2-substituted cephem compounds

Abstract

The present invention relates to 2-substituted cephem compounds of Formula (I) having a quaternary ammonium group on the 3-side chain, preferably together with a cathechol group, or pharmaceutically acceptable salts thereof, which exhibit potent antimicrobial spectrum against a variety of bacteria including Gram negative bacteria and/or Gram positive bacteria, corresponding pharmaceutical compositions, methods of making, treatment methods for bacterial infections or uses thereof.

1 . A compound of the Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
 R 2A  and R 2B  is selected from:
 a) R 2A  is hydrogen, optionally substituted amino, —SO 3 H, optionally substituted amino sulfonyl, carboxyl, optionally substituted (lower alkyl)oxycarbonyl, optionally substituted carbamoyl, hydroxyl, or substituted carbonyloxy; and R 2B  is hydrogen, provided that R 2A  and R 2B  are not hydrogen at the same time, or 
 b) R 2A  and R 2B  are taken together to form optionally substituted methylidene or optionally substituted hydroxyimino; 
 
 R 3  is hydrogen, —OCH 3  or —NH—CH(═O); 
 R 5A  and R 5B  is selected from:
 a) R 5A  and R 5B  are each independently hydrogen, or lower alkyl and R 5A  and R 5B  are not hydrogen at the same time, 
 b) R 5A  and R 5B  may be taken together with the neighboring atom to form optionally substituted carbocycle or a optionally substituted heterocyclic group, or 
 c) R 5A  and R 5B  may be taken together to form optionally substituted methylidene; 
 
 L is —CH 2 —, —CH═CH—, —CH 2 —CH═CH—, —CH═CH—CH 2 —, —S—, —CH 2 —S—, —CH═CH—S— or —CH═CH—CH 2 —S—; 
 E is an optionally substituted divalent group having at least one quaternary ammonium ion; 
 R 10  is hydrogen or a group represented by the formula (I-B): 
 
       
         
           
           
               
               
           
         
         wherein,
 ring A is a benzene ring, monocyclic heterocycle or fused heterocycle; 
 n is an integer from 0 to 2; 
 each R 4  is independently hydrogen, halogen, oxo, —OH, —CN, —NO 2 , —O—C(═O)—R 9 , —C(═O)—R 9 , —C(═O)—OH, —C(═O)—OR 9 , —OR 9′ , —NR 9 R 9 , —SO 2 R 9 , —SR 9 , —NR 9 —C(═O)—R 9 , optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that two hydroxyl groups on ring A bind respectively to carbon atoms each adjacently locates; 
 each R 9  is independently lower alkyl or halo(lower)alkyl; 
 G is a single bond, optionally substituted lower alkylene, optionally substituted alkenylene or optionally substituted alkynylene; 
 B is non-existent, a single bond or a 5- or 6-membered heterocyclic group containing at least 1-3 nitrogen atoms; 
 D is non-existent, a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR 6 —, —NR 6 —C(═O)—, —C(═O)—NR 6 —, —C(═O)—C(═O)—, —NR 6 —C(═O)—NR 6 —, —C(═O)—C(═O)—NR 6 —, —C(═O)—NR 6 —C(═O)—, —NR 6 —C(═O)—C(═O)—, —NR 6 —NR 6 —C(═O)—, —C(═O)—NR 6 —NR 6 —, —N═N—C(═O)—, —C(═O)—N═N—, —C═N—NR 6 —C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR 6 —, —NR 6 —C(═O)—C(═N—OR 6 )—, —C(═N—OR 6 )—C(═O)—NR 6 —, —NR 6 —C(═N—OR 6 )—, —C(═N—OR 6 )—NR 6 —, —C(═O)—C(═N—OR 6 )—, —C(═N—OR 6 )—C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —NR 6 —, —NR 6 —S(═O) 2 —, —NR 6 —CH 2 —, —CH 2 —NR 6 — or —S(═O) 2 —; 
 
         each R 6  is independently hydrogen or optionally substituted lower alkyl; 
         provided that: 
         when R 10  is hydrogen, E is an optionally substituted divalent cyclic group having at least one quanternary ammonium ion and at least two hydroxyl groups which bind respectively to carbon atoms each adjacently locates on the cyclic group-; or 
       
       an ester at carboxyl group, an amino-protected compound when the amino is present on a ring in the 7-side chain; or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein R 5A  is hydrogen and R 5B  is lower alkyl. 
     
     
         3 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein, R 10  is a group represented by the formula (I-B): 
       
         
           
           
               
               
           
         
         wherein each symbol is as defined in  claim 1 . 
       
     
     
         4 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein ring A is a benzene ring or monocyclic heterocycle. 
     
     
         5 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein, ring A is fused heterocycle. 
     
     
         6 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 R 10  is hydrogen; and 
 E is an optionally substituted divalent cyclic group having at least one quanternary ammonium ion and at least two hydroxyl groups which bind respectively to carbon atoms each adjacently locates on the cyclic group. 
 
     
     
         7 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein:
 G is a single bond, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH═CH—, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —CH 2 —CH(CH 3 )—, —CH 2 —CH( i Pr)- or —CH 2 —CH(Ph)-; and 
 wherein  i Pr is isopropyl and Ph is phenyl. 
 
     
     
         8 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein:
 B is non-existent, a single bond or a group represented by the formula: 
 
       
         
           
           
               
               
           
         
       
       and
 the bond of the left side is attached to G and the bond of the right side is attached to D. 
 
     
     
         9 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein:
 D is non-existent, a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR 6 —, —O—, —C(═O)—C(═O), —NR 6 —C(═O)—NR 6 —, —C(═O)—C(═O)—NR 6 —, —C(═O)—NR 6 —C(═O)—, —NR 6 —C(═O)—C(═O)—, —NR 6 —C(═O)—, —C(═O)—NR 6 —, —NR 6 —NR 6 —C(═O)—, —C(═O)—NR 6 —NR 6 —, —N═N—C(═O)—, —C(═O)—N═N—, —C═N—NR 6 —C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR 6 —, —NR 6 —C(═O)—C(═N—OR 6 )—, —C(═N—OR 6 )—C(═O)—NR 6 —, —NR 6 —C(═N—OR 6 )—, —C(═O)—C(═N—OR 6 )—, —C(═N—OR 6 )—C(═O)— or —C(═N—OR 6 )—NR 6 —; and 
 wherein R 6  is as defined in  claim 1 . 
 
     
     
         10 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, the formula (I-C-1): 
       
         
           
           
               
               
           
         
         is a group selected from the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 each R 4a , R 4b  and R 4c  is independently hydrogen, halogen, —OH, —CN, —C(═O)—R 9 , —C(═O)—OH, —C(═O)—OR 9 , —OR 9 , optionally substituted lower alkyl, or optionally substituted cycloalkyl; 
 each R 6  and R 9  independently are as defined in  claim 1 ; and 
 the wavy line means that the bond is in cis or trans configuration, or a mixture thereof. 
 
     
     
         11 . The compound of Formula (I) according to  claim 10  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, the Formula (I-C-1): 
       
         
           
           
               
               
           
         
         is a group selected from the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 R 6  is hydrogen, methyl, ethyl, tert-buthyl, carboxymethyl, 0.2-carboxypropan-2-yl or 1-carboxyethyl; and 
 the wavy line means that the bond is in cis or trans configuration, or a mixture thereof. 
 
     
     
         12 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, the formula (I-C-1): 
       
         
           
           
               
               
           
         
         is a group selected from the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 each R 4a  R 4b  and R 4d  is independently hydrogen, halogen, —OH, —CN, —C(═O)—R 9 , —C(═O)—OR 9 , —OR 9 , optionally substituted lower alkyl, or optionally substituted cycloalkyl; and 
 R 6  and R 9  are as defined in  claim 1 ; 
 the wavy line means that the bond is in cis or trans configuration, or a mixture thereof. 
 
     
     
         13 . The compound of Formula (I) according to  claim 12  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, the Formula (I-C-1): 
       
         
           
           
               
               
           
         
         is a group selected from the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein E is an optionally substituted, saturated or unsaturated, monocyclic or fused cyclic group having at least one quaternary ammonium ion represented by the formula (I-D): 
       
         
           
           
               
               
           
         
       
       wherein,
 the dashed line is a bond in the ring; 
 the bond to the cationic nitrogen atom binds to L, and the other bond binds to R 10 ; provided, 
 when a cationic nitrogen atom binds to R 10 , the dashed line is absent, and 
 when a cationic nitrogen atom does not bind to R 10 , the dashed line is a single bond between the cationic nitrogen atom and a neighboring atom or an alkylene group between the cationic nitrogen atom and a ring member atom other than said neighboring atom. 
 
     
     
         15 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein E is an optionally substituted, saturated or unsaturated, monocyclic or fused cyclic group having at least one quaternary ammonium ion represented by the formula (I-E): 
       
         
           
           
               
               
           
         
         wherein:
 the bond to the cationic nitrogen atom binds to L, and the other bond binds to R 10 ; R x  is optionally substituted lower alkyl. 
 
       
     
     
         16 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein L is —S—, —CH 2 —S—, —CH═CH—S— or —CH═CH—CH 2 —S— and E is an optionally substituted pyridinium group or an optionally substituted fused pyridinium group. 
     
     
         17 . The compound of Formula (I) according to  claim 16  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, E is a group selected from the following formulae which are optionally substituted on the ring; 
       
         
           
           
               
               
           
         
         wherein the bond to the cationic nitrogen atom binds to R 10 , the other bond binds to L. 
       
     
     
         18 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein E is a group selected from the following formulae which are optionally substituted on the ring: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein,
 the bond to the quaternary nitrogen atom binds to L, and the other bond binds to R 10 ; 
 p is an integer from 1 to 3; 
 n is an integer of 1 or 2; 
 R x  is optionally substituted lower alkyl. 
 
     
     
         19 . The compound of Formula (I) according to  claim 13  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, E is selected from the group consisting of the formulae (2), (3), (7), (10), (11), (26), (27), (41), (42), (59), (60) and (77). 
     
     
         20 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein E is a group selected from the following formulae which are optionally substituted on the ring: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, the bond to the quaternary nitrogen atom binds to L, and the other bond binds to R 10 . 
       
     
     
         21 . The compound of Formula (I) according to  claim 20  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein E-R 10  is a group selected from the following formulae: 
       
         
           
           
               
               
           
         
         wherein, the bond to the quaternary nitrogen atom binds to L. 
       
     
     
         22 . The compound of Formula (I) according to  claim 21  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein E-R 10  is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein, the bond to the quaternary nitrogen atom binds to L. 
       
     
     
         23 . The compound of Formula (I) according to  claim 16  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein -L-E- is represented by the formula; 
       
         
           
           
               
               
           
         
         wherein, the bond to the quaternary nitrogen atom binds to R10, the other bond binds to cephem at 3 position. 
       
     
     
         24 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen or —OCH 3 . 
     
     
         25 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the aminos is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein R 1  is an optionally substituted phenyl. 
     
     
         26 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein R 1  is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein, X is N, C(—H) or C(—Cl). 
       
     
     
         27 . The compound of Formula (I) according to  claim 26  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according, wherein, X is N. 
     
     
         28 . The compound of Formula (I) according to  claim 26  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, X is C(—H) or C(—Cl). 
     
     
         29 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to wherein, R 2A  is hydrogen, optionally substituted amino, —SO 3 H, optionally substituted amino sulfonyl, carboxyl, optionally substituted carbamoyl, hydroxyl, or substituted carbonyloxy, and R 2B  is hydrogen. 
     
     
         30 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein, R 2A  is:
 substituted amino shown below: 
 
       
         
           
           
               
               
           
         
         substituted amino sulfonyl shown below: 
       
       
         
           
           
               
               
           
         
         wherein, ring B represents an optionally substituted heterocyclic group; 
         substituted carbamoyl shown below: 
       
       
         
           
           
               
               
           
         
         wherein, ring B represents an optionally substituted heterocyclic group; or 
         substituted carbonyloxy shown below: 
       
       
         
           
           
               
               
           
         
         wherein, ring B represents an optionally substituted heterocyclic group. 
       
     
     
         31 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein, R 2A  and R 2B  are taken together to form:
 substituted methylidene shown below: 
 
       
         
           
           
               
               
           
         
         substituted hydroxyimino shown below: 
       
       
         
           
           
               
               
           
         
         wherein, R 9  is optionally substituted lower alkyl. 
       
     
     
         32 . The compound of Formula (I) according to  claim 1  or an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein R 2A  and R 2B  are taken together to form substituted hydroxyimino shown below: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 7  and R 8  are each independently hydrogen, halogen, hydroxyl, carboxyl, optionally substituted lower alkyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, or 
 R 7  and R 8  may be taken together with a neighboring atom to form an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
 Q is a single bond, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and 
 m is an integer from 0 to 3. 
 
     
     
         33 . A compound of Formula (I-G-1): 
       
         
           
           
               
               
           
         
         an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein, each symbol is as defined above as in  claim 1 . 
       
     
     
         34 . The compound of Formula (I-G-1) according to  claim 33  or, an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt, wherein, R 5A  is hydrogen and R 5B  is lower alkyl; R 10  is a group represented by the Formula (I-B); 
       
         
           
           
               
               
           
         
         each symbol is as defined above as in  claim 33 . 
       
     
     
         35 . The compound of Formula (I-G-1) according to  claim 33  or, an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof, wherein:
 X is C(—H), C(—Cl) or N; 
 each R 7  and R 8  is independently hydrogen or lower alkyl; 
 R3 is hydrogen; 
 m is 0 or 1; 
 Q is a single bond; 
 L is —CH2-; 
 E is a group selected from the following formulae; 
 
       
         
           
           
               
               
           
         
         wherein: 
         Rx is lower alkyl, p is an integer from 1 to 3; 
         G is a single bond or lower alkylene; 
         B is non-existent, a single bond; 
         D is non-existent, a single bond, —C(═O)—, —C(═O)—C(═O)—, —NR 6 —C(═O)—C(═O)—, —NR 6 —C(═O)— or —NH—C(═O)—C(═N—OR 6a ); 
         R 6  is hydrogen or lower alkyl; 
         R 6a  is hydrogen, methyl, carboxymethyl, or 2-carboxypropane-2-yl; 
         the formula (1-B-2); 
       
       
         
           
           
               
               
           
         
       
       is a group selected from the following formulae; 
       
         
           
           
               
               
           
         
         wherein: 
         each R 4a , R 4b  and R 4c  is independently hydrogen, halogen or lower alkyl; and 
         R 4d  is hydrogen, lower alkyl or lower cycloalkyl. 
       
     
     
         36 . A pharmaceutical composition, which comprises a compound of Formula (I) according to  claim 1 , an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The pharmaceutical composition according to  claim 36 , which possesses antimicrobial activity. 
     
     
         38 . The compound of Formula (I) according to  claim 1 , an ester at carboxyl group, an amino-protected compound when the amino is present on the ring in the 7-side chain, or a pharmaceutically acceptable salt thereof according to, wherein the Formula (I-C-1) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is defined as a fused heterocycle ring system comprised of at least two (2) rings fused together; 
 R 4  optionally is substituted on each of the at least two (2) rings of the fused heterocycle ring system defined as ring A, such that each R4 substituent on each ring of the fused heterocycle ring system independently are selected from identical or different substituents; 
 wherein:
 each R 4  as defined above optionally is substituted independently on each ring of the fused heterocycle ring is selected from hydrogen, halogen, oxo, —OH, —CN, —NO 2 , —O—C(═O)—R 9 , —C(═O)—R 9 , —C(═O)—OH, —C(═O)—OR 9 , —OR 9′ , —NR 9 R 9 , —SO 2 R 9 , —SR 9 , —NR 9 —C(═O)—R 9 , optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 provided that two hydroxyl groups on ring A bind respectively to carbon atoms each adjacently locates; and 
 n is an integer from 0 to 2. 
 
 
     
     
         39 . A method for treating bacterial infections, which comprises administering a compound of Formula (I) according to  claim 1  to a subject in need thereof. 
     
     
         40 . The method according to  claim 39 , wherein the bacterial infections are caused by Gram-Negative bacteria or Gram-Positive bacteria. 
     
     
         41 . The method according to  claim 39 , wherein the compounds of Formula (I) exhibit potent antimicrobial activity against beta-lactamase producing Gram negative bacteria; 
     
     
         42 . The method according to  claim 39 , wherein the Gram negative bacteria is selected from:
 Gram negative bacteria of enterobacteria selected from  E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia  or  Proteus;      Gram negative bacteria colonized in respiratory system selected from  Haemophilus, Moraxella;      Gram negative bacteria of glucose non fermentation selected from  Pseudomonas aeruginosa, Pseudomonas  other than  P. aeruginosa, Stenotrophomonas, Burkholderia  or  Acinetobacter;      Gram negative multidrug-resistant bacteria selected from Class B type metallo-beta-lactamase producing Gram negative bacteria, and extended-spectrum beta-lactamase (ESBL) producing bacteria; or   Gram beta-lactam drug resistant Gram negative bacteria selected from ESBL producing bacteria.   
     
     
         43 . The method according to  claim 39 , wherein the Gram positive bacteria is selected from methicillin-resistant  Staphylococcus aureus  (MRSA) or penicillin-resistant  Streptococcus pneumoniae  (PRSP). 
     
     
         44 . A method for treating biothreat organisms, which comprises administering a compound of Formula (I) according to  claim 1  to a subject in need thereof. 
     
     
         45 . The method according to  claim 43 , wherein the biothreat organisms are selected from  Yersinia pestis, Bacillus anthracis, Francisella tularensis, Burkholderia mallei Burkholderia pseudomallei, Brucella suis, Brucella melitensis  or  Brucella abortus.    
     
     
         46 . A method for treating Gram-negative bacterial infections, which comprises administering a compound of Formula (I) according to  claim 1  to a subject in need thereof. 
     
     
         47 . A method for treating Gram-positive bacterial infections, which comprises administering a compound of Formula (I) according to  claim 1  to a subject in need thereof.