US2023109833A1PendingUtilityA1
Metabolically stable n-acylaminooxadiazoles useful as antibacterial agents
Est. expiryAug 21, 2037(~11.1 yrs left)· nominal 20-yr term from priority
Inventors:Zachary D. AronSteven M. KwasnyMatthew C. TorhanJay P. BarborSteven C. CardinaleMichelle M. ButlerTimothy OppermanKenneth C. Keiler
A61K 31/4985A01N 43/38C07D 271/107A01N 43/60A61L 2/16A61P 31/04A61K 31/496C07D 271/113C07D 413/12A01N 43/82C07D 471/04Y02A50/30C07D 271/10A61K 31/4725A01N 43/08A61L 2103/15
58
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention is related to the development of therapeutics and prophylactics for the treatment and/or prevention of bacterial infections in humans and other mammals. A new class of small molecules is disclosed that inhibits the bacterial trans-translation/ribosome rescue mechanism and thus blocks infection of host cells by bacteria. Also disclosed are methods of using the small molecule inhibitors in the treatment/prevention of bacterial infections.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A bacterial trans-translation inhibitor compound having the structure of Formula II:
wherein:
R 1 is an aryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 6-membered heteroaryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 5-membered heteroaromatic ring containing 2, 3, or 4 heteroatoms bearing 0-3 substituents (in addition to the oxadiazole group); an unsubstituted cycloalkyl ring of 5, 6, or 7 carbon atoms; an unsubstituted linear or branched chain aliphatic group containing 5-8 carbon atoms; a substituted linear or branched chain aliphatic group containing 1-6 carbon atoms bearing 1-8 substituents (1-2 substituents per aliphatic chain carbon, or up to 3 substituents on a terminal aliphatic chain carbon) selected from alkyl, cycloalkyl, substituted aryl (bearing 1-4 substituents), heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl; a substituted cycloalkyl ring of 3-8 carbon atoms bearing 1-8 substituents (1-2 substituent per ring carbon) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which cycloalkyl ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings; a substituted heterocyclic ring of 3-8 ring atoms made up of carbon atoms and at least one ring member selected independently from oxygen, nitrogen, and sulfur atoms and bearing 1-8 substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which heterocyclic ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings;
R 2 is a hydrogen; a straight chain aliphatic group; a branched chain aliphatic group; cycloalkyl; haloalkyl; hydroxy; alkoxy; alkylamino; alkylthio; haloalkoxy; sulfonyl; sulfinyl; carboxy; alkoxycarbonyl; or an amido group;
Ar is a 5- or 6-membered aryl or heteroaryl ring bearing X—R 3 at C3 or C4 of a 6-membered ring relative to the carboxamide moiety or bearing X—R 3 at C3 of a 5-membered ring relative to the carboxamide moiety, wherein Ar may optionally bear up to 3 additional substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl;
X is oxygen, nitrogen, sulfur, or carbon, wherein if X is carbon, then X has the formula —CHR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; wherein if X is a nitrogen, then X has the formula —NR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; and wherein if X is a sulfur, then X has the formula —S—, —SO—, —SO 2 —, or —SNR—, wherein R is hydrogen or a linear, cyclic or branched chain aliphatic group; and
R 3 is a branched chain aliphatic group of 5-9 carbon atoms; a cycloalkyl group of 4-8 carbon atoms; a 4- to 8-member heterocyclic ring linked to X through a ring carbon atom, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, bearing 1-4 substituents (in addition to the X moiety) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; or, where Ar is a heteroaryl ring, then R 3 may be an unsubstituted 4- to 8-member heterocyclic ring or an aryl or heteroaryl ring; or, where X is nitrogen, then R 3 can also be unsubstituted aryl or heteroaryl; or, where X is carbon or nitrogen, R 3 can also be an unsubstituted 4- to 8-member heterocyclic ring, or X and R 3 can together form a non-aromatic, substituted 4- to 8-member heterocyclic ring bearing 1-4 carbon substituents and/or 1-2 nitrogen substituents (in addition to the Ar moiety), where the carbon substituents are selected from alkyl, haloalkyl, nitro, oxo (O═), halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, or alkoxycarbonyl and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, and the nitrogen substituents are selected from alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, alkoxycarbonyl, or aminocarbonyl groups and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings; or a pharmaceutically acceptable salt thereof.
2 . A trans-translation inhibitor compound according to claim 1 , selected from the group consisting of:
Compound No.
MBX-
Structure
4237
4258
4284
4285
4288
4289
4290
4292
4293
4304
4305
4306
4307
4308
4309
4310
4314
4357
4468
4469
4470
4498
4499
4770
4780
4801
4802
4925
4926
3653
3999A
4076
4237
4257
4285
4288
4292
4293
4304
4305
4306
4307
4308
4309
4310
4311
4357
4470
4499
4770
4780
4801
4802
4804
4925
5246
5720
5793
5804
5834
5910
5939A
6205
6211
6236
6282
6976
6977
6983
or a pharmaceutically acceptable salt thereof.
3 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to a subject in need thereof at least one compound according to claim 1 .
4 . The method according to claim 3 , wherein the mammal is a human.
5 . A method of inhibiting trans-translation-mediated bacterial growth in a mammal comprising administering an effective amount of a composition comprising at least one compound according to claim 1 .
6 . The method according to claim 5 , wherein the mammal is a human.
7 . The method according to claim 3 , wherein the bacterial infection is selected from M. tuberculosis, N. gonorrhoeae, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis , and S. pneumoniae.
8 . A pharmaceutical composition comprising at least one trans-translation inhibitor compound according to claim 1 , and a pharmaceutically acceptable carrier or excipient.
9 . A method of inhibiting growth of bacterial cells on a solid surface comprising the step of contacting the surface with at least one trans-translation inhibitor compound according to claim 1 .
10 . A method of disinfecting a solid surface comprising the step of contacting the surface with at least one trans-translation inhibitor compound according to claim 1 .
11 . The method according to claim 9 or 10 , wherein said solid surface is selected from the group consisting of implantable medical devices, central venous catheters (CVCs), implantable pumps, artificial heart valves, cardiac pacemakers, cardio-pulmonary bypass (CPB) pumps, heart-lung machines, dialysis equipment, artificial respirators, breathing apparatuses, water pipes, air ducts, air filters, water filters, and plumbing fixtures.
12 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to a subject in need thereof an effective amount of a trans-translation inhibitor compound of Formula II:
wherein:
R 1 is an aryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 6-membered heteroaryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 5-membered heteroaromatic ring containing 2, 3, or 4 heteroatoms bearing 0-3 substituents (in addition to the oxadiazole group); an unsubstituted cycloalkyl ring of 5, 6, or 7 carbon atoms; an unsubstituted linear or branched chain aliphatic group containing 5-8 carbon atoms; a substituted linear or branched chain aliphatic group containing 1-6 carbon atoms bearing 1-8 substituents (1-2 substituents per aliphatic chain carbon, or up to 3 substituents on a terminal aliphatic chain carbon) selected from alkyl, cycloalkyl, substituted aryl (bearing 1-4 substituents), heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl; a substituted cycloalkyl ring of 3-8 carbon atoms bearing 1-8 substituents (1-2 substituent per ring carbon) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which cycloalkyl ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings; a substituted heterocyclic ring of 3-8 ring atoms made up of carbon atoms and at least one ring member selected independently from oxygen, nitrogen, and sulfur atoms and bearing 1-8 substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which heterocyclic ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings;
R 2 is a hydrogen; a straight chain aliphatic group; a branched chain aliphatic group; cycloalkyl; haloalkyl; hydroxy; alkoxy; alkylamino; alkylthio; haloalkoxy; sulfonyl; sulfinyl; carboxy; alkoxycarbonyl; or an amido group;
Ar is a 5- or 6-membered aryl or heteroaryl ring bearing X—R 3 at C3 or C4 of a 6-membered ring relative to the carboxamide moiety or bearing X—R 3 at C3 of a 5-membered ring relative to the carboxamide moiety, wherein Ar may optionally bear up to 3 additional substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl;
X is oxygen, nitrogen, sulfur, or carbon, wherein if X is carbon, then X has the formula —CHR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; wherein if X is a nitrogen, then X has the formula —NR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; and
wherein if X is a sulfur, then X has the formula —S—, —SO—, —SO 2 —, or —SNR—, wherein R is hydrogen or a linear, cyclic or branched chain aliphatic group; and
R 3 is a branched chain aliphatic group of 5-9 carbon atoms; a cycloalkyl group of 4-8 carbon atoms; a 4- to 8-member heterocyclic ring linked to X through a ring carbon atom, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, bearing 1-4 substituents (in addition to the X moiety) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; or, where Ar is a heteroaryl ring, then R 3 may be an unsubstituted 4- to 8-member heterocyclic ring or an aryl or heteroaryl ring; or, where X is nitrogen, then R 3 can also be unsubstituted aryl or heteroaryl; or, where X is carbon or nitrogen, R 3 can also be an unsubstituted 4- to 8-member heterocyclic ring, or X and R 3 can together form a non-aromatic, substituted 4- to 8-member heterocyclic ring bearing 1-4 carbon substituents and/or 1-2 nitrogen substituents (in addition to the Ar moiety), where the carbon substituents are selected from alkyl, haloalkyl, nitro, oxo (O═), halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, or alkoxycarbonyl and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, and the nitrogen substituents are selected from alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, alkoxycarbonyl, or aminocarbonyl groups and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings; or a pharmaceutically acceptable salt thereof.
13 . The method according to claim 12 , wherein the trans-translation inhibitor compound is selected from the group consisting of:
Compound No.
MBX-
Structure
4237
4258
4284
4285
4288
4289
4290
4292
4293
4304
4305
4306
4307
4308
4309
4310
4314
4357
4468
4469
4470
4498
4499
4770
4780
4801
4802
4925
4926
3653
3999A
4076
4237
4257
4285
4288
4292
4293
4304
4305
4306
4307
4308
4309
4310
4311
4357
4470
4499
4770
4780
4801
4802
4804
4925
5246
5720
5793
5804
5834
5910
5939A
6205
6211
6236
6282
6976
6977
6983
or a pharmaceutically acceptable salt thereof.
14 . The method according to claim 12 , wherein the mammal is a human.
15 . The method according to claim 12 , wherein the bacterial infection is selected from M. tuberculosis, N. gonorrhoeae, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis , and S. pneumoniae.
16 . A pharmaceutical composition comprising at least one trans-translation inhibitor compound according to claim 12 , and a pharmaceutically acceptable carrier or excipient.
17 . A bacterial trans-translation inhibitor compound having the structure of Formula IIa:
wherein:
R 1 is an aryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 6-membered heteroaryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 5-membered heteroaromatic ring containing 2, 3, or 4 heteroatoms bearing 0-3 substituents (in addition to the oxadiazole group); an unsubstituted cycloalkyl ring of 5, 6, or 7 carbon atoms; an unsubstituted linear or branched chain aliphatic group containing 5-8 carbon atoms; a substituted linear or branched chain aliphatic group containing 1-6 carbon atoms bearing 1-8 substituents (1-2 substituents per aliphatic chain carbon, or up to 3 substituents on a terminal aliphatic chain carbon) selected from alkyl, cycloalkyl, substituted aryl (bearing 1-4 substituents), heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl; a substituted cycloalkyl ring of 3-8 carbon atoms bearing 1-8 substituents (1-2 substituent per ring carbon) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which cycloalkyl ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings; a substituted heterocyclic ring of 3-8 ring atoms made up of carbon atoms and at least one ring member selected independently from oxygen, nitrogen, and sulfur atoms and bearing 1-8 substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which heterocyclic ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings;
R 2 is a hydrogen; a straight chain aliphatic group; a branched chain aliphatic group; cycloalkyl; haloalkyl; hydroxy; alkoxy; alkylamino; alkylthio; haloalkoxy; sulfonyl; sulfinyl; carboxy; alkoxycarbonyl; or an amido group;
Ar is a 5- or 6-membered aryl or heteroaryl ring bearing X—R 3 at C3 or C4 of a 6-membered ring relative to the carboxamide moiety or bearing X—R 3 at C3 of a 5-membered ring relative to the carboxamide moiety, wherein Ar may optionally bear up to 3 additional substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl;
X is oxygen, nitrogen, sulfur, or carbon, wherein if X is carbon, then X has the formula-CHR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; wherein if X is a nitrogen, then X has the formula —NR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; and wherein if X is a sulfur, then X has the formula —S—, —SO—, —SO 2 —, or —SNR—, wherein R is hydrogen or a linear, cyclic or branched chain aliphatic group; and
R 3 is a branched chain aliphatic group of 5-9 carbon atoms; a cycloalkyl group of 4-8 carbon atoms; a 4- to 8-member heterocyclic ring linked to X through a ring carbon atom, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, bearing 1-4 substituents (in addition to the X moiety) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; or, where Ar is a heteroaryl ring, then R 3 may be an unsubstituted 4- to 8-member heterocyclic ring or an aryl or heteroaryl ring; or, where X is nitrogen, then R 3 can also be unsubstituted aryl or heteroaryl; or, where X is carbon or nitrogen, R 3 can also be an unsubstituted 4- to 8-member heterocyclic ring, or X and R 3 can together form a non-aromatic, substituted 4- to 8-member heterocyclic ring bearing 1-4 carbon substituents and/or 1-2 nitrogen substituents (in addition to the Ar moiety), where the carbon substituents are selected from alkyl, haloalkyl, nitro, oxo (O═), halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, or alkoxycarbonyl and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, and the nitrogen substituents are selected from alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, alkoxycarbonyl, or aminocarbonyl groups and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings; or a pharmaceutically acceptable salt thereof.
18 . A trans-translation inhibitor compound according to claim 17 , selected from the group consisting of:
Compound No.
MBX-
Structure
4237
4258
4284
4285
4288
4289
4290
4292
4293
4304
4305
4306
4307
4308
4309
4310
4314
4357
4468
4469
4470
4498
4499
3653
3999A
4076
4237
4257
4285
4288
4292
4293
4304
4305
4306
4307
4308
4309
4310
4311
4357
4470
4499
4770
4780
4801
4802
4804
4925
5246
5720
5793
5804
5834
5910
5939A
6205
6211
6236
6282
6976
6977
6983
19 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to a subject in need thereof at least one compound according to claim 17 .
20 . The method according to claim 19 , wherein the mammal is a human.
21 . A method of inhibiting trans-translation-mediated bacterial growth in a mammal comprising administering an effective amount of a composition comprising at least one compound according to claim 17 .
22 . The method according to claim 19 , wherein the mammal is a human.
23 . The method according to claim 19 , wherein the bacterial infection is selected from M. tuberculosis, N. gonorrhoeae, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis , and S. pneumoniae.
24 . A pharmaceutical composition comprising a compound according to claim 17 , and a pharmaceutically acceptable carrier or excipient.
25 . A method of inhibiting growth of bacterial cells on a solid surface comprising the step of contacting the surface with at least one compound according to claim 17 .
26 . A method of disinfecting a solid surface comprising the step of contacting the surface with at least one compound according to claim 17 .
27 . The method according to claim 25 or 26 , wherein said solid surface is selected from the group consisting of implantable medical devices, central venous catheters (CVCs), implantable pumps, artificial heart valves, cardiac pacemakers, cardio-pulmonary bypass (CPB) pumps, heart-lung machines, dialysis equipment, artificial respirators, breathing apparatuses, water pipes, air ducts, air filters, water filters, and plumbing fixtures.
28 . A method of treating or preventing a bacterial infection in a mammal, comprising administering to a subject in need thereof an effective amount of at least one trans-translation inhibitor compound of Formula IIa:
wherein:
R 1 is an aryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 6-membered heteroaryl ring bearing 0-3 substituents (in addition to the oxadiazole group); a 5-membered heteroaromatic ring containing 2, 3, or 4 heteroatoms bearing 0-3 substituents (in addition to the oxadiazole group); an unsubstituted cycloalkyl ring of 5, 6, or 7 carbon atoms; an unsubstituted linear or branched chain aliphatic group containing 5-8 carbon atoms; a substituted linear or branched chain aliphatic group containing 1-6 carbon atoms bearing 1-8 substituents (1-2 substituents per aliphatic chain carbon, or up to 3 substituents on a terminal aliphatic chain carbon) selected from alkyl, cycloalkyl, substituted aryl (bearing 1-4 substituents), heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl; a substituted cycloalkyl ring of 3-8 carbon atoms bearing 1-8 substituents (1-2 substituent per ring carbon) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which cycloalkyl ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings; a substituted heterocyclic ring of 3-8 ring atoms made up of carbon atoms and at least one ring member selected independently from oxygen, nitrogen, and sulfur atoms and bearing 1-8 substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, amino, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl, which heterocyclic ring may optionally be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings;
R 2 is a hydrogen; a straight chain aliphatic group; a branched chain aliphatic group; cycloalkyl; haloalkyl; hydroxy; alkoxy; alkylamino; alkylthio; haloalkoxy; sulfonyl; sulfinyl; carboxy; alkoxycarbonyl; or an amido group;
Ar is a 5- or 6-membered aryl or heteroaryl ring bearing X—R 3 at C3 or C4 of a 6-membered ring relative to the carboxamide moiety or bearing X—R 3 at C3 of a 5-membered ring relative to the carboxamide moiety, wherein Ar may optionally bear up to 3 additional substituents selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl;
X is oxygen, nitrogen, sulfur, or carbon, wherein if X is carbon, then X has the formula-CHR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; wherein if X is a nitrogen, then X has the formula —NR—, wherein R is hydrogen, C4-C8 alkyl, C4-C8 cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; and wherein if X is a sulfur, then X has the formula —S—, —SO—, —SO 2 —, or —SNR—, wherein R is hydrogen or a linear, cyclic or branched chain aliphatic group; and
R 3 is a branched chain aliphatic group of 5-9 carbon atoms; a cycloalkyl group of 4-8 carbon atoms; a 4- to 8-member heterocyclic ring linked to X through a ring carbon atom, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, bearing 1-4 substituents (in addition to the X moiety) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, haloalkoxy, sulfonyl, or sulfinyl; or, where Ar is a heteroaryl ring, then R 3 may be an unsubstituted 4- to 8-member heterocyclic ring or an aryl or heteroaryl ring; or, where X is nitrogen, then R 3 can also be unsubstituted aryl or heteroaryl; or, where X is carbon or nitrogen, R 3 can also be an unsubstituted 4- to 8-member heterocyclic ring, or X and R 3 can together form a non-aromatic, substituted 4- to 8-member heterocyclic ring bearing 1-4 carbon substituents and/or 1-2 nitrogen substituents (in addition to the Ar moiety), where the carbon substituents are selected from alkyl, haloalkyl, nitro, oxo (O═), halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, or alkoxycarbonyl and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, and the nitrogen substituents are selected from alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, alkoxycarbonyl, or aminocarbonyl groups and/or additional fused cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings; or a pharmaceutically acceptable salt thereof.
29 . A trans-translation inhibitor compound according to claim 28 , selected from the group consisting of:
Compound No.
MBX-
Structure
4237
4258
4284
4285
4288
4289
4290
4292
4293
4304
4305
4306
4307
4308
4309
4310
4314
4357
4468
4469
4470
4498
4499
3653
3999A
4076
4237
4257
4285
4288
4292
4293
4304
4305
4306
4307
4308
4309
4310
4311
4357
4470
4499
4770
4780
4801
4802
4804
4925
5246
5720
5793
5804
5834
5910
5939A
6205
6211
6236
6282
6976
6977
6983
30 . The method according to claim 28 , wherein the bacterial infection is selected from M. tuberculosis, N. gonorrhoeae, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis , and S. pneumoniae.
31 . The method according to claim 28 , wherein the mammal is a human.
32 . A pharmaceutical composition comprising at least one trans-translation inhibitor compound according to claim 28 , and a pharmaceutically acceptable carrier or excipient.Cited by (0)
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