

1 H NMR spectrum (500 MHz, in ppm, DMSO-d6): 0.81 (d, J=6.9 Hz, 3 H); 0.91 to

1.02 (m, 18 H); 1.06 (m, 6 H); 1.10 (d, J=6.9 Hz, 3 H); 1.19 to 1.26 (m, 6 H): 1.35 (s, 3 H); 1.44 (dd, J=10.5 and 14.5 Hz, 1 H); 1.79 (m, 1 H); 1.84 to 2.09 (m, 15 H): 2.1 1 to 2.18 (m, 6 H); 2.73 (m, 1 H): 3.02 (dd, J=2.7 and 7.8 Hz,1 H); 3.06 to 3.20 (m, 3 H); 3.35 to 3.42 (m, 8 H); 3.60 to 3.69 (m, 2 H); 3.77 (broad s, 4 H); 3.80 (m, 1 H); 3.85 (t, J=2.7 Hz, 1 H); 4.16 (m, 1 H); 4.36 (dd, J=2.7 and 9.9 Hz, 1 H); 4.48 to 4.53 (m, 3 H); 4.59 (d, J = 7.1 Hz, 1 H); 4.73 to 4.80 (m, 2 H); 4.87 (d, J=4.3 Hz, 1 H); 5.00 (d, J=7.1 Hz, 1 H).

Pre aration 2.3:

3.5 g of the compound obtained in Preparation 2.2 dissolved in 140 ml of DCM and 3.6 ml of pyridine are placed under argon with stirring. The yellow solution obtained is cooled to -10 C, followed by rapid addition of trichloromethyl chloroformate (diphosgene), and stirring is continued at -10 C for 3 hours. 0.368 g of 4-dimethylaminopyridine dissolved in 10 ml of DCM is then added. The reaction medium is maintained at -5' C for a further 30 minutes and is then allowed to warm to room temperature, and stirring is continued for 20 hours. The solvent is evaporated off and 150 ml of EtOAc are added to the crude reaction product. The mixture is stirred for 15 minutes at room temperature and the precipitate formed is then filtered off. It is rinsed with 70 ml of EtOAc and the filtrate is evaporated to dryness under vacuum. 3.92 g of a mixture of the expected compounds (structures 2.3. a and 2.3. b) are obtained. The mixture is used as obtained for the following stage.

Preparation 2.4:

a) Condensation of the amine (benzylamine)

1 .5 g of the compound obtained in Preparation 2.3 are placed in 30 ml of DMF in a 100 ml round-bottomed flask, and 0.61 ml of benzylamine are then added. The mixture is stirred for 24 hours at room temperature, followed by addition of 100 g of ice and 100 ml of water. The precipitate formed is filtered off by suction and washed with a minimum amount of water. After drying in an oven under vacuum at 35 C, 1.18 g of the expected compound are obtained.

b) Deprotection

1 .18 g of the compound obtained in the preceding step are placed in 20 ml of MeOH, and 0.63 g of K2C03 is added. The heterogeneous medium is stirred at room

temperature for 3 hours and then filtered through a No. 4 sinter funnel. The filtrate is taken up in 100 ml of EtOAc and washed with saturated aqueous NaCI solution. The organic phase is dried over MgS04, filtered and then evaporated to dryness. 1 .05 g of crude compound are obtained, which product is purified by chromatography on a Merck column (30 g of 15-40 μιη silica) with a 30/70 to 60/40 EtOAc/heptane elution gradient. 0.466 g of the expected product is obtained.

MS: method c

Retention time Tr (min) = 5.21 ; [M+H]+: m/z 1 125; base peak: m/z 981 [M-H+HC02H]-: m/z 1 169.

1 H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.80 (d, J=6.8 Hz, 3 H);

0.92 (d, J=6.8 Hz, 3 H); 0.96 to 1 .02 (m, 9 H); 1 .05 (m, 6 H); 1.08 to 1 .15 (m, 9 H); 1 .18 (m, 6 H); 1 .67 to 2.18 (m, 10 H); 1.73 (s, 3 H); 2.18 (d, J=6.8 Hz, 2 H); 2.59 to 2.67 (m, 1 H); 2.80 (t, J=8.8 Hz, 1 H); 2.92 (dd, J=2.7 and 8.1 Hz, 1 H); 2.94 to 3.06 (m, 3 H); 3.27 to 3.35 (partially masked m, 1 H); 3.38 (s, 3 H); 3.41 (d, J=9.Q Hz, 1 H); 3.45 (s, 3 H); 3.49 to 3.56 (m, 1 H); 3.60 to 3.72 (m, 4 H ); 3.80 (s, 3 H ); 3.82 (m, 1 H); 3.87 (broad d, J=5.4 Hz, 1 H); 4.01 to 4.17 (m, 3 H); 4.34 to 4.39 (m, 2 H); 4.45 (d, J=7.8 Hz, 1 H); 4.50 to 4.57 (m, 2 H); 4.85 (d, J=7.3 Hz, 1 H); 4.93 (d, J=2A Hz, 1 H); 5.13 (broad s, 1 H); 7.18 to 7.36 (m, 6 H).

Preparation 3:

Preparation 3.1 :

1 1.1 g of the compound prepared in Preparation 1 are placed in 220 ml of toluene. 9.07 g of 1 ,1 '-carbonyldiimidazole are added and the reaction medium is then heated at 60°C for 45 minutes. It is allowed to cool to room temperature and the precipitate is filtered off and washed with toluene. The toluene phase is washed with 100 ml of water and then dried over MgS04. After filtration, the solvent is evaporated off to dryness and 14.26 g of the expected product are recovered.

MS: method a

Retention time Tr (min) = 1.22; [M+H]+: m/z 1206; [M-H+HCOOH]-: m/z 1250.

1 H NMR spectrum (500 MHz, In ppm, DMSO-ds): 0.80 (d, J=6.8 Hz, 3 H);

0.83 (d, J=7.3 Hz, 3 H); 0.90 (d, J=6.8 Hz, 3 H); 0.98 (dt, J=3.2 and 6.4 Hz, 9 H); 1 .03 (d. J = 7.3 Hz, 3 H); 1.13 (d, J=6.8 Hz, 3 H); 1.16 (d, J=6.4 Hz, 3 H); 1.24 (t, J=2.9 Hz, 6 H);

1.29 (d, J=5.9 Hz, 3 H); 1.53 (m, 4 H); 1 .78 (m, 1 H); 1 .84 to 1.91 (m, 1 H); 1.98 (m, 1 H);

2.02 to 2.11 (m, 3 H); 2.16 (m, 3 H); 2.21 (m, 1 H); 2.34 (dd, J=5.9 and 14.2 Hz,1 H);

2.73 (dq, J=7.2 and 7.3 Hz, 1 H); 3.08 to 3.17 (m, 3 H); 3.38 (m, 1 H); 3.41 (s, 3 H);

3.44 (s, 3 H); 3.56 (d, J=5.9 Hz, 1 H); 3.66 to 3.74 (m, 5 H); 3.78 (ddd, J=2.9 and 6.0 and 1 1.6 Hz, 1 H); 3.96 (m, 1 H); 4.07 to 4.20 (m, 3 H); 4.39 (s, 1 H); 4.58 (m, 2 H); 4.63 (d,

J=9.3 Hz, 1 H); 4.76 (d, J=9.8 Hz, 1 H); 4.91 (s, 2 H); 5.22 (d, J=6.8 Hz, 1 H); 7.12 (d,

J=10.3 Hz, 2 H); 7.61 (d, J=1.5 Hz, 2 H); 8.29 (d, J=8.8 Hz, 2 H).

Preparation 3.2:

14.01 g of the compound obtained in Preparation 3.1 are placed in 140 ml of THF,

34.8 ml of 1 N HCI solution are added and stirring is continued for 24 hours at room temperature. The reaction medium is poured into 200 ml of DCM and washed with 100 ml of water and then with 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous phases are extracted with 200 ml of DCM, and the organic phases are combined, dried over Na2S04, filtered and then evaporated to dryness under vacuum. 1 1.48 g of the expected product are obtained.

CLAIMS

. Compound of formula (I):

in which:

Y represents a hydrogen atom, a group -(C=0)- R2R3 or a group -(C=0)-0-Ri 8; - Z represents:

• a hydrogen atom.

• a group -C-i-6-alkyl, which is unsubstituted or substituted with one or more groups R4,

• a group -C3_7-cycloalkyl, which is unsubstituted or substituted with a group -NH-(C=0)-Ri9 or with a group -NH-SO2-R20,

• a group -C3-6-heterocycloalkyl,

• a group -NH-(C=0)-Rs;

Ri represents a hydrogen atom, a group -C2-6-alkenyl, a group -C2-6-alkynyl or a group -Ci_6-alkyl which is unsubstituted or substituted with a group -C1-4- fluoroalkyl or with a heteroaryl group which is unsubstituted or substituted with a group 3-(3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5-ylmethyl;

R2 represents a hydrogen atom or a group -C-i-6-alkyl;

R3 represents:

• a group -C3_7-cycloalkyl, which is unsubstituted or substituted with a group

-C-i-3-alkyl substituted with a group -NH-SO2-R21.

• a heteroaryl group,

• a linear or branched group -C-i-6-alkyl, which is unsubstituted or substituted with a group chosen from:

• a group -NH-Re,

• a group -NH-SO2-R7,

• a group -NH-(C=0)-Rs,

• a group -C3_7-cycloalkyl, which is unsubstituted or substituted with a group -Cs-e-heterocycloalkyl,

• a group -C3-6-heterocycloalkyl,

• an aryl group, which is unsubstituted or substituted with one or more groups chosen independently from a halogen atom and a group -C-i-4-fluoroalkyl,

• a heteroaryl group, which is unsubstituted or substituted with a group -C-i-3-alkyl, a group -Ci-4-alkoxy, a group -Ci-4-fluoroalkyl or a group -C3_6-heterocycloalkyl,

• or alternatively with one or more groups -Ci-4-alkoxy;

or alternatively R2 and R3, together with the nitrogen atom to which they are attached, constitute a group -C3_6-heterocycloalkyl chosen from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; the said heterocycloalkyi group being unsubstituted or substituted with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group -Ci-4-fluoroalkyl:

R4 independently represents a group chosen from:

• a hydroxyl group,

• a deuterium,

• a halogen atom,

• a group -C3-7-cycloalkyl,

• an aryl group, which is unsubstituted or substituted with one or more groups -Rg,

• a heteroaryl group,

• a group -C3-6-heterocycloalkyl,

• a group -Ci-4-alkoxy,

• a group -(C=O)-NH-R 0,

• a group -NH-R11 ,

• a group -NH-(C=0)-Ri2,

• or a group -NH(SOi3)-Ri3;

R5 represents a heteroaryl group;

Re represents a heteroaryl group, which is unsubstituted or substituted with one or more halogen atoms;

R7 represents a group -Ci_4-fluoroalkyl, an aryl group or a heteroaryl group, the said aryl and heteroaryl groups being unsubstituted or substituted with one or more groups Rr;

R8 represents a heteroaryl group, which is unsubstituted or substituted with one or more groups R ;

Rg represents a halogen atom, a group -C-i -4-alkoxy, a formyl group (CHO) or a group -C-| -4-alkyl, which is unsubstituted or substituted with a hydroxyl group;

R-io represents a heteroaryl group, which is unsubstituted or substituted with a group -Ci_3-alkyl;

R11 represents:

• a group -C -i o-heterocycloalkyl, which is unsubstituted or substituted with one or more oxide groups,

• a heteroaryl group or an aryl-Ci _4-alkyl group, the said heteroaryl or aryl groups being unsubstituted or substituted with one or more groups independently chosen from a halogen atom, a hydroxyl group, a nitro group and a group -Ci-3-alkyl;

R-12 represents:

• a group -Ci-4-alkoxy,

• a group -Ci-4-alkyl, which is unsubstituted or substituted with a group -NR14R15 or with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group -C-i-3-alkyl,

• a heteroaryl group, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a group -Ci -3-alkyl;

R-13 represents:

• a group -Ci-4-alkyl,

• a group -Ci-4-fluoroalkyl,

• an aryl group, which is unsubstituted or substituted with a nitro group,

• or a heteroaryl group, which is unsubstituted or substituted with a group

-N 16 17;

R-I4, R-| 5, R-I6 and R17 each independently represent:

• a hydrogen atom,

• or a group -C-i-4-alkyl;

R-I 8 represents a group -Ci 4-alkyl or a benzyl group;

R-19 represents an aryl group or a heteroaryl group;

R20 represents a group -C1-4-alkyl or an aryl group;

R21 represents an aryl group;

Rr represents:

• a halogen atom,

• a group -Ci-4-alkoxy,

• a group -C-i-4-fluoroalkyl,

• a group -OCF3,

• a nitro group,

• a group -IM H2,

• a group -NHCH3;

F¾' represents:

• a ydroxyl group.

• a group -Ci-6-alkyl.

which:

Ri , R2, R3 and Z are as defined in Claim 1.

Compound according to Claim 1 , of formula (IB):

in which:

Ri and Z are as defined in Claim 1.

Compound according to Claim 1 , of formula (li):

in which:

R-i , R-|8 and Z are as defined in Claim 1 .

5. Compound of formula (I) according to Claim 1 , characterized in that:

- Y represents a hydrogen atom, a group -(C=0)- R2R3 or a group -(C=0)-OMe;

Z represents:

• a hydrogen atom,

• a group -C-i-6-alkyl, which is unsubstituted or substituted with one or more groups R4,

• a cyclopropyl group, a cyclobutyl group, a 3-(benzoylamino)cyclobutyl group, a 3-[(pyrazin-2-ylcarbonyl)amino]cyclobutyl group, a 3- [(methylsulfonyl)amino]cyclobutyl group, a 3- [(phenylsulfonyl)amino]cyclobutyl group, a cyclopentyl group, a cyclohexyl group,

• a tetrahydro-2H-pyranyl group,

• a group -NH-(C=0)-R5;

i represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted with a 1 ,2,3-triazole group substituted with a 3-(3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5-ylmethyl group;

R2 represents a hydrogen atom or a methyl group;

R3 represents:

• a cyclohexyl group, a 1 -{[(phenylsulfonyl)amino]methyl}cyclohexyl group or a 1-{[(phenylsulfonyl)amino]methyl}cyclopentyl group,

• a 5,6,7,8-tetrahydroquinolin-5-yl group,

• or a linear or branched group Ci_4-alkyl, which is unsubstituted or substituted with a group chosen from:

• -NH-R6,

• -NH-(C=0)-R8,

• a 1 -morpholin-4-ylcyclopentyl group,

• a tetrahyd ro-2 H-pyranyl group, a tetrahydrofuranyl group or a morpholin-4-yl group,

• a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a chlorine atom and a group -CF3,

• a 1 H-pyrrolo[2,3-b]pyridinyl group, a 4-methyl-5, 6,7,8- tetrahydroquinazolin-2-yl group, a 6-methoxy-1 H-benzimidazol-2-yl group, a pyridinyl group, which is unsubstituted or substituted with a group -CF3 or with a morpholin-4-yl group,

• or alternatively with one or more methoxy groups;

or alternatively R2 and R3, together with the nitrogen atom to which they are attached, constitute a -C3_6-heterocycloalkyl group chosen from: azetidine, morpholine, 4-[5-(trifluoromethyl)pyridin-2-yl]piperazine;

R4 independently represents a group chosen from:

• a hydroxyl group,

• a deuterium,

• a fluorine atom,

• a cyclopropyl group,

• a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a fluorine atom, a methoxy group, a - CH2OH group and a -CHO group,

• a pyridyl group,

• a morpholinyl group, a tetrahyd ro-2 H-pyranyl group,

• a methoxy group,

• a group -(C=O)-NH-R1 0,

• a group -N H-R1 1 ,

• a group -N H-(C=0)-Ri 2,

• or a group -NH(S02)-Ri;~;

R5 represents a pyridyl group;

Re represents a quinolyl group, the said quinolyl group being unsubstituted or substituted with a chlorine atom;

R7 represents a -CF3 group, a phenyl, pyridyl, pyrazolyl, 1 H-pyrrolo[2,3-b]pyridyl or indolyl group, the said phenyl, pyridyl, pyrazolyl, 1 H-pyrrolo[2,3-b]pyridyl or indolyl groups being unsubstituted or substituted with one or more groups Ry;

RQ represents a pyrazinyl group, the said pyrazinyl group being unsubstituted or substituted with one or more groups R2';

R-I O represents a 1 ,8-naphthyridinyl group substituted with a methyl group;

R11 represents a tetrahydrothiophene-1 ,1 -dioxide, quinolyl, pyridyl or benzyl group, the said quinolyl, pyridyl or benzyl groups being unsubstituted or substituted with a chlorine atom, a hydroxy I group, a nitro group or a methyl group;

R-I 2 represents:

• a tert-butoxy group,

• a group -Ci -4-aikyl, which is unsubstituted or substituted with a group chosen from a group -NRi R-i 5, pyridyl or pyrazolyl, the said pyridyl or pyrazolyl groups being unsubstituted or substituted with a methyl group,

• a pyrazinyl or pyridyl, which is unsubstituted or substituted with one or more groups chosen from a hydroxy I group and a methyl group;

R-13 represents:

• a group -CF3,

• a phenyl group, which is unsubstituted or substituted with a nitro group,

• or a pyridyl group, which is unsubstituted or substituted with a group

-NR16R17;

R-I4, R-15, R-I6 and R17 each independently represent:

• a hydrogen atom,

• a methyl group or an isopropyl group;

Ry represents:

• a fluorine atom, a chlorine atom,

• a methoxy group,

• a group -CF3,

• a group -OCF3,

• a nitro group,

• a group -N H2,

• a group -NHCH3;

2' represents:

• a hydroxyl group,

• a methyl group.

6. Compound of formula (I) according to Claim 1 , characterized in that:

- Y represents a hydrogen atom or a group -(C=0)- 2 3;

Z represents:

• a hydrogen atom,

• a methyl group, an isopropyl group, a 2,2-dimethyl propyl group,

• a group CD3,

• a 2-fluoroethyl group,

• a cyclopropylmethyl group,

• a 2-phenylethyl group,

• a [(7-methyl-1 ,8-naphthyridin-2-yl)amino]-4-oxobutyl group,

• a 2-{[(2-nitrophenyl)sulfonyl]amino}ethyl group,

• a cyclopropyl group,

· a tetrahydro-2H-pyranyl group;

i represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group;

R2 represents a hydrogen atom or a methyl group;

R3 represents:

· a methyl group,

• a 2-{[(2,6-difluorophenyl)sulfonyl]amino}-1 ,1-dimethylethyl group,

• a 1 ,1 -dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl group,

• a 2-{[(2-fluorophenyl)sulfonyl]amino}-1 ,1 -dimethylethyl group,

• a 1 , 1 -dimethyl-2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group, · a 1 , 1 -dimethyl-2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group,

• a 2-methyl-1 -[(phenylsulfonyl)amino]propan-2-yl group,

• a 2-methyl-1 -{[(5-nitro-1 H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl group,

• a 2-methyl-1 -{[(trifluoromethyl)sulfonyl]amino}propan-2-yl group,

• a 2-methyl-1 -{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl group,

· a 1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl group,

• a 1 , 1 -dimethyl-2-morpholin-4-ylethyl group,

• a benzyl group,

• a 2-(4-pyridyl)ethyl group.

Compound of formula (I) according to any one of Claims 1 to 6, characterized in that it corresponds to the following compounds:

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-2-(1- {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5.7,9, 11 .13-hexamethyl-6,14-dioxo-12- {[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methyibutanoate;

(2R,3S,4R,5RI7S,9SI10S,11 R,12SI13R)-7-[(benzylcarbamoyl)oxy]-2-(1{[(2R,3R,4R!5R!6R)-5-hydroxy-3,4-dimethoxy-6-methylteirahydro-2H-pyran- 2- yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 11 ,13-hexamethyl-6, 14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacycloietradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,7R)-4-cyclopropyl-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)- 3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyi]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6, 4-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,5R,7R)-2,5-dimeihyl-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(meihoxyimino)-6-methylteirahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(meihoxyimino)-6-methyitetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 11 , 13-hexamethyl-6, 14-dioxo-7-({[2-(pyridin-4-yl)ethyl]carbamoyl}oxy)-12-{[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,7R)-4-cyclopropyl-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 - {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-rnethyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 11 ,13-hexamethyl-6, 14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,7R)-2,5-dimethyl-4-(2H3)methyl-1 ,4-oxazepan-7-yl]oxy}-2-(1- {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9,11 ,13-hexamethyl-6, 14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(dimethylcarbamoyl)oxy]-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 11 ,13-hexamethyl-6, 14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyciotetradecan-4-yi 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,7R)-2,5-dimethyl-4-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4- (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,7R)-4-(2-fluoroethyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1- {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 11 ,13-hexamethyl-6, 14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[(2S,7R)-2,5-dimethyl-4-{4-[(7-methyl-1 ,8-naphthyridin-2-yl)amino]-4-oxobutyl}-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)- 3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}- 3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-1 ,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R!6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methyipropan-2-yl)carbamoyl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yijoxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9,11 ,13-hexamethyl-7-{[(2-methyl-1-{[(5-nitro-1 H-pyrazol-4-yi)suifonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyc!otetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-hydroxy-2-(1 -{[(2R,3R,4R,5R,6R)- 5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yijoxy}propan-2-yl)- 10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl- 1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyitetrahydro-2H-pyran-2-yi]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(rnethoxyimino)-6-rnethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-7-{[(2-meihyl-1- {[(trifluoromethyl)sulfonyl]amino}propan-2-yl)carbamoyi]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyi-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-1 ,4-oxazepan-7-yl]oxy}-7-hydroxy-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yi 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyitetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-rnethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyi]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12- {[(2S,5RJR)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5R!7S,9S,10S, 1 1 R,12S,13R)-2-(1 -{[(2R,3R!4R!5R!6R)-5-hydroxy- 3,4-dirnethoxy-6-rneihyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R!6R)-3-hydroxy-4-(methoxyimino)-6-meihyltetrahydro-2H-pyran-2-ylloxyJ-S.SJ^J I S- examethyl^-i^-methyl-H^-nitrophenyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12- {[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacycloietradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5R,7S,9S!10S, 1 1 R,12S!13R)-2-(1 -{[(2R,3R!4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-meihylietrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S,3R!6R)-3-hydroxy-4-(meihoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5J,9,1 1 ,13-hexamethyl-7-[({2-methyl-1 - [(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12- {[(2S,5S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yi]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5RJS.9S,10S, 1 1 R,12S,13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10- {[(2S!3R,6R)-3-hydroxy-4-(rnethoxyimino)-6-methylteirahydro-2H-pyran-2-y oxyJ-S.SJ^.H S-hexamethyl^-t^-meihyl-l -[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12-{[(2S,5R,7R)-2!4,5-trimethyl-1 !4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5RJS,9S,10S, 1 1 R,12S,13R)-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R!3R,4R,5R,6R)-5-hydroxy-3,4-dimet oxy-6-methyltetra ydro-2H-pyran-2-yl]oxy}-1 -methylethyl)- 10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-meihyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2S,7R)-4-isopropyl-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}- 3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5R,7S,9S!10S, 1 1 R,12S!13R)-12-{[(2S,5R,7R)-4- (cyclopropylmethyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)- 10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 , 13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5R!7S,9S,10S,11 R,12S,13R)-12-{[(2S!7R)-4-(cyclopropylmethyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-7-[({1 , 1 -dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R!6R)-5-hydroxy-3,4-dimethoxy-6-methylteirahydro-2H-pyran-2-yl]oxy}-1 -methyleihyl)-10-{[(2S!3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yi 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2SJR)-2,5-dimethyl-4- (tetrahydro-2H-pyran-4-yl)-1 !4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R!4R!5R!6R)-5-hydroxy-3.4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)- 10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3.5.7,9,11 .134iexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5RJS,9SI10SI11 R,12SI13R)-12-{[(2S,5S,7R)-4-(cyciopropylmethyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R!5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylJoxy}-1 -methylethyl)-10-{[(2S,3R!6R)-3-hydroxy-4-(methoxyimino)-6-meihyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11 ,13-hexamethyl-6,14-dioxooxacycloteiradecan-4-yl 3-methylbutanoate:

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,5R,7R)-4-(2,2-dimethylpropyl)-2,5-dimeihyl-1 ,4-oxazepan-7-yl]oxy}-2-(2-{[(2R!3R,4R,5R,6R)- 5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro- 2H-pyran-2-yl]oxy}-3,5.7,9.1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 ,1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)- 5-hydroxy-3,4-dimethoxy-6-rnethyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro- 2H-pyran-2-yl]oxy}-3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S!4R,5R!7S,9S,10S, 1 1 ,12S,13R)-7-{[(1 ,1 -dimethyl-2-morpholin-4-ylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3!4-dimethoxy-6-methylietrahydro-2H-pyran-2-yl]oxy}-1 -methyleihyl)-10-{[(2S!3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}- 3,5,7!9!1 1 ,13-hexameihyl-6!14-dioxo-12-{[(2S,7R)-2,4,5-trimeihyl-1 ,4-oxazepan-7-yi]oxy}oxacyclotetradecan-4-yi 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S, 1 1 R,12S,13R)-7-{[(2-{[(2,6-difiuorophenyl)sulfonyl]amino}-1 ,1 -dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R!5R,6R)-5-hydroxy-3,4-dimethoxy-6-meihyltetrahydro-2H-pyran-2 yl]oxy}-1 -methyleihyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(meihoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5.7,9,1 1 .13-hexamethyl-6,14-dioxo-12 {[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S, 1 1 R,12S,13R)-7-({[1 ,1 -dimethyl-2-({[4- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2- {[(2R!3R,4R!5R!6R)-5-hydroxy-3!4-dimethoxy-6-methyltetrahydro-2H-pyran-2 yl]oxy}-1 -methylethyl)-10-{[(2S!3R!6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9,1 1 , 13-hexamethyl-6,14-dioxo-12

{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R!7S,9S!10S, 1 1 R,12S!13R)-7-{[(2-{[(2-fluorophenyl)sulfonyl]amino}-1 , 1 -dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methylteirahydro-2H-pyran-2 yl]oxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,1 1 , 13-hexamethyl-6,14-dioxo-12 {[(2S,7R)-2,4,5-trimethyl-1 .4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

(2R,3S,4R,5R,7S,9S,10S, 1 1 R,12S,13R)-7-({[1 ,1 -dimethyl-2-({[2- (trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2- {[(2R,3R,4R!5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2 yl]oxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3, 5,7,9, 1 1 , 13-hexamethyl-6,14-dioxo-12

{[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S!4R,5R!7S,9S,10S,11 R,12S,13R)-7-({[1 ,1-dimethyl-2-({[4- (trifluoromeihoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2- {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yl]oxy}-1 -meihyleihyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H^yran-2-yl]oxy}-3,5J,9 1 .13-hexamethyl-6,14-dioxo-12- {[(2S,7R)-2,4,5-trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3- methylbutanoate;

• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 ,1-dimethyl-2- [(phGnylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R!5R,6R)-5- hydroxy-3,4-dimethoxy^-methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)- 10-({(2S,3R,6R)-3-hydroxy-6-methyl-4-[(2,2,2-trifluoroethoxy)imino]tetrahydro- 2H-pyran-2-yl}oxy)-3,5,7,9, 1 1 , 13-hexamethyl-6.14-dioxo-12-{[(2S,7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;

• (2R,3S!4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1 !1-dimethyl-2- [(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-10-{[(2S,3R,6R)-4-(ethoxyimino)- 3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-(2-{[(2R!3R,4R,5R!6R)-5- hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H^yran-2-yljoxy}-1 -methylethyl)- 3,5,7,9,1 1 ,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1 ,4- oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-melhylbutanoate.

Process for preparing a compound of formula (I) according to Claim 1 , in which Y represents a group -(C=0)-N 2R3, characterized in that:

a compound of formula (IB):

in which Ri and Z are as defined for the compounds of formula (I) in Claim 1 , is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I) in Claim 1 , in the presence of a carbonyl derivative and a base.

9. Process for preparing a compound of formula (I) according to Claim 1 , in which Y represents a group -(0=0)-Νί¾Ι¾ characterized in that:

b-1 ) a compound of formula (V):

in which -| , F¾ and F¾ are as defined for a compound of formula (I) in Claim 1 , is nd of formula (VI):

b-2) the compound of formula (VI) thus obtained is reacted with a compound of formula (VII):

ZNH2 (VII)

in which Z is as defined for compound (I) in Claim 1 , in the presence of a reducing agent.

10. Process for preparing a compound of formula (I) according to Claim 1 , in which Y represents a hydrogen atom, characterized in that:

c-1 ) a compound of formula (VIII):

in which Ri is as defined for compound (I) in Claim 1 , is reacted with an oxidizing agent to obt

c-2) the compound of formula (IX) thus obtained is reacted with a compound of formula (VII):

ZNH2 (VII)

in which Z is as defined for compound (I) in Claim 1 , in the presence of a reducing agent.

11. Process for preparing a compound of formula (I) according to Claim 1 , in which Y represents a group -(C=0)-0-R-i8, characterized in that:

compo

(XXI)

in which Z and Ri are as defined for a compound of formula (I) in Claim 1 , reacted with an alcohol of formula HO-R-is (XXII) in which R-ie is as defined for compound of formula (I) in Claim 1 , in the presence of a base.

Compound of formula (V):

in which:

- Ri , R2 and R3 are as defined for the compounds of formula (I) in Claim 1.

13. Compound of formula (VIM):

(VIII)

in which:

- Ri is as defined for the compounds of formula (I) in Claim 1.

14. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 7, in the form of a base or of an acid-addition salt.

15. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 7, in the form of a base or of an acid-addition salt, and also at least one pharmaceutically acceptable excipient.

16. Compound according to any one of Claims 1 to 7, for its use for the prevention and/or treatment of bacterial infections caused by gram-positive microorganisms and mycobacteria.

17. Compound according to any one of Claims 1 to 7, for its use for the prevention and/or treatment of infectious diseases chosen from tuberculosis, leprosy, nocardiosis, diphtheria, pulmonary mycobacterial infection, cutaneous mycobacterial infection, atypic mycobacterial infection and mycobacteriosis.