INHIBITORS OF ANTIMOCROBIAL RESISTANCE AND METHOS USING SAME

Abstract

In one aspect, the present disclosure relates to compounds which inhibit one or more -lactamases and/or penicillin binding proteins (PBPs), and pharmaceutical compositions thereof. In another aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the -lactamase is selected from the group consisting of NDM-1, KPC-2, and OXA-48. In certain embodiments, the PBP is PBP-3.

Claims

1. A compound of formula (I), or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof: ##STR00183## wherein: R.sup.1a and R.sup.1b are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted C.sub.2-C.sub.12 heterocyclyl, optionally substituted C.sub.6-C.sub.12 aryl, and C(O)(optionally substituted C.sub.1-C.sub.6 alkyl); A.sup.1 and A.sup.2 are each independently selected from the group consisting of a bond, optionally substituted phenylenyl and optionally substituted C.sub.2-C.sub.9 heteroarylenyl; A.sup.3 is selected from the group consisting of optionally substituted C.sub.6-C.sub.12 aryl and optionally substituted C.sub.2-C.sub.12heteroaryl; L.sup.1 and L.sup.2 are each independently selected from the group consisting of a bond, optionally substituted C.sub.1-C.sub.3 alkylenyl, C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-O, C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-, (optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl, C(O)(optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), and C(O)(optionally substituted C.sub.3-C.sub.8 cycloalkylenyl)C(O); R.sup.2 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl, wherein R.sup.2 can combine with A.sup.2 to form an optionally substituted C.sub.3-C.sub.8 heterocycloalkyl; X is selected from the group consisting of N(R.sup.1a)(R.sup.1b) and optionally substituted C.sub.2-C.sub.12 heterocyclyl; Y is selected from the group consisting of a bond, N(R.sup.2), (CH.sub.2).sub.1-3N(R.sup.2)**, O, and S; * indicates a bond between L.sup.1 and A.sup.1; ** indicates a bond between Y and L.sup.2; *** indicates a bond between A.sup.2 and A.sup.3; and each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

2. The compound of claim 1, wherein at least one of the following applies: (a) A.sup.1 is a bond; (b) A.sup.2 is a bond; (c) L.sup.1 is a bond; (d) X is ##STR00184## and (e) Y is a bond or NH.

3. The compound of claim 1, which is a compound of formula (Ia): ##STR00185## wherein: A.sup.1 and A.sup.2 are each independently selected from the group consisting of optionally substituted phenylenyl and optionally substituted C.sub.2-C.sub.9 heteroarylenyl; A.sup.3 is selected from the group consisting of optionally substituted C.sub.6-C.sub.12 aryl and optionally substituted C.sub.2-C.sub.12heteroaryl; L.sup.1 and L.sup.2 are each independently selected from the group consisting of a bond, optionally substituted C.sub.1-C.sub.3 alkylenyl, C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-O, C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-, (optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl, C(O)(optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), and C(O)(optionally substituted C.sub.3-C.sub.8 cycloalkylenyl)C(O); R.sup.1a and R.sup.1b are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted C.sub.2-C.sub.12 heterocyclyl, optionally substituted C.sub.6-C.sub.12 aryl, and C(O)(optionally substituted C.sub.1-C.sub.6 alkyl); R.sup.2 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl, wherein R.sup.2 can combine with A.sup.2 to form an optionally substituted C.sub.3-C.sub.8 heterocycloalkyl; Y is selected from the group consisting of N(R.sup.2), (CH.sub.2).sub.1-3N(R.sup.2)**, O, and S; * indicates a bond between L.sup.1 and A.sup.1; ** indicates a bond between Y and L.sup.2; *** indicates a bond between A.sup.2 and A.sup.3; and each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

4. The compound of claim 1, wherein A.sup.1 is selected from the group consisting of: ##STR00186## wherein: R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl.

5. The compound of claim 4, wherein at least one of the following applies: (a) at least one selected from R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d, is H; (b) at least two selected from R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d are H; and (c) at least three selected from R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d are H.

6. The compound of claim 1, wherein A.sup.1 is selected from the group consisting of: ##STR00187##

7. The compound of claim 1, wherein A.sup.2 is selected from the group consisting of: ##STR00188## wherein: Z is selected from the group consisting of O, S, and NR.sup.4; R.sup.4 is selected from the H and optionally substituted C.sub.1-C.sub.6 alkyl; and R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl.

8. The compound of claim 7, wherein at least one of the following applies: (a) at least one selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d is H; (b) at least two selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are H; and (c) at least three selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are H.

9. The compound of claim 1, wherein A.sup.2 is selected from the group consisting of ##STR00189##

10. The compound of claim 1, wherein A.sup.3 is selected from the group consisting of: ##STR00190## wherein: R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, (optionally substituted C.sub.1-C.sub.6 alkylenyl)C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl.

11. The compound of claim 10, wherein at least one of the following applies: (a) R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e are each independently selected from the group consisting of H, C(O)OH, OH, and CH.sub.2C(O)OH; (b) at least one selected from R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e is H; (c) at least two selected from R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e are H; (d) at least three selected from R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e are H; (e) at least four selected from R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e are H; and (f) at least one selected from R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, and R.sup.6e is selected from the group consisting of C(O)OH, CH.sub.2C(O)OH, OMe, OBn, and OH.

12-13. (canceled)

14. The compound of claim 1, wherein A.sup.3 is selected from the group consisting of ##STR00191##

15. The compound of claim 1, wherein L.sup.1 is selected from the group consisting of CH.sub.2, CH.sub.2C(O), CH.sub.2CH.sub.2C(O), C(O)CH.sub.2CH.sub.2O, ##STR00192##

16. The compound of claim 1, wherein at least one of the following applies: (a) L.sup.2 is selected from the group consisting of CH.sub.2, C(O), and C(O)CH.sub.2O; (b) R.sup.1a and R.sup.1b are each independently selected from the group consisting of H, CH.sub.3, C(O)CH.sub.3, and ##STR00193## (c) R.sup.2 is H; and (d) Y is selected from the group consisting of NH, CH.sub.2NH**, and (CH.sub.2).sub.3NH**.

17. (canceled)

18. The compound of claim 1, wherein one of the following applies: (a) R.sup.1a is H and R.sup.1b is H; (b) R.sup.1a is CH.sub.3 and R.sup.1b is H; (c) R.sup.1a is C(O)CH.sub.3 and R.sup.1b is H; or (d) R.sup.1a is ##STR00194## and R.sup.1b is H.

19-20. (canceled)

21. The compound of claim 1, which is selected from the group consisting of: 2-hydroxy-4-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 2-(4-(((3-(((4-(3-(methylamino)-3-oxopropyl)benzyl)amino)methyl)phenyl)amino)methyl)-[1,1-biphenyl]-2-yl)acetic acid; 5-((((5-(dimethylcarbamoyl)thiophen-2-yl)methyl)amino)methyl)-2-hydroxybenzoic acid; 5-(((5-(acetamidomethyl)pyridin-2-yl)amino)methyl)-2-hydroxybenzoic acid; 2-hydroxy-4-(5-(((3-(((4-(3-(methylamino)-3-oxopropyl)benzyl)amino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 2-hydroxy-4-(5-((methylamino)methyl)furan-2-yl)benzoic acid; 4-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 3-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)phenol; 2-hydroxy-5-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 2-hydroxy-3-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 3-(5-(((3-((methylamino)methyl)phenyl)amino)methyl)furan-2-yl)benzoic acid; 4-(5-(((3-(aminomethyl)phenyl)amino)methyl)furan-2-yl)-2-hydroxybenzoic acid; 3-(5-(((3-(aminomethyl)phenyl)amino)methyl)furan-2-yl)-2-hydroxybenzoic acid; 4-(5-(((3-(aminomethyl)phenyl)amino)methyl)thiophen-2-yl)-2-hydroxybenzoic acid; 4-(((3-(aminomethyl)phenyl)amino)methyl)-3-hydroxy-[1,1-biphenyl]-4-carboxylic acid; 3-(((3-(aminomethyl)phenyl)amino)methyl)-3-hydroxy-[1,1-biphenyl]-4-carboxylic acid; 5-(4-(((3-aminophenyl)amino)methyl)phenyl)nicotinic acid; 5-(((3-(aminomethyl)phenyl)amino)methyl)-3-hydroxy-[1,1-biphenyl]-3,4-dicarboxylic acid; 4-(6-(((3-(aminomethyl)phenyl)amino)methyl)pyridin-2-yl)-2-hydroxybenzoic acid; 3-(((3-(aminomethyl)phenyl)amino)methyl)-3-hydroxy-5-methyl-[1,1-biphenyl]-4-carboxylic acid; 3-(((3-(aminomethyl)phenyl)amino)methyl)-3,5-dihydroxy-[1,1-biphenyl]-4-carboxylic acid; 3-((3-(aminomethyl)phenyl)carbamoyl)-3-hydroxy-[1,1-biphenyl]-4-carboxylic acid; 4-(2-(3-(aminomethyl)phenyl)isoindolin-5-yl)-2-hydroxybenzoic acid; 3-hydroxy-3-(((3-((methylamino)methyl)phenyl)amino)methyl)-[1,1-biphenyl]-4-carboxylic acid; 3-hydroxy-3-(((3-(2-(methylamino)-2-oxoethyl)phenyl)amino)methyl)-[1,1-biphenyl]-4-carboxylic acid; 3-(((3-(aminomethyl)-5-hydroxyphenyl)amino)methyl)-3-hydroxy-[1,1-biphenyl]-4-carboxylic acid; 3-(((5-(aminomethyl)pyridin-3-yl)amino)methyl)-3-hydroxy-[1,1-biphenyl]-4-carboxylic acid; 4-(5-(((3-(aminomethyl)phenyl)amino)methyl)pyridin-3-yl)-2-hydroxybenzoic acid; 4-(2-(((3-(aminomethyl)phenyl)amino)methyl)pyridin-4-yl)-2-hydroxybenzoic acid; 4-(4-(((3-(aminomethyl)phenyl)amino)methyl)pyridin-2-yl)-2-hydroxybenzoic acid; 3-methoxy-5-(2-(methylamino)-2-oxoethoxy)-[1,1-biphenyl]-3,4-dicarboxylic acid; 3-(benzyloxy)-5-(2-(methylamino)-2-oxoethoxy)-[1,1-biphenyl]-3,4-dicarboxylic acid; 3-(benzyloxy)-5-(2-((4-(3-(methylamino)-3-oxopropyl)phenyl)amino)-2-oxoethoxy)-[1,1-biphenyl]-3,4-dicarboxylic acid; 2-(((3-(3-aminophenyl)propyl)amino)methyl)-[1,1-biphenyl]-3-carboxylic acid; 2-(((3-(3-((4-(3-(methylamino)-3-oxopropyl)benzyl)amino)phenyl)propyl)amino)methyl)-[1,1-biphenyl]-3-carboxylic acid; 2-(((3-cyano-4-(4-(dimethylcarbamoyl)piperidin-1-yl)benzyl)amino)methyl)-[1,1-biphenyl]-3-carboxylic acid; 2-hydroxy-5-((((5-(4-(3-(methylamino)-3-oxopropyl)piperidine-1-carbonyl)thiophen-2-yl)methyl)amino)methyl)benzoic acid; and 2-hydroxy-5-(((5-((4-(methylcarbamoyl)cyclohexane-1-carboxamido)methyl)pyridin-2-yl)amino)methyl)benzoic acid.

22. A compound of formula (II), or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof: ##STR00195## wherein: A.sup.4 is selected from the group consisting of optionally substituted C.sub.6-C.sub.10 aryl and optionally substituted C.sub.2-C.sub.9 heteroaryl; R.sup.7a, R.sup.7b, R.sup.7c, and R.sup.7d, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl; R.sup.8 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; each occurrence of R.sup.9a and R.sup.9b is independently selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.10 is selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted C.sub.2-C.sub.12 heterocyclyl, optionally substituted C.sub.6-C.sub.12 aryl; T.sup.1 is selected from the group consisting of N and CR.sup.7c; T.sup.2 is selected from the group consisting of N and CR.sup.7d; n is an integer selected from the group consisting of 1, 2, and 3; and each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

23. The compound of claim 22, wherein A.sup.4 is selected from the group consisting of: ##STR00196## wherein: R.sup.11a, R.sup.11b, R.sup.11c, R.sup.11d, R.sup.11e, R.sup.11f, and R.sup.11g, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, O(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O)OR.sup.A, O(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O)N(R.sup.A)(R.sup.B), C(O)R.sup.A, C(O)OR.sup.A, C(O)N(R.sup.A)(R.sup.B), CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl; and T.sup.3 is selected from the group consisting of N and CR.sup.11b; optionally wherein A.sup.4 is selected from the group consisting of ##STR00197##

24. (canceled)

25. The compound of claim 23, wherein at least one of the following applies: (a) R.sup.11a, R.sup.11b, R.sup.11c, R.sup.11d, R.sup.11e, R.sup.11f, and R.sup.11g, if present, are each independently selected from the group consisting of H, Me, OMe, F, C(O)NH(Me), C(O)H, OCH.sub.2C(O)OH, and OCH.sub.2C(O)NMe.sub.2; and (b) A.sup.4 is selected from the group consisting of ##STR00198##

26. (canceled)

27. The compound of claim 22, wherein at least one of the following applies: (a) T.sup.1 is N; (b) T.sup.2 is N; (c) R.sup.7a is H; and (d) R.sup.7b is H.

28. The compound of claim 22, wherein at least one of the following applies: (a) R.sup.8 is H; (b) R.sup.9a is H and R.sup.9b is H; (c) n is 1; (d) R.sup.10 is H; and (e) the compound is selected from the group consisting of: (5-(5-(methylcarbamoyl)pyridin-3-yl)pyrimidin-2-yl)glycine; (5-(2-methyl-3-(methylcarbamoyl)quinolin-6-yl)pyrimidin-2-yl)glycine: (5-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrimidin-2-yl)glycine; (5-(4-(2-(dimethylamino)-2-oxoethoxy)-3-formyl-5-methoxyphenyl)pyrimidin-2-yl)glycine; and (5-(4-(carboxymethoxy)-3-formyl-5-methoxyphenyl)pyrimidin-2-yl)glycine.

29-32. (canceled)

33. A compound of formula (III), or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof: ##STR00199## wherein: R.sup.12a, R.sup.12b, R.sup.12c, R.sup.12d, and R.sup.12e are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)R.sup.A, C(O)OR.sup.A, C(O)N(R.sup.A)(R.sup.B), CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl, wherein at least one selected from the group consisting of R.sup.12a, R.sup.12b, R.sup.12c, R.sup.12d, and R.sup.12e is C(O)OH; R.sup.13a, R.sup.13b, R.sup.13c, R.sup.13d, and R.sup.13e are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)R.sup.A, C(O)OR.sup.A, C(O)N(R.sup.A)(R.sup.B), CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl, wherein at least one selected from the group consisting of R.sup.13a, R.sup.13b, R.sup.13c, R.sup.13d, and R.sup.13e is C(O)OH; and each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

34. The compound of claim 33, wherein at least one of the following applies: (a) R.sup.12a, R.sup.12b, R.sup.12c, R.sup.12d, and R.sup.12e are each independently selected from the group consisting of H, OH, and C(O)OH; (b) R.sup.13a, R.sup.13b, R.sup.13c, R.sup.13d, and R.sup.13e are each independently selected from the group consisting of H, OMe, OCH.sub.2Ph, and C(O)OH; (c) the compound is ##STR00200## (d) the compound is 5-hydroxy-3-methoxy-[1,1-biphenyl]-3,4-dicarboxylic acid; and (e) the compound is 3-(benzyloxy)-5-hydroxy-[1,1-biphenyl]-3,4-dicarboxylic acid.

35-37. (canceled)

38. A compound of formula (IV), or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof: ##STR00201## R.sup.14a and R.sup.14b are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, and optionally substituted C.sub.7-C.sub.12 aralkyl; R.sup.15a and R.sup.15b are each independently selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.16 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.17a and R.sup.17b are each independently selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.18 is optionally substituted aryl; o is an integer selected from the group consisting of 0, 1, 2, and 3; and each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

39. The compound of claim 38, wherein at least one of the following applies: (a) R.sup.14a and R.sup.14b are each independently selected from the group consisting of H and CH.sub.2CH.sub.2Ph; (b) R.sup.15a and R.sup.15b are each independently H; (c) R.sup.16 is H; (d) R.sup.17a and R.sup.17b are each independently H; (e) o is 1; (f) R.sup.18 is phenyl optionally substituted with at least one hydroxyl; (g) R.sup.18 is ##STR00202## and (h) the compound is 2-amino-3-(3,4-dihydroxyphenyl)-N-phenethylpropanamide.

40-46. (canceled)

47. The compound of claim 1, wherein each occurrence of alkyl, cycloalkyl, aralkyl, alkylenyl, phenylenyl, heteroarylenyl, heterocyclyl, heteroaryl, phenyl, naphthyl, and aryl is independently optionally substituted with at least one substituent C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 hydroxyalkyl, halogen, CN, NO.sub.2 OR.sup.I, N(R.sup.I)(R.sup.II), C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.8 halocycloalkoxy, phenyl, heteroaryl, heterocyclyl, (C.sub.1-C.sub.6 alkylenyl)C(O)N(R.sup.I)(R.sup.II), (C.sub.1-C.sub.6 alkylenyl)C(O)OR.sup.I, O(C.sub.1-C.sub.3 alkylenyl)C(O)OR.sup.II, O(C.sub.1-C.sub.3 alkylenyl)C(O)N(R.sup.I)(R.sup.II), C(O)R.sup.I, C(O)OR.sup.I, OC(O)R.sup.I, OC(O)OR.sup.I, SR.sup.I, S(O)R.sup.I, S(O).sub.2R.sup.I, S(O).sub.2N(R.sup.I)(R.sup.II), S(O).sub.2NR.sup.IC(O)NHR.sup.II, N(R.sup.I)S(O).sub.2R.sup.II, N(R.sup.I)C(O)R.sup.II, and C(O)NR.sup.IR.sup.II, wherein R.sup.I and R.sup.II is independently selected from the group consisting of H, C(O)(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.12 aralkyl, phenyl, naphthyl, and heteroaryl.

48. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier; wherein optionally the pharmaceutical composition further comprises at least one additional antibiotic agent, optionally wherein the at least one additional antibiotic agent is one or more selected from the group consisting of benzathine, benzylpenicillin (penicillin G), benzathine penicillin G, benzathine penicillin V, phenoxymethylpenicillin (penicillin V), procaine penicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, temocillin, amoxicillin, ampicillin, mecillinam, piperacillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, cefazolin, cephalexin, cephalosporin C, cephalothin, cefapirin, cefuroxime, cefaclor, cefprozil, cefaclor, cefamandole, cefuroxime, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cepirome, ceftaroline, ceftobiprole, biapenem, doripenem, ertapenem, faropenem, Imipenem, meropenem, panipenem, razupenem, tebipenem, thienamycin, aztreonam, tigemonam, nocardicin A, and tabtoxinine.

49-50. (canceled)

51. A method of treating, preventing, or ameliorating a bacterial infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1.

52. The method of claim 51, wherein the subject is further administered at least one additional antibiotic agent, optionally wherein the at least one additional antibiotic agent is one or more selected from the group consisting of benzathine, benzylpenicillin (penicillin G), benzathine penicillin G, benzathine penicillin V, phenoxymethylpenicillin (penicillin V), procaine penicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, temocillin, amoxicillin, ampicillin, mecillinam, piperacillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, cefazolin, cephalexin, cephalosporin C, cephalothin, cefapirin, cefuroxime, cefaclor, cefprozil, cefaclor, cefamandole, cefuroxime, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cepirome, ceftaroline, ceftobiprole, biapenem, doripenem, ertapenem, faropenem, Imipenem, meropenem, panipenem, razupenem, tebipenem, thienamycin, aztreonam, tigemonam, nocardicin A, and tabtoxinine; optionally wherein the subject is co-administered the at least one compound and the at least one additional antibiotic agent or the at least one compound and the at least one additional antibiotic agent are coformulated.

53-55. (canceled)

56. A method of inhibiting a -lactamase and/or penicillin binding protein (PBP) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1.

57. The method of claim 56, wherein at least one of the following applies: (a) the -lactamase is selected from the group consisting of NDM-1, KPC-2, and OXA-48; (b) the PBP is PBP-3; (c) the subject is further administered at least one additional antibiotic agent, optionally wherein the at least one additional antibiotic agent is one or more selected from the group consisting of benzathine, benzylpenicillin (penicillin G), benzathine penicillin G, benzathine penicillin V, phenoxymethylpenicillin (penicillin V), procaine penicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, temocillin, amoxicillin, ampicillin, mecillinam, piperacillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, cefazolin, cephalexin, cephalosporin C, cephalothin, cefapirin, cefuroxime, cefaclor, cefprozil, cefaclor, cefamandole, cefuroxime, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cepirome, ceftaroline, ceftobiprole, biapenem, doripenem, ertapenem, faropenem, Imipenem, meropenem, panipenem, razupenem, tebipenem, thienamycin, aztreonam, tigemonam, nocardicin A, and tabtoxinine; optionally wherein the subject is co-administered the at least one compound and the at least one additional antibiotic agent or the at least one compound and the at least one additional antibiotic agent are coformulated; and (d) the subject is a mammal, optionally the mammal is a human.

58-64. (canceled)

Description

BRIEF DESCRIPTION OF THE FIGURES

[0012] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

[0013] FIG. 1A provides a schematic overview of DNA encoded library screening. During cycle 1, the amine of the headpiece, the initial DNA strand with free amine as the functional group for chemical reactions, is reacted with functional group 1 (FG1) on cycle 1 building blocks, followed by cycle 1 DNA ligation onto the headpiece. This is pooled and split to the correct number of cycle 2 building blocks. The process is repeated where functional group 2 (FG2) on cycle 1 building blocks is reacted with functional group 3 (FG3) on cycle 2 building blocks, and DNA strands are ligated. The fully constructed library is pooled and incubated with a His-tagged protein. The binders are enriched by washing out the non-binders and repeating the binding-washing cycle 2-3 times. The binders are then identified by deep sequencing the DNA barcode tags. Finally, the hit compounds are synthesized in the absence of the DNA tag and assayed to identify the lead compounds. FIG. 1B shows a model compound in a -lactamase focused library. The synthesized DNA-encoded library (DEL) contains a small molecule that comprises a linker (C1a) and two building blocks (C1b and C2) that end in a carboxylate or tetrazole functional group. The small molecule is built on a core DNA structure headpiece where DNA barcodes for each building block are added.

[0014] FIG. 2A: hydrolyzed meropenem is shown bound in the active site of NDM-1 (PDB: 5N0H), a class B -lactamase. The carboxylate-binding pocket includes residues such as K211, which forms two H-bonding interactions with the carboxylic acid on meropenem. The carboxylic acid also coordinates with Zn2 and a water molecule present inside the carboxylate-binding pocket. FIG. 2B: hydrolyzed meropenem is bound in the active site of OXA-48 (PDB: 6PT1), a class D -lactamase. Meropenem is covalently linked to the catalytic residue S70. The carboxylic acid in the carboxylate-binding pocket forms H-bonding interactions with R250, T209, and S118.

[0015] FIG. 3A provides non-limiting, exemplary DECL building blocks. C1 includes acid-halides, ester-protected di-acids, N-boc-protected di-amines, aldehyde-amines, and aldehyde-amines. C2 includes amino-acids, boronic acid-acids, aldehyde-acids, and esters. FIG. 3B shows affinity selection results. Analysis of selection results for NDM-1 -lactamase as the target. The enrichment score (AC-zscore-n) of selection against NTC (-axis) is plotted against selection against NDM-1 (x-axis). FIG. 3C: the structure of the most enriched compound CDD-2335 is extrapolated from the deep sequencing analysis data.

[0016] FIG. 4A: a total of 4 hit compounds from OXA-48 screening were synthesized in the absence of the DNA and the linker (C1a), wherein C1b and C2 are highlighted. CDD-2746 (FIG. 4B) and CDD-2801 (FIG. 4C) were synthesized in the addition of the linker as well as in the absence of the methyl amide for SAR studies. X-ray crystal structure of OXA-48 in complex with CDD-2725 (PDB ID: 8SQF) (FIG. 4D) and CDD-2801 (PDB ID: 8SQG) (FIG. 4E). Both inhibitors bind in a similar binding pose with C1 positioned in the carboxylate-binding pocket and C2 pointing towards R214.

[0017] FIG. 5A: three hit compounds from NDM-1 screening were synthesized in the absence of the DNA and the linker (C1a), wherein C1b and C2 building blocks are highlighted. CDD-2376 is the most potent inhibitor with a low-micromolar inhibition constant. FIG. 5B: CDD-2376 was synthesized with the addition of the linker as well as in the absence of C1b to determine the lead compound necessary for further SAR study. Truncating the molecule eliminates inhibition activity. FIG. 5C: zinc-concentration dependent experiment was conducted to determine the mechanism of inhibition of CDD-2376. The inhibition constant at low (1 M) and high (10 M) concentrations of zinc had a minor difference, suggesting its inhibition through binding inside the active site instead of stripping the zinc away from the active site.

[0018] FIG. 6 provides the structure of CDD-2376.

[0019] FIG. 7 provides accumulation data in bacteria of tetracycline (positive control), clindamycin (negative control), and the NDM-1 inhibitors. CDD-2376 has the lowest amount of accumulation in bacteria, followed by CDD-2653, then CDD-2616. Accumulation of CDD-2616 is similar to the tetracycline positive control.

[0020] FIGS. 8A-8B provide molecular docking studies of hit compounds to the active site of NDM-1. Compounds CDD-2376 (FIG. 8A) and CDD-2616 (FIG. 8B) were docked inside the active site of a crystal structure of NDM-1 (PDB: 4EYL). The carboxylic acid group present in each of compounds CDD-2376 and CDD-2616 were positioned between the two zinc ions of NDM-1, and each form a H-bond with Asn220, which residue is known to interact with the hydrolyzed -lactam ring. Additionally, the hydroxyl substituent adjacent to the carboxylic acid group binds to Lys211 inside the acid-binding pocket.

[0021] FIG. 9 provides a synthetic scheme for the preparation of qDOS38_1.

[0022] FIGS. 10A-10B provide synthetic schemes for the preparation of qDOS38_2.

DETAILED DESCRIPTION OF THE INVENTION

[0023] -lactam antibiotics represent about 65% of all antibiotic sales or 15 billion dollars per year worldwide. However, antibiotic resistance is an increasing threat to conventional therapies. The Centers for Disease Control and Prevention (CDC) has reported at least 2.8 million infections and 35,000 deaths related to antibiotic resistance every year in the US.

[0024] Clavulanate and avibactam are commonly prescribed inhibitors along with sulbactam, tazobactam, relebactam, and vaborbactam. Clavulanate, sulbactam, and tazobactam, however, comprise a -lactam moiety, which increases their susceptibility to hydrolysis by -lactamase enzymes, thereby limiting their utility.

[0025] Avibactam and relebactam have a diazabicyclooctane (DBO) structure, which can react with -lactamase to generate an acyl-enzyme intermediate by covalent bond formation with the enzyme active site. However, unlike compounds with a -lactam core, this reaction is reversible, and avibactam and relebactam can recyclize back to the intact drug molecule. Vaborbactam has a cyclic boronic acid core that covalently interacts with the catalytic serine residue inside the -lactamase active site. Similar to avibactam and relebactam, the cyclic boronate core is not hydrolyzed and thus is an effective inhibitor of -lactamase enzymes.

[0026] Vaborbactam and relebactam were discovered to inhibit class A carbapenemases such as KPC enzymes and are used in combination with carbapenems. Although avibactam is effective against KPC-2, a clinical isolate containing a KPC-2 variant with a D179Y mutation and some laboratory mutations, including the S130G mutation, were discovered to increase resistance to avibactam. There are currently no clinically available inhibitors for any class B -lactamases including NDM-1. There is only one inhibitor, avibactam, which is effective against OXA-48. Relebactam and vaborbactam are ineffective against OXA-48.

[0027] Although there are increasing efforts to create novel carbapenemase inhibitors, many currently existing drug discovery efforts are a mere optimization of the three known pharmacophores, -lactam, DBO, and boronate. Furthermore, all of the available inhibitors containing such pharmacophores are covalent inhibitors that attach to the nucleophilic serine in the active site of -lactamase enzymes. While there has been some successful drug discovery against KPC-2, NDM-1, and OXA-48 -lactamases using fragment-based drug discovery and virtual screening, most of the compounds that are past the pre-clinical phase contain known pharmacophores.

[0028] DNA-encoded library (DEL) technology was first proposed by Brenner and Lemer in 1992 as a new method of creating a diverse chemical library while utilizing DNA sequence as a barcode for identification of compounds subsequent to screening. Conventional high-throughput screening methods are relatively expensive and only explore a limited amount of chemical space. This limits the wide usage of chemical libraries in academic settings and is challenging for pharmaceutical companies to maintain large chemical screening libraries. In contrast, DEL uses significantly fewer resources and reagents and thus is receiving considerable attention among pharmaceutical companies and more widely in the drug discovery field.

[0029] DEL technology takes advantage of combinatorial synthesis and a DNA barcoding system to screen a wide range of chemical space while efficiently identifying hit compounds by DNA sequencing. DELs are created using split-and-pool combinatorial synthesis. The libraries are designed to contain drug-like molecules that are made out of building blocks with diverse chemical and biophysical properties.

[0030] The starting DNA-containing headpiece is split into a number of wells, each containing its own building block. After the attachment of the first building block, the contents of the wells are pooled and evenly split again into wells, each with a compound from the second set of building blocks. Upon addition of the second building block, a DNA fragment encoding the building block is ligated to the molecules in each well. This process is repeated for two or three cycles until the desired library is synthesized. The split-and-pool method allows synthesis of all possible combinations of building blocks in the most efficient manner. These molecules are covalently attached to a unique synthetic DNA barcode sequence that enables the identification of molecules that bind to a target after affinity enrichment steps. The population of candidate hit molecules enriched in a binding selection to the target protein is identified by next-generation sequencing of their associated DNA barcodes. Normalized Z-scores are used in calculating an enrichment score for each compound compared to a non-target control.

[0031] In addition to the pharmacophore -lactam ring, all -lactam antibiotics have a carboxylate group that significantly contributes to the binding energy of the molecules inside the active site. The carboxylate binding pocket is adjacent to but separate from the catalytic residues in the active site and is present in all four classes of -lactamase enzymes. Other functional groups, such as sulfonic acid and tetrazole, are also known to bind in the same pocket. In the conventional creation of DELs, it is common to eschew these functional groups to avoid generating libraries of compounds that are overly hydrophilic. One skilled in the art of medicinal chemistry may often consider drug-like molecules having a middle range of hydrophobicity and lipophilicity ideal, as such properties favor permeation through a cell membrane while also being water-soluble.

[0032] For targeting Gram-negative bacteria, however, a drug molecule can also penetrate through outer membrane porins, thus the hydrophilicity can be increased, and, indeed, -lactam antibiotics are hydrophilic molecules. Thus, the present disclosure describes the first effort to create a -lactamase-focused DEL containing a core functionality with a known affinity for -lactamases. It has been hypothesized that such an approach greatly increases the likelihood of identifying compounds which bind strongly one or more of the three classes of -lactamase enzymes, as well as other enzymes containing a carboxylate binding pocket.

[0033] Thus, in one aspect, the present disclosure relates to the discovery of new small molecule inhibitors of -lactamase enzymes including, but not limited to NDM-1, KPC-2, and OXA-48, as well as bacterial penicillin binding proteins (PBPs), using DNA-encoded library (DEL) technology.

[0034] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0035] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of about 0.1% to about 5% or about 0.1% to 5% should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement about X to Y has the same meaning as about X to about Y, unless indicated otherwise. Likewise, the statement about X, Y, or about Z has the same meaning as about X, about Y, or about Z, unless indicated otherwise.

[0036] In this document, the terms a, an, or the are used to include one or more than one unless the context clearly dictates otherwise. The term or is used to refer to a nonexclusive or unless otherwise indicated. The statement at least one of A and B or at least one of A or B has the same meaning as A, B, or A and B. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0037] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

Definitions

[0038] The term about as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0039] The term acyl as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a formyl group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a haloacyl group. An example is a trifluoroacetyl group.

[0040] The term alkenyl as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, CHCCCH.sub.2, CHCH(CH.sub.3), CHC(CH.sub.3).sub.2, C(CH.sub.3)CH.sub.2, C(CH.sub.3)CH(CH.sub.3), C(CH.sub.2CH.sub.3)CH.sub.2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

[0041] The term alkoxy as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0042] The term alkyl as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0043] The term alkylene or alkylenyl as used herein refers to a bivalent saturated aliphatic radical (e.g., CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., CH.sub.2) different (e.g., CH.sub.2CH.sub.2) carbon atoms.

[0044] The term alkynyl as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to CCH, CC(CH.sub.3), CC(CH.sub.2CH.sub.3), CH.sub.2CCH, CH.sub.2CC(CH.sub.3), and CH.sub.2CC(CH.sub.2CH.sub.3) among others.

[0045] The term amine as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group).sub.3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to RNH.sub.2, for example, alkylamines, arylamines, alkylarylamines; R.sub.2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R.sub.3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term amine also includes ammonium ions as used herein.

[0046] The term amino group as used herein refers to a substituent of the form NH.sub.2, NHR, NR.sub.2, NR.sub.3.sup.+, wherein each R is independently selected, and protonated forms of each, except for NR.sub.3.sup.+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An amino group within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An alkylamino group includes a monoalkylamino, dialkylamino, and trialkylamino group.

[0047] The term aralkyl as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0048] The term aryl as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.

[0049] The term cycloalkyl as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term cycloalkenyl alone or in combination denotes a cyclic alkenyl group.

[0050] A disease is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

[0051] In contrast, a disorder in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

[0052] A disease or disorder is ameliorated if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

[0053] As used herein, the terms effective amount, pharmaceutically effective amount and therapeutically effective amount refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0054] The terms halo, halogen, or halide group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0055] The term haloalkyl group, as used herein, includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0056] The term heteroaryl as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

[0057] Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

[0058] The term heteroarylalkyl as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0059] The term heteroarylene or heteroarylenyl as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring.

[0060] The term heterocyclylalkyl as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

[0061] The term heterocyclyl as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase heterocyclyl group includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed herein.

[0062] The term hydrocarbon or hydrocarbyl as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.

[0063] As used herein, the term hydrocarbyl refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (C.sub.a-C.sub.b)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C.sub.1-C.sub.4)hydrocarbyl means the hydrocarbyl group can be methyl (C.sub.1), ethyl (C.sub.2), propyl (C.sub.3), or butyl (C.sub.4), and (C.sub.0-C.sub.b)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.

[0064] The term independently selected from as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase X.sup.1, X.sup.2, and X.sup.3 are independently selected from noble gases would include the scenario where, for example, X.sup.1, X.sup.2, and X.sup.3 are all the same, where X.sup.1, X.sup.2, and X.sup.3 are all different, where X.sup.1 and X.sup.2 are the same but X.sup.3 is different, and other analogous permutations.

[0065] The term monovalent as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.

[0066] The term organic group as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R).sub.2, CN, CF.sub.3, OCF.sub.3, R, C(O), methylenedioxy, ethylenedioxy, N(R).sub.2, SR, SOR, SO.sub.2R, SO.sub.2N(R).sub.2, SO.sub.3R, C(O)R, C(O)C(O)R, C(O)CH.sub.2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R).sub.2, OC(O)N(R).sub.2, C(S)N(R).sub.2, (CH.sub.2).sub.0-2N(R)C(O)R, (CH.sub.2).sub.0-2N(R)N(R).sub.2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R).sub.2, N(R)SO.sub.2R, N(R)SO.sub.2N(R).sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R).sub.2, N(R)C(S)N(R).sub.2, N(COR)COR, N(OR)R, C(NH)N(R).sub.2, C(O)N(OR)R, C(NOR)R, and substituted or unsubstituted (C.sub.1-C.sub.100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted.

[0067] The terms patient, subject, or individual are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0068] As used herein, the term pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0069] As used herein, the language pharmaceutically acceptable salt refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0070] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, -hydroxybutyric, salicylic, galactaric and galacturonic acid.

[0071] Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

[0072] As used herein, the term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The pharmaceutically acceptable carrier may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0073] The term phenylene or phenylenyl as used herein refers to a bivalent phenyl radical (e.g., 1,4-phenylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from a benzene moiety.

[0074] The term room temperature as used herein refers to a temperature of about 15 C. to 28 C.

[0075] The term solvent as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0076] The term substantially as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term substantially free of as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt % to about 5 wt % of the material, or about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt % or less. The term substantially free of can mean having a trivial amount of, such that a composition is about 0 wt % to about 5 wt % of the material, or about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt % or less, or about 0 wt %.

[0077] The term substituted as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term functional group or substituent as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R).sub.2, CN, NO, NO.sub.2, ONO.sub.2, azido, CF.sub.3, OCF.sub.3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R).sub.2, SR, SOR, SO.sub.2R, SO.sub.2N(R).sub.2, SO.sub.3R, C(O)R, C(O)C(O)R, C(O)CH.sub.2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R).sub.2, OC(O)N(R).sub.2, C(S)N(R).sub.2, (CH.sub.2).sub.0-2N(R)C(O)R, (CH.sub.2).sub.0-2N(R)N(R).sub.2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R).sub.2, N(R)SO.sub.2R, N(R)SO.sub.2N(R).sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R).sub.2, N(R)C(S)N(R).sub.2, N(COR)COR, N(OR)R, C(NH)N(R).sub.2, C(O)N(OR)R, and C(NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C.sub.1-C.sub.100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl.

[0078] A therapeutic treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0079] The terms treat, treating and treatment, as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.

Compounds

[0080] In one aspect, the present disclosure provides a compound of formula (I), or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof:

##STR00002##

wherein: [0081] R.sup.1a and R.sup.1b are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted C.sub.2-C.sub.12 heterocyclyl, optionally substituted C.sub.6-C.sub.12 aryl, and C(O)(optionally substituted C.sub.1-C.sub.6 alkyl); [0082] A.sup.1 and A.sup.2 are each independently selected from the group consisting of a bond, optionally substituted phenylenyl and optionally substituted C.sub.2-C.sub.9 heteroarylenyl; [0083] A.sup.3 is selected from the group consisting of optionally substituted C.sub.6-C.sub.12 aryl and optionally substituted C.sub.2-C.sub.12 heteroaryl; [0084] L.sup.1 and L.sup.2 are each independently selected from the group consisting of a bond, optionally substituted C.sub.1-C.sub.3 alkylenyl, C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-O, C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-, (optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl, C(O)(optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), and C(O)(optionally substituted C.sub.3-C.sub.8 cycloalkylenyl)C(O); [0085] R.sup.2 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl, [0086] wherein R.sup.2 can combine with A.sup.2 to form an optionally substituted C.sub.3-C.sub.8 heterocycloalkyl; [0087] X is selected from the group consisting of N(R.sup.1a)(R.sup.1b) and optionally substituted C.sub.2-C.sub.12 heterocyclyl; [0088] Y is selected from the group consisting of a bond, N(R.sup.2), (CH.sub.2).sub.1-3N(R.sup.2)**, O, and S; [0089] * indicates a bond between L.sup.1 and A.sup.1; [0090] ** indicates a bond between Y and L.sup.2; [0091] *** indicates a bond between A.sup.2 and A3; and [0092] each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

[0093] In certain embodiments, A.sup.1 is a bond. In certain embodiments, A.sup.2 is a bond. In certain embodiments, L.sup.1 is a bond. In certain embodiments, X is

##STR00003##

In certain embodiments, Y is a bond or NH.

[0094] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

##STR00004##

wherein: [0095] A.sup.1 and A.sup.2 are each independently selected from the group consisting of optionally substituted phenylenyl and optionally substituted C.sub.2-C.sub.9 heteroarylenyl; [0096] A.sup.3 is optionally substituted C.sub.6-C.sub.12 aryl; [0097] L.sup.1 and L.sup.2 are each independently selected from the group consisting of bond, optionally substituted C.sub.1-C.sub.3 alkylenyl, C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-O, C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)-, (optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), C(O)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl, C(O)(optionally substituted C.sub.3-C.sub.8 heterocycloalkylenyl)(optionally substituted C.sub.1-C.sub.3 alkylenyl)C(O), and C(O)(optionally substituted C.sub.3-C.sub.8 cycloalkylenyl)C(O); [0098] R.sup.1a and R.sup.1b are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.12 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted C.sub.2-C.sub.12 heterocyclyl, optionally substituted C.sub.6-C.sub.12 aryl, and C(O)(optionally substituted C.sub.1-C.sub.6 alkyl); [0099] R.sup.2 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl, [0100] wherein R.sup.2 can combine with A.sup.2 to form an optionally substituted C.sub.3-C.sub.8 heterocycloalkyl; [0101] Y is selected from the group consisting of N(R.sup.2), (CH.sub.2).sub.1-3N(R.sup.2)**, O, and S; [0102] * indicates a bond between L.sup.1 and A.sup.1; [0103] ** indicates a bond between Y and L.sup.2; [0104] *** indicates a bond between A.sup.2 and A.sup.3; and [0105] each occurrence of R.sup.A and R.sup.B is independently selected from the group consisting of H, C(O)(optionally substituted C.sub.1-C.sub.6 alkyl), optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.7-C.sub.12 aralkyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl.

[0106] In certain embodiments, A.sup.1 is selected from the group consisting of:

##STR00005##

wherein: [0107] R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl.

[0108] In certain embodiments, at least one selected from R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d, is H. In certain embodiments, at least two selected from R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are H. In certain embodiments, at least three selected from R.sup.3a, R.sup.3b, R.sup.3c, and R.sup.3d are H.

[0109] In certain embodiments, A.sup.1 is

##STR00006##

In certain embodiments, A.sup.1 is

##STR00007##

In certain embodiments, A.sup.1 is

##STR00008##

In certain embodiments, A.sup.1 is

##STR00009##

In certain embodiments, A.sup.1 is

##STR00010##

In certain embodiments, A.sup.1 is

##STR00011##

In certain embodiments, A.sup.1 is

##STR00012##

[0110] In certain embodiments, A.sup.2 is selected from the group consisting of:

##STR00013##

wherein: [0111] Z is selected from the group consisting of O, S, and NR.sup.4; [0112] R.sup.4 is selected from the H and optionally substituted C.sub.1-C.sub.6 alkyl; and [0113] R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d, if present, are each independently selected from the group consisting of H, halogen, OR.sup.A, C(O)OR.sup.A, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.8 cycloalkyl.

[0114] In certain embodiments, at least one selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d is H. In certain embodiments, at least two selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are H. In certain embodiments, at least three selected from R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are H.

[0115] In certain embodiments A.sup.2 is

##STR00014##