UREA DERIVATIVES AS ANTIBACTERIAL AGENTS
This invention relates to compounds of the Formula (I): or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which is useful for the treatment of diseases or conditions mediated by LpxC.
1 . A compound represented by Formula (I)
or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
(i) T is selected from the group consisting of H, alkyl, alkenyl and alkynyl, wherein said alkyl, alkenyl and alkynyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclenyl, heterocycloalkylalkyl, heterocyclenylalkyl, —OH, alkoxyl, —O-alkenyl, —O-alkynyl, hydroxyalkyl, hydroxyalkenyl, —O-aryl, —O-aralkyl, —SH, —S-alkyl, —S-alkenyl, —S-alkynyl, —S-aryl, —S-aralkyl, —NR 1 R 2 , -alkyl-NR 1 R 2 , -alkenyl-NR 1 R 2 ,
wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, aralkyl, cycloalkylalkyl, cycloalkenylalkyl, heteroaryl, heteroaralkyl, or
R 1 and R 2 together with the N atom to which each is attached form heterocyclyl, heterocyclenyl, or heteroaryl;or
T and H together with the C atom to which each is attached form spirocycloalkyl or spiroheterocyclyl, wherein each of said spirocycloalkyl and spiroheterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, aralkyl, aralkenyl, cycloalkenylalkyl, cycloalkylalkyl, halo and haloalkyl;
(ii) X is O, S or NH;
(iii) R 4 and R 5 are independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is substituted with aryl wherein said aryl can be unsubstituted or optionally independently substituted with alkynyl, halo, aryl, heteroaryl, heterocyclenyl or heterocyclyl, wherein said alkynyl, heteroaryl, heterocyclenyl or heterocyclyl can be unsubstituted or substituted with an additional aryl; or
R 4 and R 5 together with the N atom to which each is attached, form a heterocyclyl or heterocyclenyl, wherein each of said heterocyclyl and heterocyclenyl is substituted with A; or
R 4 and R 5 together with the N atom to which each is attached form a heterocyclic structure represented by the structure:
wherein Y, Q, Z, or V are each independently selected from the group consisting of C(O), C(S), C(NH), S(O), S(O) 2 and C(R 6 R 7 ), wherein q is 0-1, wherein each of R 6 and R 7 are independently selected from the group consisting of H, alkyl, and alkenyl, wherein each of said alkyl or alkenyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, aralkyl, aralkenyl, cycloalkenylalkyl, cycloalkylalkyl, halo and haloalkyl;
further wherein M is N or CR, wherein R is H, halo, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, OH, —O-alkyl, —O-alkenyl, —O-alkynyl, —O-aryl, —O-aralkyl, —O-cycloalkenyl, —O-cycloalkyl, —O-heteroaryl, —O-heterocyclenyl, —O-heterocyclyl, —SH, —S-alkyl, —S-alkenyl, —S-alkynyl, —S-aryl, —S-aralkyl, —S-cycloalkenyl, —S-cycloalkyl, —S-heteroaryl, —S-heterocyclenyl, or —S-heterocyclyl;
A is selected from the group consisting of, -aryl-alkynyl-aryl, -aryl-C(O)aralkyl, -aryl, -biaryl, -alkynyl-aryl, -aryl-heteroaryl and -aryl-alkynyl-heteroaryl, wherein said , -aryl-alkynyl-aryl, -aryl-C(O)aralkyl, -aryl, -biaryl, -alkynyl-aryl, -aryl-heteroaryl, and -aryl-alkynyl-heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of halo, haloalkyl, —N(R 1 )(R 2 ), haloalkoxyl, -alkyl-CN, hydroxyalkyl, —OH, heterocyclyl, heterocyclenyl, alkyl, alkenyl, dialkylaminoalkoxyl and heterocyclylalkoxyl.
2 . The compound of claim 1 , wherein T is hydroxyalkyl.
3 . The compound according to claim 1 , wherein X is O.
4 . The compound according to claim 1 , wherein each of said R 4 and R 5 is independently hydrogen or (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is substituted with aryl, wherein said aryl can be unsubstituted or optionally independently substituted with alkynyl, halo or heteroaryl, wherein said alkynyl is substituted with an additional aryl.
5 . The compound according to claim 4 , wherein said (C 1 -C 6 )alkyl can be straight chain alkyl or branched alkyl.
6 . The compound according to claim 5 , wherein said alkyl is methyl, ethyl or branched ethyl.
7 . The compound according to claim 4 , wherein said alkynyl is ethynyl.
8 . The compound according to claim 4 , wherein said halo is bromo.
9 . The compound of claim 4 , wherein said heteroaryl is N-pyrazole.
10 . The compound according to claim 1 , wherein said R 4 and R 5 together with the N atom to which each is attached form heterocyclyl, substituted with A.
11 . The compound according to claim 10 , wherein said heterocyclyl is piperazinyl, piperidinyl, pyrollidinyl.
12 . The compound according to claim 10 , wherein A is phenyl-ethynyl-phenyl, ethynyl-phenyl, phenyl-C(O)-benzyl, phenyl, biphenyl, phenyl-heteroaryl, phenyl-heteroaryl-heterocyclyl or phenyl-ethynyl-heteroaryl,
wherein said phenyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of chloro, bromo, —NH 2 , dialkylamino, trihaloalkyl, —O-trihaloalkyl and cyanoalkyl;
wherein said biphenyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of propyl, fluro, heterocyclyl, dimethylaminoethoxyl and heterocyclylalkoxyl;
wherein said heteroaryl is selected from the group consisting of pyrimidinyl, pyridinyl, thiophenyl, thiazolyl, pyrazinyl and pyrazolyl, further wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of halo, alkyl, —NH 2 and heterocyclyl; and
wherein said heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl.
13 . The compound according to claim 12 , wherein said heteroaryl is selected from the group consisting of 5-pyrimidinyl, 4-pyridinyl, 3-thiophenyl, 5-thiazolyl, 2-pyrazinyl and 5-pyrazolyl.
14 . The compound according to claim 12 , wherein said heterocyclyl is selected from the group consisting of 4-morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl.
15 . The compound according to claim 12 , wherein said biphenyl is substituted with 4-morpholinylethoxyl.
16 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or ester thereof.
17 . (canceled)
18 . A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with at least one pharmaceutically acceptable carrier.
19 . The pharmaceutical composition of claim 18 , further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) receptor mediated disease.
20 . A method of treating a disorder associated with UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), said method comprising administering to a patient in need of such treatment a pharmaceutical composition of claim 18 .
21 . The method of claim 20 , wherein said disorder is a microbial infection.
22 - 29 . (canceled)