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1. (WO2017002086) COMPOSÉS BICYCLIQUES CONTENANT DE L'AZOTE ET LEUR UTILISATION DANS LE TRAITEMENT D'INFECTIONS BACTÉRIENNES
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

A compound of Formula (I):


or a pharmaceutically acceptable derivative thereof;

wherein:

Ri is:

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, S02R3, CN, halogen, COOR3, CONR3R4, NR3COR4, or NR3CONR4R5,


(g) OR3;

R2 is:

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, SO2R3, CN, halogen, COOR3, CONR3R4, NR3COR4, NR3CONR4R5, =NOCH3, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

(c) cycloalkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, S02R3, CN, (CH2)nNR3R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5,

(d) heterocycloalkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, SO2R3, CN, (CH2)nNR3R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5,

(e) aryl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, S02R3, CN, (CH2)nNR3R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5 or

(f) heteroaryl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, SOR3, S02R3, CN, (CH2)nNR3R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5;

and R5 are each independently:

hydrogen or

Ci-C6 alkyl;

n is 0,1,2 or 3;

M is hydrogen or a cation.

2. A compound according to Claim 1, selected from:

(25,5JR)-N-[(25)-l-oxo-l-{[(25)-pyrrolidin-2-ylmethoxy]amino}propan-2-yl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5J?)-N-[(25)-l-oxo-l-{[(2/?)- piperidine-2-ylmethoxy] amino }propan-2-yl] -7-oxo-6- (sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5i?)-N-{(25)-l-[(2-aminoethoxy)amino]-l-oxopropan-2-yl}-7-oxo-6-(sulfooxy-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5^)-N (25)-l-oxo -{[(35)-pyrroHdin-3-yloxy]amino}propan-2-yl]-7-oxo-6-(sulfooxy 1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5 ?) -N-(2-oxo-2-{[(25)-pyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-(2-oxo-2-{[(35)-pyrrolidin-3-yloxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2-carboxamide;

(25,5i?)-N-{2-[(2-aminoethoxy)amino]-2-oxoethyl}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo

[3.2. l]octane-2-carboxamide;

(25,5?)-N-[(25)-3-amino- l-oxo-{ [(35)-pyrrolidin-3-yloxy]amino }propan-2yl]-7-oxo-6-(sulfooxy)- 1 ,6diazabicyclo [3.2.1 ]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-amino-l- oxo-l-{[(25)-pyrolidin-2-yl-methoxy]amino}propan-2yl]-7-oxo-6-(sulfooxy)-l,6diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[(25)-2-annno-l-oxo-l-{[(25)-pyrolidin-2-yl-methoxy]amino}propan-2yl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-3-carboxamide;

(25,5 ?) -N-(2-oxo-2-{[(3R)-pyrrolidin-3-yloxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-({[(25)-pyrrolidin-2-ylmethoxy]amino}-2-hydroxy-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-[(2-amino)-2-hydroxy-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-({[(35)-pyrrolidin-3-yloxy]amino}-2-hydroxy-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-({[(35)-pyrrolidin-3-yloxy]amino}-2-cyano-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[2-(hydroxyamino)-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-({[N-[2-2H-tetrazole-2-yl)-ethoxy]amino}-3-oxopropyl]-6-(sulfooxy)-7-oxo- l,6-diazabicyclo[3.2. l]octane-2-carboxamide;

(25,5i?)-N-[(25)-3-({[N-[2-lH-tetrazole-l-yl)-ethoxy]amino}-3-oxopropyl]-6-(sulfooxy)-7-oxo- l,6-diazabicyclo[3.2. l]octane-2-carboxamide;

(25,5i?)-N-[2-{[{[4-(aminomethyl)phenyl]methyl}oxy]amino}-2-oxoethyl]-6-sulfooxy-7-oxo-1 ,6-diazabicyclo [3.2.1 ]octane-2-carboxamide ;

(25,5i?)-N-[2-{[{[2-anrinophenyl]methyl}oxy]amino}-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5?)-N-[2-{[{[3-armnophenyl]methyl}oxy]amino}-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5i?)-N-[2-{[{[4-armnophenyl]methyl}oxy]amino}-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5) -N-(2-oxo-2-{[2-(2H-l,2,3-triazol-2-yl)ethoxy]amino}ethyl) )-7-oxo -6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5 ?) -N-(2-oxo-2-{[2-(lH-l,2,3-triazol-l-yl)ethoxy]amino}ethyl) -7-oxo -6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[2-(lH-l,2,4 riazol-l-yl)ethoxy]amino}ethyl)- 7-oxo 6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25, 57?) -N-(2-oxo-2-{[2-(2-(lH-pyrazol-l-yl)ethoxy]amino}ethyl)- 7-oxo 6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[(25, 47?)-4-hydroxypyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[(25, 45)-4-hydroxypyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[(25, 4R)-4-aminopyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[(25, 45)-4-aminopyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{[(25, 47?)-4-cyanopyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,57?) -N-(2-oxo-2-{ [(25, 45)-4-cyanopyrrolidin-2-ylmethoxy]amino }ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide.

or a stereoisomer or a pharmaceutically acceptable derivative thereof.

3. A compound according to Claim 1, selected from:

Sodium salt of (25,57?)-N-[(25)-l-oxo-l-{[(25)-pyrrolidin-2-ylmethoxy]amino}propan-2-yl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-l-oxo-l-{[(27?)- piperidine-2- ylmethoxy] amino }propan-2-yl] -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-{(25)-l-[(2-annnoethoxy)amino]-l-oxopropan-2-yl}-7-oxo-6-(sulfooxy-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-l-oxo-l-{[(35)-pyrrolidin-3-yloxy]amino}propan-2-yl]-7-oxo- 6- (sulfooxy l,6-diazabicyclo[3.2. l]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25)-pyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-(2-oxo-2-{[(35)-pyrrolidin-3-yloxy]amino}ethyl)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Sodium salt of (25,57?)-N-{2-[(2-aminoethoxy)amino]-2-oxoethyl}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Trifluoro acetate salt of (25,57?)-N-[(25)-3-amino-l-oxo-{[(35)-pyrrolidin-3-yloxy] amino }propan-2yl]-7-oxo-6-(sulfooxy)-l,6diazabicyclo [3.2.1]octane-2-carboxamide;

Trifluoroacetate salt of (25,57?)-N-[(25)-3-amino-l- oxo-l-{[(25)-pyrolidin-2-yl-methoxy]amino }propan-2yl]-7-oxo-6-(sulfooxy)- 1 ,6diazabicyclo[3.2. l]octane-2-carboxamide;

Trifluoroacetate salt of (25,57?)-N-[(25)-2-amino-l-oxo-l-{[(25)-pyrolidin-2-yl-methoxyjamino }propan-2yl]-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2. l]octane-3-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(37?)-pyrrolidin-3-yloxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-3-({[(25)-pyrrolidin-2-ylmethoxy]amino}-2-hydroxy-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-3-[(2-amino)-2-hydroxy-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-3-({[(35)-pyrrolidin-3-yloxy]amino}-2-hydroxy-3-oxopropyl]- 7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[(25)-3-({ [(35)-pyrrolidin-3-yloxy]amino}-2-cyano-3-oxopropyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?)-N-[2-(hydroxyammo)-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5?)-N-[(25)-3-({[N-[2-2H-tetrazole-2-yl)-ethoxy]amino}-3-oxopropyl]-6-(sulfooxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5JR)-N-[(25)-3-({[N-[2-lH-tetrazole-l-yl)-ethoxy]amino}-3-oxopropyl]-6-(sulfooxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5?)-N-[2-{[{[4-(aminomethyl)phenyl]methyl}oxy]amino}-2-oxoethyl]-6-sulfooxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5?)-N-[2-{[{[2-aminophenyl]methyl}oxy]amino}-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,,57?)-N-[2-{[{[3-aminophenyl]methyl}oxy]amino}-2-oxoethyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,,5^)-N-[2-{[{[4-aminophenyl]methyl}oxy]amino}-2-oxoetliyl]-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5) -N-(2-oxo-2-{ [2-(2H-l,2,3-triazol-2-yl)ethoxy] amino Jethyl) )-7-oxo -6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[2-(lH-l,2,3-triazol-l-yl)ethoxy]amino}ethyl) -7-oxo -6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[2-(lH-l,2,4-triazol-l-yl)ethoxy]amino}ethyl)- 7-oxo 6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25, 57?) -N-(2-oxo-2-{[2-(2-(lH-pyrazol-l-yl)ethoxy]amino}ethyl)- 7-oxo 6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25, 47?)-4-hydroxypyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25, 45)-4-hydroxypyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25, 47?)-4-aminopyrrolidin-2-ylmethoxy] amino } ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25, 45)-4-aminopyrrolidin-2-ylmethoxy] amino } efhyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{ [(25, 47?)-4-cyanopyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,57?) -N-(2-oxo-2-{[(25, 45)-4-cyanopyrrolidin-2-ylmethoxy]amino}ethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide.

or a stereoisomer thereof.

4. A pharmaceutical composition comprising a compound according to any one of Claims

1 to 3.

5. The pharmaceutical composition according to Claim 4, further comprising at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

6. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is selected from a group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, penems, carbapenems, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, or oxazolidinone antibacterial agents.

7. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a beta-lactam antibacterial agent.

8. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a cephalosporin antibiotic selected from a group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime, cefteram, cefetamet, cefcapene, cefditoren, cefuroxime, ceftaroline and ceftolozane.

9. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound according to any one of Claims 1 to 3.

10. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition according to any one of Claims 4 to 8.