| 主权项 |
1. A compound represented by Formula (I): or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: A is a glycopeptide or lipoglycopeptide antimicrobial molecule having a structure represented by the following Formula (A1): or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and —Ra—Y—Rb—(Z)x; or R1 is a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, —Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x;R2 is hydrogen or a saccharide group optionally substituted with Ra—Y—Rb—(Z)x, —Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x;R3 is —ORc, —NRcRc, —O—Ra—Y—Rb—(Z)x, —NRc—Ra—Y—Rb—(Z)x, —NRcRe, or —O—Re;R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, —C(O)Rd and a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, —Rf, or —C(O)—Ra—Y—Rb—(Z)x, or R4 and R5 can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with —NRc—Ra—Y—Rb—(Z)x;R5 is selected from the group consisting of hydrogen, halo, —CH(Rc)—NRcRc, —CH(Rc)—NRcRe, —CH(Rc)—NRc—Ra—Y—Rb—(Z)x, —CH(Rc)—Rx, and —CH(Rc)—NRc—RaC(O)—Rx;R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, —C(O)Rd and a saccharide group optionally substituted with —Ra—Y—Rb—(Z)x, —Rf, —C(O)Rf, or —C(O)—Ra—Y—Rb—(Z)x, or R5 and R6 can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with —NRc—Ra—Y—Rb—(Z)x;R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —Ra—Y—Rb—(Z)x, and —C(O)Rd;R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and —Ra—Y—Rb—(Z)x;R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;R10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R8 and R10 are joined to form —Ar1—O—Ar2—, where Ar1 and Ar2 are independently arylene or heteroarylene;R11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic, or R10 and R11 are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring;R12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, —C(O)Rd, —C(NH)Rd, —C(O)NRcRc, —C(O)ORd, —C(NH)NRcRc, —Ra—Y—Rb—(Z)x, and —C(O)—Rb—Y—Rb—(Z)x, or R11 and R12 are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring;R13 is hydrogen or —OR14;R14 is hydrogen, —C(O)Rd or a saccharide group;Ra is each independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;Rb is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;Rc is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and —C(O)Rd;Rd is each independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;Re is each a saccharide group;Rf is each independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic;Rx is an N-linked amino saccharide or an N-linked heterocycle;X is each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo and iodo;Y is each independently selected from the group consisting of, —CH2—, —O—, —S—, —S—S—, —NRc—, —S(O)—, —SO2—, —NRcC(O)—, —OSO2—, —OC(O)—, —N(Rc)SO2—, —C(O)NRc—, —C(O)O—, —SO2NRc—, —SO2O—, —P(O)(ORc)O—, —P(O)(ORc)NRc—, —OP(O)(ORc)O—, —OP(O)(ORc)NRc—, —OC(O)O—, —NRcC(O)O—, —NRcC(O)NRc—, —OC(O)NRc—, —C(O)—, and —N(Rc)SO2NRc—;Z is each independently selected from the group consisting of hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic; and a saccharide;x is 1 or 2; and B is a bisphosphonate is selected from the group consisting of: wherein:each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;X is H, OH, NH2, or a halo group;X1 are both H, or each is independently selected from the group consisting of H, OH, NH2, and a halo group; andL1 is the point of attachment to Rb; L is a hydrolysable linker for covalently coupling B to A; and m is 1, 2, 3, 4, 5, 6 or 7,
wherein B-L- is represented by the following formula (BL1):
Aa-Z (BL1)wherein:
Aa indicates the point of attachment to the glycopeptide or lipoglycopeptide antimicrobial molecule A; andZ is selected from the group consisting of each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, amino, substituted amino, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and —Ra—Y—Rb—Y—Rb—B;each Ra is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene, substituted arylene, —(CO)-alkylene-, substituted —(CO)-alkylene-, —(CO)-alkenylene-, substituted —(CO)-alkenylene-, —(CO)-alkynylene-, substituted —(CO)-alkynylene-, —(CO)-arylene- and substituted —(CO)-arylene-;each Rb is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene and substituted arylene;each Y is independently selected from the group consisting of a covalent bond, —CH2—, —O—, —S—S—, —NRc—, —S(O)—, —SO2—, —NRcC(O)—, —OSO2—, —OC(O)—, —N(Rc)SO2—, —C(O)NRc—, —C(O)O—, —SO2NRc—, —SO2O—, —P(O)(ORc)O—, —P(O)(ORc)NRc—, —OP(O)(ORc)O—, —OP(O)(ORc)NRc—, —OC(O)O—, —NRcC(O)O—, —NRcC(O)NRc—, —OC(O)NRc—, —C(O)—, and —N(Rc)SO2NRc—;each Rc is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and —C(O)Rd—;each Rd is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;B is a phosphonated group;each Q is independently selected from the group consisting of nitro, chloro, bromo, iodo and fluoro;q is 2 or 3;r is 1, 2, 3, 4 or 5;w1 and w2 are each integers ≧0 such that their sum (w1+w2) is 1, 2 or 3; ande and f are integers ≧0 such that e+f=4;with the proviso that at least one R in Formula (BL1) is —Ra—Y—Rb—Y—Rb—B. |
