US 2011/0172174 A1 · Antibacterial agents

Abstract

Antibacterial compounds of formula I are provided: As well as stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.

A compound according to the formula I:

or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof,
wherein
E is absent or selected from the group consisting of
(1) H,
(2) substituted or unsubstituted
(3) substituted or unsubstituted C2-C6-alkenyl,
(4) substituted or unsubstituted C2-C6-alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heterocyclyl, and
(7) substituted or unsubstituted heteroaryl;
L is absent or selected from the group consisting of
(1) substituted or unsubstituted
(2) —(NH)0-1—(CH2)j—NR3L—(CH2)k—,
(3) —(NH)0-1—C(R1L,R2L)—NR3L—C(R1L,R2L)—,
(4) —C(R1L,R2L)—O—C(R1L,R2L)—,
(5) —(CH2)j—NR3L—C(R1L,R2L)—CONH—(CH2)k—,
(6) —CO—C(R1L,R2L)—NHCO—,
(7) —CONH—,
(8) —NHCO—,
wherein
R1L, R2L, and R3L are independently selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) C1-C6-alkyl substituted with aryl,
(d) C1-C6-alkyl substituted with heterocyclyl, and
(e) C1-C6-alkyl substituted with heteroaryl,
or R1L and R3L, together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S,
j is an integer of 0-4;
k is an integer of 0-4;
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C3-C8-cycloalkyl,
(2) substituted or unsubstituted aryl,
(3) substituted or unsubstituted heterocyclyl, and
(4) substituted or unsubstituted heteroaryl;
G is absent or selected from the group consisting of
(1) —(CH2)i—O—(CH2)i—,
(2) —(CH2)i—S—(CH2)i—,
(3) —(CH2)i—NRg—(CH2)i—,
(4) —C(═O)—,
(5) —NHC(═O)—,
(6) —C(═O)NH—,
(7) —(CH2)iNHCH2C(═O)NH—,
(8) —C≡C—,
(9) —C≡C—C≡C—, and
(10) —C═C—;
wherein
Rg is H or substituted or unsubstituted C1-C6-alkyl;
i is an integer of 0-4;
Y is selected from the group consisting of
(1) substituted or unsubstituted C3-C8-cycloalkyl,
(2) substituted or unsubstituted aryl,
(3) substituted or unsubstituted heterocyclyl, and
(4) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) —(C═O)—,
(2) —C1-C6-alkyl-(C═O)—,
(3) —C2-C6-alkenyl-(C═O)—,
(4) —C2-C6-alkynyl-(C═O)—, and
(5) —CH2—;
or when B is absent, X and A, together with the atoms to which they are attached can form a heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
B is a absent or
wherein R1b and R2b, are independently selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted, or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl,
(h) C1-C6-alkyl substituted with aryl,
(i) C1-C6-alkyl substituted with heterocyclyl, and
(j) C1-C6-alkyl substituted with heteroaryl,
or R1b and R2b, together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
q is an integer of 0-4;
R3 is H or substituted or unsubstituted C1-C6-alkyl,
or R3 and A together with the atoms to which they are attached can form a substituted or unsubstituted 3-10 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S;
R4 is H or substituted or unsubstituted C1-C6-alkyl,
or R4 and A, together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
n is an integer of 0-2;
A is selected from the group consisting of
(1) —(CH2)rC(R1a,R2a)(CH2)sOR3a, and
(2) —(CH2)rC(R1a, R2a)N(R4a,R5a),
wherein R1a and R2a are independently selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl,
(e) substituted or unsubstituted heteroaryl,
(f) C1-C6-alkyl substituted with aryl,
(g) C1-C6-alkyl substituted with heterocyclyl, and
(h) C1-C6-alkyl substituted with heteroaryl,
and R3a,R4a, and R5a are independently selected from the group consisting of
(a) substituted or unsubstituted aryl,
(b) substituted or unsubstituted heterocyclyl,
(c) substituted or unsubstituted heteroaryl,
(d) C1-C6-alkyl substituted with aryl,
(e) C1-C6-alkyl substituted with heterocyclyl, and
(f) C1-C6-alkyl substituted with heteroaryl,
or R4a and R5a together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
r is an integer of 0-4;
s is an integer of 0-4;
or A is selected from the group consisting of
(1) —(CH2)rC(R1a,R2a)N(R4a)COR3a,
(2) —(CH2)rC(R1a,R2a)NHCON(R4a,R5a),
(3) —(CH2)rC(R1a,R2a)NHC(═NH)N(R4a,R5a),
(4) —CH(R1a,R2a),
(5) —C≡CH,
(6) —(CH2)rC(R1a,R2a)CN,
(7) —(CH2)rC(R1a,R2a)CO2R3a, and
(8) —(CH2)rC(R1a,R2a)CN(R4a,R5a),
wherein R1a, R2a,R3a,R4a, and R5a are independently selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl,
(e) substituted or unsubstituted heteroaryl,
(f) C1-C6-alkyl substituted with aryl,
(g) C1-C6-alkyl substituted with heterocyclyl, and
(h) C1-C6-alkyl substituted with heteroaryl,
or R4a and R5a together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
r is an integer of 0-4;
s is an integer of 0-4;
Q is absent or selected from the group consisting of
(1) —C(═O)N(R1,R2),
(2) —NHC(═O)N(R1,R2),
(3) —N(OH)C(═O)N(R1,R2),
(4) —CH(OH)C(═O)N(R1,R2),
(5) —CH[N(R2q,R3q)]C(═O)N(R1,R2),
(6) —CHR1qC(═O)N(R1,R2),
(7) —CO2H,
(8) —C(═O)NHSO2R4q,
(9) —SO2NH2,
(10) —N(OH)C(═O)R1q,
(11) —N(OH)SO2R4q,
(12) —NHSO2R4q,
(13) —SH,
(14) —CH(SH)(CH2)0-1C(═O)N(R1,R2),
(15) —CH(SH)(CH2)0-1CO2H,
(16) —CH(OH)(CH2)0-1CO2H,
(17) —CH(SH)CH2CO2R1q,
(18) —CH(OH)(CH2)SO2NH2,
(19) —CH(CH2SH)NHCOR1q,
(20) —CH(CH2SH)NHSO2R4q,
(21) —CH(CH2SR5q)CO2H,
(22) —CH(CH2SH)NHSO2NH2,
(23) —CH(CH2OH)CO2H,
(24) —CH(CH2OH)NHSO2NH2,
(25) —C(═O)CH2CO2H,
(26) —C(═O)(CH2)0-1CONH2,
(27) —OSO2NHR5q,
(28) —SO2NHNH2,
(29) —P(═O)(OH)2,
R1 is selected from the group consisting of
(1) —H,
(2) —OH,
(3) —OC1-6-alkyl,
(4) —N(R2q,R3q), and
(5) substituted or unsubstituted C1-6-alkyl;
R2 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) substituted or unsubstituted C2-C6-alkenyl,
(4) substituted or unsubstituted C2-C6-alkenyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heterocyclyl,
(7) substituted or unsubstituted heteroaryl,
(8) C1-C6-alkyl substituted with aryl,
(9) C1-C6-alkyl substituted with heterocyclyl, and
(10) C1-C6-alkyl substituted with heteroaryl,
or R1 and R2, together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S,
R1q, R2q, R3q,R4q, and R5q are selected from H or C1-C6 alkyl,
wherein B is absent, or E, L, G, and B are absent, or E, L, and G are absent, or E, L, and B are absent, or E, L, D, G, and B are absent.

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Antibacterial agents

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Antibacterial agents

Life of this patent

Abstract

Claims18