RU2793931C2 - Benzylamine-containing heterocyclic compounds and compositions effective against mycobacterial infections - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound having one of following formulas ND-011544, ND-011598, ND-011622, ND-10885. The invention also relates to a pharmaceutical composition for the treatment of pathological conditions characterized by mycobacterial activity or infection, containing effective amount of a compound according to the invention and a physiologically acceptable carrier.

EFFECT: compounds having mycobacterial activity.

6 cl, 8 dwg, 1 ex

Description

RELATED APPLICATIONS

This application claims priority over U.S. Provisional Application No. 62/220192, filed September 17, 2015, the entire contents of which are incorporated herein by reference.

STATEMENT REGARDING PUBLIC RESEARCH

This invention was made with government support under grant R01AI054193 from the National Institutes of Health (NIH). The government has certain rights to this invention.

BACKGROUND OF THE INVENTION

There is an urgent need for new treatments for mycobacterial infections on a global and national scale. Mycobacterial infections are caused by pathogens such as Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and closely related species such as Mycobacterium avium (MAC). Every twenty seconds, one person dies from TB, and the cure rate for MAC infection can be as low as 30%. More than one third of people in the world are infected with MBT, representing a significant threat to global health. Of greatest concern is the rapid increase in the number of hard-to-kill, drug-resistant MBT strains. They currently infect 450,000 people worldwide, and they appear with increased frequency in the United States. TB is an airborne pathogen and is easily spread from person to person by coughing, making even one case potentially very dangerous. Available treatments for these strains are of limited effectiveness but extremely expensive.

This document describes agents that can be a method of treating an infection caused by MBT, or an infection caused by MAC, or both. There is an unfulfilled need in the medical field for compounds effective against the MBT pathogen, or the MAC pathogen, or both, and the compounds of the present invention are considered effective against drug-resistant strains as single agents or as part of combination therapy.

DESCRIPTION OF GRAPHICS

On FIG. 1 is a graphical representation of the in vivo tolerability observed in mice for two exemplary compounds ND-11598 and ND-11622 administered orally at 100 mg/kg for two weeks and orally at 250 mg/kg for one week. The mice showed no signs of malaise, weight loss, and all survived after the course of treatment.

On FIG. 2 is a graphical representation of the in vivo efficacy of ND-10885 in mice infected with Mycobacterium avium 101 when administered orally at doses of 25 mg/kg and 100 mg/kg. Panel A is the log 10 reduction in colony forming units (CFU) of bacteria in the lungs treated with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg), and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Box B is the log 10 reduction in colony forming units (CFU) of bacteria in the spleen when treated with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg), and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Panel C is the log 10 reduction in colony forming units (CFU) of bacteria in the liver with treatment with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg) and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Statistically confirmed improvement in the effectiveness of the combination of drugs in the lungs and spleen.

On FIG. 3 shows in tabular form the in vitro activity of several compounds against various serotypes of Mycobacterium avium and a strain of M. avium resistant to gentamicin. Rifampin is included as a positive control and DMSO as a negative control. MIC values are presented in µg/mL and determined using resazurin dye.

On FIG. 4 tabulates the in vitro activity of several compounds against Mycobacterium intracellulare (ATCC 13950). Rifampin, clarithromycin, ethambutol and azithromycin are included as positive controls and DMSO as negative controls. MIC values are presented in µg/mL and determined using resazurin dye.

On FIG. 5 tabulates the in vitro activity of several compounds against clinical strains of Mycobacterium avium, with clarithromycin used as a positive control. MIC values are presented in μg/ml and determined using the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

On FIG. 6 presents in tabular form the in vitro activity of several compounds against clinical strains of Mycobacterium kansasii; clarithromycin was used as a positive control. MIC values are presented in μg/ml and determined using the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

On FIG. 7 is a graphical representation of the MIC values of ND-11176 and clofazimine, both alone and in combination, against Mycobacterium abscessus as assessed by the "chessboard" method. Clarithromycin was used as a positive control. MIC values are presented in µg/mL and determined using resazurin dye. In the figure, dark cells represent the dead, lighter cells represent the living.

On FIG. Table 8 shows compounds and screening results against Mycobacterium tuberculosis (MBT) H37Rv in various media (GAS, 7H12), low oxygen conditions (LORA), toxicity to Vero cells, and activity against Mycobacterium avium (101 and 2151 ) and Mycobacterium intracellulare. The dye resazurin was used to determine the MIC values in relation to M. avium and M. intracellulare, and MABA was used to determine the MIC in relation to MBT.

DESCRIPTION OF SOME MODES FOR CARRYING OUT THE INVENTION

In one embodiment, the invention provides a compound having one of the following formulas:

where each X is independently N, C-R3 or C-R4; with the proviso that no more than two X's are N and one or more C-R3 or C-R4 groups may be attached to another C-R3 or C-R4 to form a fused ring;

where R1 and R2 are each independently hydrogen, an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonyloxy group, an alkylthio group, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу, карбонильную группу, карбоксилатную группу , carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group, hydroxy group, isocyanato group, , an isocyano group, a mercapto group, a nitro group, an oxo group, a perhaloalkenyl group, a perhaloalkoxy group, a perhaloalkyl group, a perhaloalkynyl group, a perhaloarylalkyl group, a perhaloaryl group, a perhalocycloalkyl group, a phosphate group, a phosphine group, a phospho group, a sulfate group, a sulfo group, a sulfonyl group, their oxidized form, their a substituted form, their form containing heteroatoms, or a combination thereof;

where each R3 is independently hydrogen, a "C" group, an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonyloxy group, an alkylthio group группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу, карбонильную группу, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group, , isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfate group, sulfo group, sulfonyl group, their oxidized form , their substituted form, their form containing heteroatoms, or a combination thereof; And

where each R4 is independently hydrogen, a "D-group", an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonyloxy group, an alkylthio group группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу, карбонильную группу, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group, , isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfate group, sulfo group, sulfonyl group, their oxidized form , their substituted form, their form containing heteroatoms, or a combination thereof;

or its resonant form, or its salt, or the salt of its resonant form.

In another embodiment, the invention provides a composition that contains a compound and a physiologically acceptable carrier.

In another embodiment, the invention provides a method that includes administering a compound or composition to a subject in need thereof for treating said subject.

In some embodiments, the form of the compound is not particularly limited. For example, it may be a resonance form, a salt form, or a salt of the resonance form. Mixtures of different shapes are possible, and compositions that contain mixtures of shapes.

In some embodiments, the compound is in the form of a salt. In some embodiments of the invention, the connection is in resonant form. In some embodiments, the resonant form is an ionic resonant form.

In some embodiments, each R1-R4 group may independently and optionally be selected from one or more substituent groups described herein. In some embodiments, each R1-R4 group may independently and optionally be further substituted with one or more substituent groups described herein. In some embodiments, each R1-R4 group may independently and optionally be attached directly to the corresponding parent structure via one or more chemical bonds, or may independently and optionally be indirectly attached to the corresponding parent structure via one or more divalent substituent intermediates. groups described in this document. Combinations of 1, 2, 3 or 4 divalent intermediate substituent groups are possible.

In some embodiments, R1 and R2 are each independently hydrogen, an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonylthiooxy group, , алкинильную группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу, карбонильную group, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group , imino group, isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfate group, sulfonyl group, their an oxidized form, a substituted form thereof, a heteroatom-containing form thereof, or a combination thereof.

In some embodiments, each R3 is independently hydrogen, a "C-group", an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonyloxy group , алкилтиогруппу, алкинильную группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу , carbonyl group, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, hydroxyaminocyclic group, , hydroxy group, imino group, isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfonyl group, sulfonyl group , their oxidized form, their substituted form, their form containing heteroatoms, or a combination thereof. Each R3 group may independently and optionally be further substituted with one or more substituent groups described herein. In some embodiments, each R3 group may independently and optionally be attached directly to the pendant group via one or more chemical bonds, or may independently and optionally be indirectly attached to the pendant group via one or more divalent intermediate substituent groups described in this document. Combinations of 1, 2, 3 or 4 divalent intermediate substituent groups are possible.

In some embodiments of the invention in which the R3 group is further substituted with a substituent group described herein, the substituent group may independently and optionally be attached directly to the R3 group via one or more chemical bonds, or may independently and optionally be indirectly attached to the group R3 via one or more independent divalent intermediate substituent groups described herein. Combinations of 1, 2, 3 or 4 independent divalent intermediate substituent groups between the R3 group and the substituent group are possible.

In some embodiments, each R4 is independently hydrogen, a "D-group", an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, an alkylsulfonyloxy group , алкилтиогруппу, алкинильную группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу, карбазоильную группу , carbonyl group, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, hydroxyaminocyclic group, , hydroxy group, imino group, isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfonyl group, sulfonyl group , their oxidized form, their substituted form, their form containing heteroatoms, or a combination thereof. Each R4 group may independently and optionally be further substituted with one or more substituent groups described herein. In some embodiments, each R4 group may independently and optionally be attached directly to the pendant group via one or more chemical bonds, or may independently and optionally be indirectly attached to the pendant group via one or more divalent intermediate substituent groups described in this document. Combinations of 1, 2, 3 or 4 divalent intermediate substituent groups are possible.

In some embodiments of the invention in which the R4 group is further substituted with a substituent group described herein, the substituent group may independently and optionally be attached directly to the R4 group via one or more chemical bonds, or may independently and optionally be indirectly attached to the group R4 via one or more independent divalent intermediate substituent groups described herein. Combinations of 1, 2, 3 or 4 independent divalent intermediate substituent groups between the R4 group and the substituent group are possible.

In some embodiments, R1-R4 are each independently hydrogen, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a halo group, an alkenyl group, an alkynyl group, an aryl group, a hydroxy group, an acyl group, an oxo group, a mercapto group, an alkylthio group, an alkoxy group, a heterocyclic group , heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, amino group, alkylamino group, dialkylamino group, amidine group, amide group, carbamoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylaminocarbonyl group, alkylaminocarbonyl group , an aryloxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a perhaloalkyl group, a perhaloalkoxy group, a perhalocycloalkyl group, a perhaloalkenyl group, a perhaloalkynyl group, a perhaloaryl group, a perhaloarylalkyl group, an oxidized form thereof, a substituted form thereof, a form containing heteroatoms, or a combination thereof.

In some embodiments, each R1-R4 group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, halo group, alkenyl group, alkynyl group, aryl group, hydroxy group, acyl group, oxo group, mercapto group, alkylthio group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, amino group, alkylamino group, dialkylamino group, amidine group, carbamoyl group group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, their oxidized form, their substituted form, their form containing heteroatoms, or combinations thereof.

In some embodiments, each R1-R4 group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, halo group, alkenyl group, alkynyl group, aryl group, hydroxy group, acyl group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, amino group, alkylamino group, dialkylamino group, amidine group, amide group, carbomoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkoxycarbonyl group group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, their oxidized form, their substituted form, their form containing heteroatoms, or combinations thereof.

In some embodiments, each R1-R4 group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, alkenyl group, alkynyl group, aryl group, acyl group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, carbamoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, their oxidized form form, their form containing heteroatoms, or combinations thereof.

In some embodiments, each R1-R4 group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group, heteroaryl group , arylalkyl group, heteroarylalkyl group, their oxidized form, their substituted form, their form containing heteroatoms, or combinations thereof.

In some embodiments, each R1-R4 is independently hydrogen, alkyl, substituted alkyl, linear alkyl, branched alkyl allyl, substituted allyl, heteroalkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, acyl, aroyl, heteroaroyl, a substituted form thereof, their form containing heteroatoms, or a combination thereof.

In some embodiments, R1-R4 are each independently hydrogen, alkyl, substituted alkyl allyl, substituted allyl, characterized in that cycloalkyl, aryl, heteroatom substituted aryl, heteroaryl, acyl, aroyl, heteroaroyl, their substituted form, their a form containing heteroatoms, or a combination thereof.

In some embodiments, R1-R4 are each independently hydrogen, alkyl, allyl, cycloalkyl, aryl, acyl, aroyl, a substituted form thereof, a heteroatom-containing form thereof, or a combination thereof.

In some embodiments, each R1-R4 group may independently and optionally be substituted, unsubstituted, saturated, unsaturated, or include a combination of these characteristics. In the case of substituted groups, the substituent group or groups may be selected from any of those defined herein.

In some embodiments, one or more atoms in one or more R1-R4 are independently replaced by one or more independent heteroatoms, their oxidized form, or a combination thereof.

In some embodiments, each R1-R4 group may independently and optionally contain one or more atoms that are replaced by one or more heteroatoms, eg N, O, P, S, their oxidized form, or a combination thereof.

In some embodiments, one or more carbon atoms in one or more R1-R4 are independently replaced by one or more independent heteroatoms selected from the group consisting of N, O, S, or a combination thereof.

In some embodiments, one or more R1-R4 groups may be independently and optionally further substituted, one or more R1-R4 groups may be independently and optionally attached directly to the corresponding parent structure via one or more chemical bonds. or may independently and optionally be indirectly attached to the respective parent structure via one or more divalent intermediate substituent groups. Combinations of 1, 2, 3, 4 and 5 independent divalent intermediate substituent groups are possible and can be any of those defined herein.

In some embodiments, one or more R1 groups may independently and optionally be further substituted with one or more independent substituent groups described herein. In some embodiments, one or more R1 groups may independently and optionally be attached directly to the pyridine or thiazole moiety via one or more chemical bonds, or may independently and optionally be indirectly attached to the pyridine or thiazole moiety via one or more divalent intermediate substituent groups described in this document. 1, 2, 3, 4, or 5 independent divalent intermediate substituent groups are possible, and may be any of those defined herein.

In some embodiments, one or more R2 groups may independently and optionally be further substituted with one or more independent substituent groups described herein. In some embodiments, one or more R2 groups may independently and optionally be attached directly to the imidazole moiety via one or more chemical bonds, or may independently and optionally be indirectly attached to the imidazole moiety via one or more divalent intermediate substituent groups. described in this document. Possible 1, 2, 3, 4 or 5 independent divalent intermediate substituent groups, and they can be any of those defined in this document.

In some embodiments, one or more R3 groups may independently and optionally be further substituted with one or more independent substituent groups described herein. In some embodiments, one or more R3 groups may independently and optionally be attached directly to the pendant group via one or more chemical bonds, or may independently and optionally be indirectly attached to the pendant group via one or more divalent intermediate substituent groups. described in this document. Possible 1, 2, 3, 4 or 5 independent divalent intermediate substituent groups, and they can be any of those defined in this document.

In some embodiments, one or more R4 groups may independently and optionally be further substituted with one or more independent substituent groups described herein. In some embodiments, one or more R4 groups may independently and optionally be attached directly to the pendant group via one or more chemical bonds, or may independently and optionally be indirectly attached to the pendant group via one or more divalent intermediate substituent groups. described in this document. 1, 2, 3, 4, or 5 independent divalent intermediate substituent groups are possible, and may be any of those defined herein.

In some embodiments, R1 is halo, Cl, F, Br, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitrile, nitro.

In some embodiments, R1 is Cl, F, Br, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, hydroxyl, nitrile, nitro.

In some embodiments, R1 is Cl, F, or C ₁ -C ₄ alkyl.

In some embodiments, R2 is halo, Cl, F, Br, CF ₃ , alkyl, alkenyl, alkoxy.

In some embodiments, R2 is Cl, F, CF ₃ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy.

In some embodiments, R2 is Cl, F, CF ₃ , C ₁ -C ₄ alkyl.

In some embodiments, R3 is a "C-group". In some embodiments, R3 may contain one or more independent "D-group" substituents. In some embodiments, R3 may include one or more independent R4 groups replacing it. In some embodiments, R3 may be a "C-group" and also contain one or more independent R4 substituents. In some embodiments, R3 may be a "C-group" and also contain one or more independent "D-group" substituents. In some embodiments, at least one R3 is halogen.

In some embodiments, R4 is a "D-group". In some embodiments, at least one R4 is halogen.

In some embodiments, R1 is not hydrogen. In some embodiments, R2 is not hydrogen. In some embodiments, R3 is hydrogen. In some embodiments, R4 is hydrogen.

In the following formulas:

next part:

referred to in this document as a "side group".

In some embodiments of the invention in the side group:

none of the X's are nitrogen. In such an embodiment, each X in the side group is independently C-R3 or C-R4, and if there is more than one C-R3, they may be the same or different, and if there is more than one C-R4, they may be the same or different. In some embodiments of the invention, none of the X is C-R3. In some embodiments of the invention, none of the X is C-R4. In some embodiments, both C-R4 and C-R3 are present. In some embodiments, one or more C-R3 or C-R4 groups may form a ring with one or more other C-R3 groups, one or more other C-R4 groups, or a combination of C-R3 and C-R4 groups. to obtain a ring fused with the side group ring.

In other embodiments of the invention in the side group:

one or two X's are nitrogen, and the pendant group has one of the following structures:

where each X is independently C-R3 or C-R4, and if there is more than one C-R3, they may be the same or different, and if there is more than one C-R4, they may be the same or different. In some embodiments of the invention, none of the X is C-R3. In some embodiments of the invention, none of the X is C-R4. In some embodiments, both C-R3 and C-R4 are present. In some embodiments, one or more C-R3 or C-R4 groups may form a fused ring with one or more other C-R3 groups, one or more other C-R4 groups, or a combination of C-R3 and C- groups. R4.

In some embodiments, one or more C-R3 or C-R4 groups may combine and form a fused ring with one or more other C-R3 groups, one or more other C-R4 groups, or a combination of C-R3 groups and C-R4.

In some embodiments of the invention, in which one or more C-R3 or C-R4 groups can connect and form a fused ring with one or more other C-R3 groups, one or more other C-R4 groups, or a combination of C groups -R3 and C-R4, side group:

has one of the following condensed ring structures:

where each X is independently N, C-R3 or C-R4; and "E" represents the ring, shown in dotted line, which is formed from one or more R3 or R4 groups connected to one or more other R3, R4 or a combination of R3 and R4 groups. Ring E may be carbocyclic or heterocyclic, saturated or unsaturated, substituted or unsubstituted. By carbocyclic, ring E is meant to be cycloalkane, cycloalkene, aryl, or the like. In the case of a heterocyclic structure, ring E may have 1, 2, or 3 ring carbon atoms independently replaced by one or more independent oxygen, nitrogen, sulfur atoms, or a combination thereof. Considering the carbon atoms C-R3 and C-R4 shared by the two rings, ring E can contain 4-12 members, this range includes 4, 5, 6, 7, 8, 9, 10, 11, 12 members. In some embodiments, the C-R3 or C-R4 groups that form the E ring are adjacent, although they may be separated by an intermediate N, C-R3 or C-R4.

In some embodiments, the E ring is formed by joining two adjacent independent C-R3 groups. In some embodiments, the E ring is formed by joining two adjacent independent C-R4 groups. In some embodiments, the E ring is formed by joining a C-R3 group to an adjacent C-R4 group.

In some embodiments, Ring E is a carbocyclic or heterocyclic, saturated or unsaturated, substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring. In some embodiments, ring E is a carbocyclic or heterocyclic 5-6 membered ring, which may be saturated or unsaturated, substituted or unsubstituted. In some embodiments, the dotted line in the figure above represents a portion of ring E that is saturated or unsaturated, substituted or unsubstituted, or contains or does not contain heteroatoms in the ring; and the carbons of ring E are not shared between the fused ring and the side group ring.

In some embodiments of the invention in which there is an E ring, the side group has one of the following formulas:

where each Y is independently C-R5, C(R5)(R5), C=O, N, N-R5, O, S, S=O or S(=O) ₂ ; with the proviso that no more than two Y's are C=O, N, N-R5, O, S, S=O or S(=O) ₂ ;

where, when each of two adjacent Y's is independently C-R5 or N and C-R5, the bond between said adjacent Y's may be a double bond;

and where each R5 is independently hydrogen, "C-group", "D-group", acyl group, alkenyl group, alkoxy group, alkoxycarbonyl group, alkoxycarbonyloxy group, alkoxysulfonyloxy group, alkyl group, alkylamino group, alkylaminocarbonyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkylsulfonyl group группу, алкилсульфонилоксигруппу, алкилтиогруппу, алкинильную группу, амидную группу, амидиновую группу, аминогруппу, арилалкоксигруппу, арилалкильную группу, арильную группу, арилкарбонильную группу, арилкарбонилоксигруппу, арилоксигруппу, арилоксикарбонильную группу, арилоксикарбонилоксигруппу, арилоксисульфонилоксигруппу, арилсульфонильную группу, арилсульфонилоксигруппу, азидогруппу, карбамидогруппу, карбамоильную группу , carbazoyl group, carbonyl group, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heterocyclyloxy group group, hydroxyamino group, hydroxy group, imino group, isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhalogenaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, phospho group , a sulfonyl group, their oxidized form, their substituted form, their form containing heteroatoms, or a combination thereof.

Each R5 group may independently and optionally be further substituted with one or more substituent groups described herein. In some embodiments, each R5 group may independently and optionally be attached directly to the E ring via one or more chemical bonds, or may independently and optionally be indirectly attached to the E ring via one or more divalent intermediate substituent groups described herein. document. Combinations of 1, 2, 3 or 4 divalent intermediate substituent groups are possible.

In some embodiments of the invention in which the R5 group is further substituted with a substituent group described herein, the substituent group may independently and optionally be attached directly to the R5 group via one or more chemical bonds, or may independently and optionally be indirectly attached to the group R5 via one or more independent divalent intermediate substituent groups described herein. Combinations of 1, 2, 3 or 4 independent divalent intermediate substituent groups between the R5 group and the substituent group are possible.

In some embodiments of the invention in which there is an E ring, the side group has one of the following formulas:

For example, a side group may have one of the following side group formulas:

It is intended that in the above side group formulas, the positions of the various R3 and R4 groups relative to each other on the side group ring, the nitrogen positions and/or the position of the fused ring are not limited. Taking one structure as an example, and unless otherwise noted, the structure depicted as follows:

can be depicted as follows:

Additionally, in the above side group formulas, when one -R3 is shown, one or more -R3, each independently, can be attached to the side group ring. Similarly, when one -R4 is shown, one or more -R4s, each independently, can be attached to the side group ring.

In some embodiments of the invention, in which there is a ring E, the pendant group has one of the following formulas, where one or more Y, denoted below as G, each independently selected from N, N-R5, O, S, S=O or S(=O) ₂ :

in which each of the remaining Y shown is independently C-R5, C(R5)(R5) or C=O;

and where, when each of two adjacent Y's is independently C-R5 or N and C-R5, the bond between said adjacent Y's may be a double bond.

In some embodiments, R3 is a group having the following formula:

where I at each occurrence is independently a divalent substituent as described herein; and m is 0, 1, or 2 and o is 0, 1, or 2;

where J is an optionally substituted secondary amine, tertiary amine, cyclic amine, heterocycle, heterocycle containing a spiro group, N-containing heterocycle, O-containing heterocycle, N- and O-containing heterocycle, heteroaryl, N-containing heteroaryl, aryl, their an oxidized form, their form containing heteroatoms, their substituted form, or a combination thereof;

where K is at each occurrence independently R4, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, their oxidized form, their heteroatom-containing form, their substituted form, or a combination thereof; and n is 0, 1, or 2;

and where L is at each occurrence independently an optionally substituted R4, an oxidized form thereof, a heteroatom-containing form thereof, a substituted form thereof, or a combination thereof; and p is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments of the invention, I in each case may independently represent alkylene, alkenylene, alkyleneoxy, alkenyleneoxy or alkynylene, their oxidized form, their form containing heteroatoms, or their substituted form; and m is 0 or 1 and o is 0 or 1.

In some embodiments, J is an optionally substituted "C-group", a tertiary amine, a cyclic amine, a heterocycle, an N-containing heterocycle, an O-containing heterocycle, an N- and an O-containing heterocycle, heteroaryl, an N-containing heteroaryl, an aryl , their oxidized form, their form containing heteroatoms, their substituted form, or a combination thereof.

In some embodiments, K is at each occurrence independently an optionally substituted R4, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, their oxidized form, their heteroatom-containing form, a substituted form thereof, or a combination thereof; and n is 0 or 1.

In some embodiments, L is at each occurrence independently an optionally substituted R4 or "D-group", their oxidized form, their heteroatom-containing form, their substituted form; and p is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, if n, o, and p are 0, then J is a monovalent residue of an optionally substituted "C-group", a tertiary amine, a cyclic amine, a heterocycle, an N-containing heterocycle, an O-containing heterocycle, an N- and O-containing heterocycle, heteroaryl, N-containing heteroaryl, aryl, or a combination thereof, but if any of n, o, or p is not equal to 0, then J is a divalent residue of an optionally substituted "C-group", a tertiary amine, a cyclic amine, heterocycle, N-containing heterocycle, O-containing heterocycle, N- and O-containing heterocycle, heteroaryl, N-containing heteroaryl, aryl, or a combination thereof.

In some embodiments, if o and p are 0, then K is a monovalent residue of an optionally substituted R4, aryl, heteroaryl, heterocycle, cycloalkyl, cyclic group, or a combination thereof, but if either o or p is not 0, then K is a divalent residue of an optionally substituted R4, aryl, heteroaryl, heterocycle, cycloalkyl, cyclic group, or a combination thereof.

In some embodiments, R3 is or is substituted such that it contains a 3-, 4-, 5-, 6-membered ring, or a larger ring that contains one or more carbon atoms, substituted carbon atoms, and/or heteroatoms (N, O, S) in addition to their oxidized variants, including alkenes and cycloalkenes, heterocycles, and mixed carbocyclic and heterocyclic moieties.

In some embodiments of the invention, R3 includes a cyclic amine, while the nitrogen atom and carbon atoms form a C ₃ -C ₁₀ cyclic amine.

In some embodiments of the invention, R3 includes a cyclic amine, with the nitrogen atom and carbon atoms forming a C ₃ -C ₆ cyclic group.

In some embodiments, the cyclic amine has the following structure:

The index x in the cyclic amine is not particularly limited and may be any value. In some embodiments of the invention, x is 1-10. This interval includes all values and the subintervals in between, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

In some embodiments, one or more carbon atoms in the above cyclic amine structure may independently and optionally be substituted with one or more independent substituent groups described herein. In some embodiments of the invention, one or more than one carbon atom in the cyclic amine structure is oxidized. In some embodiments, one or more substituent groups may independently and optionally be attached directly to the cyclic amine structure via one or more chemical bonds, or may independently and optionally be indirectly attached to the cyclic amine structure via one or more divalent substituent intermediates. groups described in this document. Possible 1, 2, 3, 4 or 5 independent divalent intermediate substituent groups, and they can be any of those defined in this document. In some embodiments, one or more carbon atoms in the above cyclic amine structure are replaced with a heteroatom such as S, O, or N. In some embodiments, the cyclic amine is selected from the "C-group".

When nitrogen is present, the remainder of the cyclic amine ring is not particularly limited. The remainder of the ring may suitably be derived from a divalent cycloalkylene group, a divalent heterocycloalkylene group, a divalent arylene group, a divalent heteroarylene group, one or more divalent intermediate substituent groups, an oxidized form thereof, or a combination thereof. The cyclic amine may contain one or more rings. Combinations of various rings are possible.

In a cyclic amine, one or more of the ring atoms may optionally and independently be replaced by one or more heteroatoms, eg N, O, P, S, their oxidized form, or a combination thereof.

In a cyclic amine, one or more of the ring atoms may optionally and independently be substituted with one or more R ⁶ substituents. If there is more than one substituent group, they may be the same or different.

In a cyclic amine, one or more of the R ⁶ substituent groups may be further substituted with one or more additional substituent groups. If there is more than one additional substituent group, they may be the same or different.

In some embodiments, each substituent group and/or additional substituent groups may independently and optionally be selected from one or more of the substituent groups described herein.

In some embodiments, each R ⁶ group may independently and optionally be selected from one or more of the following groups: "D-group", hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, halogen group, alkenyl group, alkynyl group, aryl group, hydroxy group, acyl group, oxo group, mercapto group, alkylthio group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, amino group, alkylamino group, dialkylamido group, alkylamido group, , a carbamoyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an arylcarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an oxidized form thereof, a heteroatom-containing form thereof, a substituted form thereof, or combinations thereof.

In some embodiments, each R ⁶ group may independently and optionally be selected from one or more of the following groups: "D-group", hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, halogen group, alkenyl group, alkynyl group, aryl group, hydroxy group, acyl group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, amino group, alkylamino group, dialkylamino group, amidine group, amide group, alkylcarbonyl group, alkylcarbamoyl group , an alkoxycarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an arylcarbonyl group, an aryloxycarbonyl group, an oxidized form thereof, a heteroatom-containing form thereof, a substituted form thereof, or combinations thereof.

In some embodiments, each R ⁶ group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, alkenyl group, alkynyl group, aryl group, acyl group, alkoxy group, heterocyclic group, heteroaryl group, heteroarylcarbonyl group, aryloxy group, heteroaryloxy group, arylalkyl group, heteroarylalkyl group, arylalkoxy group, heteroarylalkoxy group, carbamoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, their oxidized form, their forms, containing heteroatoms, their substituted form, or combinations thereof.

In some embodiments, each R ⁶ group may independently and optionally be selected from one or more of the following groups: hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group, heteroaryl group, an arylalkyl group, a heteroarylalkyl group, an oxidized form thereof, a heteroatom-containing form thereof, a substituted form thereof, or combinations thereof.

Each R ⁶ group may be independently and optionally further substituted, and each R ⁶ group may independently and optionally be attached directly to the corresponding parent structure via one or more chemical bonds, or may independently and optionally be indirectly attached to the corresponding parent structure via one or more divalent intermediate substituent groups.

In some embodiments, the compound has one of the following formulas:

where A is ═C- or -S-, and the ring defined by "A-C-N" and a dotted line is a 5-6 membered ring;

where R ₁ and R ₂ defined previously;

where if there is more than one R1, they may be the same or different;

and where B has one of the following formulas:

where X and E are defined earlier.

In some embodiments of the invention, B may be a benzylamine substituted with various cycloheteroalkyls such as morpholine, piperidine, piperazine, fused or substituted at various positions, which can be easily obtained from a cyclic amine or a substituted cyclic amine. Non-limiting examples of cyclic amines include, for example, morpholine, thiomorpholine, piperidine, piperazine, and the like.

In some embodiments of the invention, B has one of the following formulas:

where R3, R4 and Y are defined previously.

Some non-limiting examples B are shown below:

Some non-limiting examples of R3 or "C-group" are shown below:

(X is O, NH)

In some embodiments, the "D-group" is hydrogen, halogen, Cl, F, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , CF ₃ , OCF ₃ , SF ₅ .

In some embodiments, the "D-group" is Cl, F, CH ₃ , CN, CF ₃ , OCF ₃ SF ₅ .

In some embodiments, the "D-group" is F, CH ₃ , CN, CF ₃ , OCF ₃ , SF ₅ .

In some embodiments, the alkyl group is a monovalent acyclic straight or branched, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical. In some embodiments, the alkyl group has the general formula (ignoring optional unsaturation, substitution, or the like) -C _n H _2n+1 . In some embodiments of the invention, n is 1-20 ((C ₁ -C ₂₀ ) alkyl), which may respectively include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C 10 , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ alkyl groups _. In some embodiments, the alkyl group may be straight or branched, substituted or unsubstituted, saturated or unsaturated, or include any combination of these characteristics. In some embodiments, one or more hydrogen atoms may optionally and independently be replaced by one or more substituent groups. In some embodiments, one or more carbon atoms may be optionally and independently replaced by one or more heteroatoms such as O, S, N, B, or any combination thereof. In some embodiments, the alkyl group may contain one or more double bonds, one or more triple bonds, or any combination thereof. In some embodiments, the alkyl group is attached to the parent structure via one or more independent divalent intermediate substituent groups. Some examples of alkyl groups, which are not intended to be limiting, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like.

In some embodiments, the cycloalkyl group is a monovalent, mono- or polycyclic, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical. In some embodiments, the cycloalkyl group has the general formula (ignoring optional unsaturation, substitution, or the like) -C _n H _2n-1 . In some embodiments, n is 3-20 ((C ₃ -C ₂₀ ) cycloalkyl), which may respectively include C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C _n , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ cycloalkyl groups. In some embodiments, the cycloalkyl group may be substituted or unsubstituted, saturated or unsaturated, mono-, bi-, tri-, or polycyclic, or include any combination of these characteristics. In some embodiments, one or more hydrogen atoms may optionally and independently be replaced by one or more substituent groups. In some embodiments, the cycloalkyl group may contain one or more sites of unsaturation, for example, it may contain one or more double bonds, one or more triple bonds, or any combination thereof to form a cycloalkenyl or cycloalkynyl group, or combinations thereof. In some embodiments, one or more carbon atoms may be optionally and independently replaced by one or more heteroatoms such as O, S, N, B, or any combination thereof. In some embodiments, the cycloalkyl group is attached to the parent structure via one or more independent divalent intermediate substituent groups. Some examples of cycloalkyl groups, which are not intended to be limiting, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl and the like. In the case of polycyclic groups, one or more rings may be bonded together via a bond or other divalent intermediate substituent group, fused (e.g. where one or more rings share two or more carbon atoms or heteroatoms), bonded via a single atom ( e.g. spiro compound) or bridged.

In some embodiments of the invention, the alkenyl group is a monovalent straight or branched, substituted or unsubstituted, unsaturated hydrocarbon radical. In some embodiments, the alkenyl group has the general formula (ignoring optional substitution, higher unsaturation, or the like) -C _n H _2n-2 . In some embodiments of the invention, n is 2-20 ((C ₂ -C ₂₀ )alkenyl), which may respectively include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ alkenyl groups. In some embodiments, the alkenyl group may be straight or branched, substituted or unsubstituted, have varying degrees of unsaturation, or include any combination of these characteristics. In some embodiments, one or more carbon atoms may be optionally and independently replaced by one or more heteroatoms such as O, S, N, B, or any combination thereof. In some embodiments of the invention, the alkenyl group is attached to the parent structure through one or more independent divalent intermediate substituent groups. Some examples of alkenyl groups, which are not intended to be limiting, include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, alkadienes, alkatrienes and the like.

In some embodiments, the alkynyl group is a monovalent, straight or branched, substituted or unsubstituted hydrocarbon radical that contains one or more carbon-carbon triple bonds. In some embodiments, the alkenyl group has the general formula (ignoring optional substitution, higher unsaturation, or the like) -C ₂ H _2n-3 . In some embodiments, n is 2-20 ((C ₂ -C ₂₀ ) alkynyl), which may respectively include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ alkynyl groups. In some embodiments, the alkynyl group may be straight or branched, substituted or unsubstituted, have varying degrees of unsaturation, or include any combination of these characteristics. In some embodiments, one or more carbon atoms may be optionally and independently replaced by one or more heteroatoms such as O, S, N, B, or any combination thereof. In some embodiments, the alkynyl group is attached to the parent structure via one or more independent divalent intermediate substituent groups. Some examples of alkynyl groups, which are not intended to be limiting, include alkadiines, alkatrienes, ethynyl, propynyl, butynyl, and the like.

In some embodiments of the invention, the aryl group is a monovalent, substituted or unsubstituted, monocyclic or polycyclic, aromatic hydrocarbon radical. In some embodiments of the invention, the aryl group is a radical, which, in accordance with the theory of Hückel, includes a cyclic delocalized (4n+2) pi-electron system. In some embodiments, the aryl group is a C ₅ -C ₂₀ aryl group. C ₅ -C ₂₀ aryl group may respectively include C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C 14 , C ₁₅ , C ₁₆ , _{C 17} , C ₁₈ , C ₁₉ and C ₂₀ aryl groups. In some embodiments of the invention, the aryl group may be substituted or unsubstituted, substituted with two or more groups that, taken together, form a cyclic group, or include any combination of these characteristics. In some embodiments of the invention, the aryl group is attached to the parent structure through one or more independent divalent intermediate substituent groups. Some examples of aryl groups, which are not intended to be limiting, include phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, pyrenyl, anthryl, indanyl, cresyl, and the like.

In some embodiments, the heterocyclic group is a monovalent, substituted or unsubstituted, saturated or unsaturated, mono- or polycyclic hydrocarbon radical that contains one or more heteroatoms in one or more rings. In some embodiments of the invention, the heterocyclic group is a C ₃ -C ₂₀ cyclic group in which one or more carbon atoms in the ring are independently replaced by one or more heteroatoms. The C ₃ -C ₂₀ heterocyclic group may respectively include C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C 11 , C ₁₂ , C ₁₃ , C ₁₄ , _{C 15} , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ are cyclic groups in which one or more carbon atoms are independently replaced by one or more heteroatoms. In some embodiments, the heteroatoms are selected from one or more of N, O, or S, or any combination thereof. In some embodiments, N or S or both may be independently substituted with one or more substituents. In some embodiments of the invention, the heterocyclic group may be substituted or unsubstituted, saturated or unsaturated, mono-, bi-, tri - or polycyclic, or include any combination of these characteristics. In some embodiments, one or more hydrogen atoms may optionally and independently be replaced by one or more substituent groups. In some embodiments, the heterocyclic group may contain one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, or any combination thereof. In some embodiments, the heterocyclic group is attached to the parent structure via one or more independent divalent intermediate substituent groups. Some examples of heterocyclic groups, which are not intended to be limiting, include cyclic amine, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanil, isochromanil, benzoxazinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1- yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazol idin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholinyl, 1,2-tetrahydrothiazine -2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1 ,2,5-oxathiazin-4-yl and the like.

In some embodiments, a heteroaryl group is a monovalent, substituted or unsubstituted, monocyclic or polycyclic, aromatic hydrocarbon radical in which one or more carbon atoms in the ring are independently replaced by one or more heteroatoms selected from O, S, and N. B In some embodiments, in addition to said heteroatom, the heteroaryl group may optionally contain up to 1, 2, 3, or 4 ring N atoms. In some embodiments, the heteroaryl group is an aryl group in which one or more ring carbon atoms are independently replaced by one or more heteroatoms. In some embodiments, the heteroaryl group is an aromatic radical which contains one or more heteroatoms and which, according to Hückel's theory, includes a cyclic delocalized (4n+2) pi electron system. In some embodiments, the heteroaryl group is a C5-C20 heteroaryl group. C ₅ -C ₂₀ heteroaryl group may respectively include C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C 11 , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , _{C 16 ,} C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ aryl groups in which one or more than one carbon atom in the ring is independently replaced by one or more heteroatoms. In some embodiments, the heteroaryl group may be substituted or unsubstituted, substituted with two or more groups which together form a cyclic group, or include any combination of these characteristics. In some embodiments, the heteroaryl group is attached to the parent structure via one or more independent divalent intermediate substituent groups. Some examples of alkynyl groups, which are not intended to be limiting, include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g. 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g. 1,2, 3-oxadiazolyl), thiadiazolyl (eg 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl and the like.

In some embodiments, the alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene groups are divalent radicals derived from the abstraction of hydrogen from the corresponding alkyl, cycloalkyl, alkenyl, alkynyl, arylene, and heteroarylene groups, and the like.

In some embodiments, the arylalkyl group is a monovalent radical derived from one or more aryl groups attached to one or more of an alkylene group, a cycloalkylene group, an alkenylene group, an alkynylene group, or a combination thereof. Alkylene, cycloalkylene, alkenylene and alkynylene groups are divalent radicals obtained by abstraction of hydrogen from the corresponding alkyl, cycloalkyl, alkenyl or alkynyl groups. In this context, any combination of an aryl group and an alkyl, cycloalkyl, alkenyl or alkynyl group is meant. In some embodiments, the aryl group is attached to the parent structure via one or more of an alkylene group, a cycloalkylene group, an alkenylene group, an alkynylene group, or a combination thereof, as the case may be. In some embodiments, the arylalkyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the heteroarylalkyl group is a monovalent radical derived from one or more heteroaryl groups attached to one or more of an alkylene group, a cycloalkylene group, an alkenylene group, an alkynylene group, or a combination thereof. Alkylene, cycloalkylene, alkenylene and alkynylene groups are divalent radicals obtained by abstraction of hydrogen from the corresponding alkyl, cycloalkyl, alkenyl or alkynyl groups. In this context, any combination of a heteroaryl group and an alkyl, cycloalkyl, alkenyl or alkynyl group is meant. In some embodiments, the heteroaryl group is attached to the parent structure via one or more of an alkylene group, a cycloalkylene group, an alkenylene group, an alkynylene group, or a combination thereof, as the case may be. In some embodiments, the heteroarylalkyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the halogen group is a monovalent halogen radical or a halogen-containing substituent group, for example, which is or contains one or more F, Br, Cl, I, or a combination thereof. As used herein, the term "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine, or fluoride, chloride, bromide, or iodide. In some embodiments, the halogen-containing substituent group may suitably include a substituent group in which one or more hydrogen atoms are independently replaced by one or more halogens. In some embodiments of the invention, the halogen group may be attached to the original structure through one or more independent divalent intermediate substituent groups.

In some embodiments, the hydroxy group is a monovalent hydroxyl radical (-OH) or a hydroxy-containing substituent group, for example, which is or contains one or more -OH. As used herein, the term "hydroxy" includes a -OH group. In some embodiments, the hydroxy-containing substituent group may suitably include a substituent group in which one or more hydrogen atoms are independently replaced by one or more -OH groups. In some embodiments of the invention, the hydroxyl group may be attached to the original structure through one or more independent divalent intermediate substituent groups.

In some embodiments, the oxo group is a monovalent radical that contains an oxygen atom =O attached by a double bond to carbon or another element. In some embodiments, the oxo group is a divalent radical that contains an oxygen atom -O- attached to two carbon atoms or two other elements. In some embodiments, the oxo group respectively includes aldehydes, carboxylic acids, ketones, sulfonic acids, amides, esters, and combinations thereof. In some embodiments, the oxo group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the mercapto or thiol group is a monovalent -SR radical or a group containing -SR. The R group is suitably selected from any of the substituent groups. In some embodiments, the mercapto group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments of the invention, the amino group is a monovalent radical -NH ₂ or a substituent group containing -NH ₂ . In some embodiments of the invention, the amino group may be attached to the original structure through one or more independent divalent intermediate substituent groups.

In some embodiments, the alkylamino group is a monovalent -NRH radical or a substituent group containing -NRH. The R group is suitably selected from any of the substituent groups. In some embodiments, the alkylamino group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the dialkylamino group is a monovalent -NRR radical or a substituent group containing -NRR. The R groups may be the same or different and are suitably and independently selected from any of the substituent groups. In some embodiments, the dialkylamino group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the acyl or carbonyl group is a monovalent radical that contains a -C(=O)R group. In some embodiments of the invention, the acyl group, respectively, includes aldehydes, ketones, and combinations thereof. The R group is suitably selected from any of the substituent groups. In some embodiments, the carbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments of the invention, the carboxyl group is a univalent radical -C(=O)OH or a substituent group containing -C(=O)OH. In some embodiments of the invention, the carboxyl group may be attached to the original structure through one or more independent divalent intermediate substituent groups.

In some embodiments of the invention, the carboxylate group is a monovalent anion -C(=O)O ^- , -C(=O)OR or -C(=O)OM, where M is a metal cation, or a substituent group containing an anion - C(=O)O ^- , -C(=O)OR or -C(=O)OM. The R group is suitably selected from any of the substituent groups. The metal cation may be suitably selected from Li, Na, K and the like. In some embodiments, the carboxylate group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the amidine group is a univalent radical -C(=NR)NRR or a substituent group containing -C(=NR)NRR. The R groups may be the same or different and are suitably and independently selected from any of the substituent groups. In some embodiments, the amidine group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the amide group is a univalent radical -E(=O)NRR or a substituent group containing -E(=O)NRR, in which E can be an atom other than carbon, such as a chalcogen (for example, S, Se, Te) or P. In some embodiments, the amide group, respectively, includes monovalent lactams, peptides, phosphoramides or sulfamides, -S(=O) ₂ NRR, -P(=O)(OH)NRR, and the like. The R groups may be the same or different and are suitably and independently selected from any of the substituent groups. In some embodiments of the invention, the amide group may be attached to the original structure through one or more independent divalent intermediate substituent groups.

In some embodiments, the carbamoyl group is a univalent radical -C(=O)NRR or a substituent group containing -C(=O)NRR. The R groups may be the same or different and are suitably and independently selected from any of the substituent groups. In some embodiments, the carbamoyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the sulfonyl group is a univalent radical -S(=O) ₂ R or a substituent group containing -S(=O) ₂ R. The R group is suitably selected from any of the substituent groups. In some embodiments, the sulfonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkylthio or sulfide group is a monovalent -SR radical or a substituent group containing -SR. The R group is suitably selected from any of the substituent groups. In some embodiments, the alkylthio group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkoxy group is a monovalent radical derived from a -O-alkyl group. In some embodiments, the alkylthio group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the aryloxy group is a monovalent radical derived from a -O-aryl group. In some embodiments, the aryloxy group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the heteroaryloxy group is a monovalent radical derived from a -O-heteroaryl group. In some embodiments, the heteroaryloxy group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the arylalkoxy group is a monovalent radical derived from a -O-arylalkyl group. In some embodiments, the arylalkoxy group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the heteroarylalkoxy group is a monovalent radical derived from a -O-heteroaryl group. In some embodiments, the heteroarylalkoxy group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkylcarbonyl group is a monovalent radical derived from a α-carbonylalkyl group. In some embodiments, the alkylcarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkoxycarbonyl group is a monovalent radical derived from an α-carbonyl-O-alkyl group. In some embodiments, the alkoxycarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkylaminocarbonyl group is a monovalent radical derived from the α-carbonylalkylamino group. In some embodiments, the heteroarylalkoxy group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the dialkylaminocarbonyl group is a monovalent radical derived from the α-carbonyldialkylamino group. In some embodiments, the dialkylaminocarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the arylcarbonyl group is a monovalent radical derived from a α-carbonyl aryl group. In some embodiments, the arylcarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the heteroarylcarbonyl group is a monovalent radical derived from a α-carbonylheteroaryl group. In some embodiments, the heteroarylcarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments of the invention, the aryloxycarbonyl group is a monovalent radical derived from an α-carbonyl-O-aryl group. In some embodiments, the aryloxycarbonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the alkylsulfonyl group is a monovalent radical derived from a sulfonylalkyl group. In some embodiments, the alkylsulfonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the arylsulfonyl group is a monovalent radical derived from a β-sulfonylaryl group. In some embodiments, the arylsulfonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloalkyl group is a monovalent radical derived from a fully or substantially fully halogenated alkyl group. In some embodiments, the perhaloalkyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloalkoxy group is a monovalent radical derived from a fully or substantially fully halogenated alkoxy group. In some embodiments, the arylsulfonyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhalocycloalkyl group is a monovalent radical derived from a fully or substantially fully halogenated cycloalkyl group. In some embodiments, the perhalocycloalkyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloalkenyl group is a monovalent radical derived from a fully or substantially fully halogenated alkenyl group. In some embodiments, the perhaloalkenyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloalkynyl group is a monovalent radical derived from a fully or substantially fully halogenated alkynyl group. In some embodiments, the perhaloalkynyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloaryl group is a monovalent radical derived from a fully or substantially fully halogenated aryl group. In some embodiments, the perhaloaryl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments, the perhaloarylalkyl group is a monovalent radical derived from a fully or substantially fully halogenated arylalkyl group. In some embodiments, the perhaloarylalkyl group may be attached to the parent structure via one or more independent divalent intermediate substituent groups.

In some embodiments of the invention regarding the replacement of one or more than one atom in each group with one or more heteroatoms, the heteroatoms may be suitably selected from N, O, P, S, B, or any combination thereof.

Substitute groups are not particularly limited. In some embodiments, the substituent group may suitably and independently be selected from one or more of an acyl group, an alkenyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxysulfonyloxy group, an alkyl group, an alkylamino group, an alkylaminocarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfonyl group, алкилсульфонилоксигруппы, алкилтиогруппы, алкинильной группы, амидной группы, амидиновой группы, аминогруппы, арилалкоксигруппы, арилалкильной группы, арильной группы, арилкарбонильной группы, арилкарбонилоксигруппы, арилоксигруппы, арилоксикарбонильной группы, арилоксикарбонилоксигруппы, арилоксисульфонилоксигруппы, арилсульфонильной группы, арилсульфонилоксигруппы, азидогруппы, карбамидогруппы, карбамоильной группы, карбазоильной group, carbonyl group, carboxylate group, carboxyl group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, halogen group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group, hydroxy group, imino group, isocyanato group, isocyano group, mercapto group, nitro group, oxo group, perhaloalkenyl group, perhaloalkoxy group, perhaloalkyl group, perhaloalkynyl group, perhaloarylalkyl group, perhaloaryl group, perhalocycloalkyl group, phosphate group, phosphine group, phospho group, sulfonic group, sulfate group groups, their oxidized form, or combinations thereof. Oxidized forms of the groups are possible. In some embodiments, the substituent group may optionally and independently be directly attached to the corresponding parent structure via one or more chemical bonds. In some embodiments, the substituent group may optionally and independently be indirectly attached to the corresponding parent structure via one or more divalent intermediate substituent groups. In some embodiments, a substituent group may optionally and independently be additionally substituted with one or more substituent groups.

Divalent intermediate substituent groups are not particularly limited. In some embodiments, the divalent intermediate substituent group may suitably and independently be selected from one or more of an azo group, an azino group, an azoxy group, a carbonyl group, a diol group, a diazoamino group, a disulfinyl group, a dithio group, a hydroxy group, a hydrazo group, an oxalyl group, a sulfonyl group , thiocarbonyl group, thionyl group, phosphonic ester group, carboxylate group, thio group; a divalent residue of one or more of the following groups: acyl group, alkenyl group, alkoxy group, alkoxycarbonyl group, alkoxycarbonyloxy group, alkoxysulfonyloxy group, alkyl group, alkylamino group, alkylaminocarbonyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkylsulfonyl group, alkylsulfonyloxy group, alkylthio group, , амидиновой группы, аминогруппы, арилалкоксигруппы, арилалкильной группы, арильной группы, арилкарбонильной группы, арилкарбонилоксигруппы, арилоксигруппы, арилоксикарбонильной группы, арилоксикарбонилоксигруппы, арилоксисульфонилоксигруппы, арилсульфонильной группы, арилсульфонилоксигруппы, азидогруппы, карбамидогруппы, карбамоильной группы, карбазоильной группы, карбонильной группы, карбоксилатной группы, карбоксильной group, cyanoto group, cyano group, cycloalkenyl group, cycloalkyl group, dialkylaminocarbonyl group, dialkylamino group, guanidino group, guanyl group, heteroarylalkoxy group, heteroarylalkyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxy group, heterocyclic group, hydroxyamino group, hydroxy group, imino group, isocyanato group, merocyanato group, a nitro group, an oxo group, a perhaloalkenyl group, a perhaloalkoxy group, a perhaloalkyl group, a perhaloalkynyl group, a perhaloarylalkyl group, a perhaloaryl group, a perhalocycloalkyl group, a phosphate group, a phosphine group, a phospho group, a sulfate group, a sulfo group, a sulfonyl group, an oxidized form thereof, or a combination thereof; their oxidized form, or combinations thereof. Oxidized forms of the groups are possible.

It is to be understood that the terms monovalent and divalent generally refer to radical species produced by the elimination of one or more protons or other atoms from the parent group or molecule. For example, a methyl group (-CH ₃ ) is a monovalent form, radical or residue of methane. Similarly, the methylene group (-CH ₂ -) is a divalent form, radical or residue of methane. These terms are used for convenience in describing the various structures and formulas herein and should not be construed as limiting a particular synthetic route.

In some embodiments of the invention, the compound may be included in a mixture of diastereomers. If necessary, the diastereomers can be separated by taking advantage of their different physical properties, such as using either recrystallization or chromatography, or a combination of both. Recrystallization can be performed in organic solvents such as, but not limited to, pentane, hexane, cyclohexane, toluene, benzene, chlorobutane, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile, methanol, ethanol, or butanol, or in a combination of organic solvents with with or without water. Chromatography can be performed using a solid phase based on silica gel or alumina, eluting with a mixture of organic solvents with or without acidic or basic modifiers such as triethylamine, aqueous ammonia, acetic acid or aqueous hydrochloric acid.

In some embodiments, the compounds are useful in the treatment and/or prevention of diseases or disorders characterized by mycobacterial activity or infection. Mycobacteria can be pathogenic or non-pathogenic. Mycobacteria can be Gram-positive or Gram-negative.

In some embodiments, the invention provides a composition that contains one or more compounds and optionally a physiologically acceptable carrier.

In some embodiments, the invention provides a method that includes administering a compound or composition to a subject in need thereof to treat the subject.

In some embodiments, the compounds, compositions, and methods are useful in treating humans (either immunocompetent, or immunocompromised, or both) and animals for tuberculosis, lepromatous, and non-tuberculous mycobacteria. Non-limiting examples of these bacteria include, but are not limited to, the following species and strains: Mycobacterium tuberculosis, eg M tuberculosis, M. bovis, M. africanum, M. microti, M. canetti; lepromatous mycobacteria, for example M. leprae, M. lepromatosis; non-tuberculous mycobacteria, e.g. M. abscessus, M. abcessus complex, M. avium, M. intracellularae, M. avium complex, M. kansasii, M. malmoense, M. xenopi, M. malmoense, M. flavences, M scrofulaceum, M chelonae, M. peregrinum, M. haemophilum, M. fortuitum, M. marinum, M. ulcerans, M. gordonae, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. terrae, M. terrae complex, M. asiaticum, M. celatum, M. shimoidei, M. simiae, M. smegmatis, M. szulgai, M. celatum, M. conspicuum, M. genavense, M. immunogenum, M. xenopi.

In some embodiments, the compounds, compositions, and methods are useful in the treatment of humans (both immunocompetent and immunocompromised) and animals for non-mycobacterial infectious diseases.

In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with a non-pathogenic mycobacterial strain of M. smegmatis, M. vaccae, M. aurum, or a combination thereof.

In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with Gram-positive bacteria S. aureus, M. luteus, or a combination thereof.

In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with the gram-negative bacteria P. aeruginosa, A. baumanii, or a combination thereof.

In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with a pathogenic mycobacterial strain of M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. mungi, M. pinnipedii, M. leprae, M. avium, mycobacterial tuberculosis complex, tuberculosis, or combinations thereof.

In some embodiments, it is known or suspected that the subject is in need of treatment for one or more diseases associated with a non-pathogenic mycobacterial strain of M. smegmatis, M. vaccae, M. aurum, gram-positive S. aureus, M. luteus, gram-negative P. aeruginosa, A. baumanii, pathogenic mycobacterial strains of M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. mungi, M. pinnipedii , M. avium, mycobacterial tuberculosis complex, tuberculosis, or combinations thereof.

In some embodiments, the invention provides a method that includes killing or inhibiting the growth of a population of one or more of a non-pathogenic mycobacterial strain of M. smegmatis, M. vaccae, M. aurum, gram-positive bacteria S. aureus, M. luteus, gram-negative bacteria P aeruginosa, A. baumanii, pathogenic mycobacterial strain M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M africanum, M. canetti, M. caprae, M. microti, M. mungi, M. pinnipedii , M. avium, mycobacterial tuberculosis complex, bacteria capable of causing tuberculosis, or combinations thereof by contacting one or more members of said population with a compound or composition.

In some embodiments of the invention, the compounds, compositions and methods are suitable for use or treatment alone or in combination with one or more additional treatments, for example, either simultaneously or with delayed administration.

In some embodiments, the compounds, compositions, and methods are suitable for use in combination with one or more additional antimicrobial treatments, e.g., including isoniazid, ethambutol, rifampin, rifabutin, aminoglycosides (e.g., streptomycin, amikacin, tobramycin), macrolides (eg, azithromycin, clarithromycin), quinolones (eg, ofloxacin, ciprofloxacin, moxifloxacin), tetracyclines (eg, doxycycline, minocycline), sulfonamides, and combinations thereof (eg, sulfonamides, trimethoprim/sulfamethoxazole), antimicrobial agents containing beta-lactam (including penicillins and cephalosporins), benzofurans (eg, nitrofurantoin), oxazolidinones (eg, linezolid), glycopeptides (eg, vancomycin), lipopeptides (eg, daptomycin), streptogramins (eg, quinpristine/dalfopristin), pleuromutilins (eg, retapamulin), polymyxins (eg colistin), lipoglycopeptides (eg telavancin), glycylcyclines (eg tigecycline), polyene antifungals (eg amphotericin B), imidazole antifungals (eg ketoconazole), allylamine antifungals (e.g. amorolfine), triazole antifungal agents (e.g. voriconazole), thiazole antifungal agents (e.g. abafungin), echinocandin antifungal agents (e.g. anidulafungin), clofazimine and the like or other antimicrobial agents (e.g. antimalarial, anthelmintic, antiprotozoal agents), cytochrome P450 (CYP) inhibitors, 1-aminobenzotriazole (AWT), cimetidine, amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, ritonavir. Combinations are possible.

In some embodiments, such as in the case of TB, the compound may be administered to a subject in need thereof, together with or in addition to one or more of isoniazid, rifampin, rifadin, rimactan, ethambutol, miambutol, pyrazinamide, antibiotic, fluoroquinolone, amikacin, kanamycin, capreomycin, bedaquiline, delamanid, PA-824, linezolid, sutezolid, or any combination thereof.

In some embodiments, the compounds, compositions and methods are suitable for use as a single agent or in combination with other agents for the treatment of inflammatory diseases. Anti-inflammatory drugs can also be co-administered during treatment. Inflammatory diseases are well known and generally refer to, are characterized by, cause, are caused by, or are influenced by inflammation. Non-limiting examples of inflammatory diseases or disorders include, without limitation, asthma, pneumonia, COPD, postinfectious inflammation, atherosclerosis, pain, dermatitis, chronic granulomatous diseases such as tuberculosis, leprosy, sarcoidosis and silicosis, nephritis, amyloidosis, rheumatoid arthritis, ankylosing spondylitis, chronic bronchitis, scleroderma, lupus, polymyositis, appendicitis, inflammatory bowel disease, ulcers, Sjogren's syndrome, Reiter's syndrome, psoriasis, pelvic inflammatory disease, orbital inflammatory disease, thrombotic disease, and unacceptable allergic reactions to environmental stimuli such as sumac root, flower pollen, insect stings, and certain foods, including atopic dermatitis and contact dermatitis.

In some embodiments, the subject is a mammal, human, livestock, cow, pig, horse, or the like.

In some embodiments, the population is present on a surface and the compound or composition is brought into contact with said surface.

Pharmaceutical Sciences, 18^th Edition, A.R. Gennaro, Ed., Mack Publishing Co., Easton, PA (1990).In some embodiments, the compound can be administered to a human patient as such or in pharmaceutical compositions, where it can be mixed with suitable carriers or excipients at doses to treat or ameliorate various pathological conditions that are characterized by mycobacterial activity or infection. A therapeutically effective dose may refer to an amount of a compound sufficient to inhibit the mycobacterial activity or infection, it being understood that such inhibition may be at various concentrations so that one skilled in the art can determine the required dosage of the compound needed to inhibit the target mycobacterial activity or infection. Therapeutically effective doses may be administered alone or as adjunctive therapy in combination with other treatments. Some exemplary techniques for making formulations and administering compounds can be found in

Pharmaceutical Sciences, ^18th Edition, A.R. Gennaro, Ed., Mack Publishing Co., Easton, PA (1990).

Suitable routes of administration, which are not intended to be limiting, may include, for example, oral, intravenous, inhalation, intraperitoneal, rectal, transmucosal, buccal, intravaginal, intestinal, topical, intradermal, parenteral, intramuscular, subcutaneous, intramedullary injection, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, peritoneal, pleural, and optionally in the form of depot formulations or sustained release formulations. It is also possible to administer the compound in a targeted drug delivery system, such as in a liposome.

The compounds can be administered systemically (eg, oral, intravenous, inhalation, intraperitoneal, rectal) or locally (eg, topical, intradermal, intrathecal, peritoneal, pleural, intraocular, intravesical, intravaginal administration or delivery directly to the site of infection).

Pharmaceutical compositions and compounds can be produced in a manner which is known per se, for example, using conventional mixing, dissolving, panning, triturating, emulsifying, encapsulating, trapping or lyophilizing methods. Thus, pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, including excipients and additives to facilitate processing of the active compounds into formulations that can be used pharmaceutically. The appropriate formulation may depend on the route of administration chosen.

The composition may contain any combination of one or more compounds of the present invention, their salts, their resonance forms, prodrugs, metabolites, isotopically labeled compounds, tautomers, isomers and/or atropisomers.

For administration by injection, the compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, the formulation employs penetrating agents suitable for the barrier through which penetration will occur. Such penetrants are known in the art.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral administration by the patient being treated. Pharmaceutical preparations for oral use can be obtained by combining the compound with a solid excipient, optionally grinding the resulting mixture and making a mixture of granules, after adding suitable additives, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, bulking agents such as sugars including lactose, sucrose, mannitol or sorbitol; cellulosic preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If necessary, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

Dragee cores are coated with appropriate coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, glaze solutions, and suitable organic solvents or solvent mixtures. Coloring agents or pigments can be added to tablet or dragee coatings to identify or define various combinations of active compound doses.

Pharmaceutical preparations that can be used orally include hard gelatin capsules as well as soft closed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fixed oils, liquid paraffin or liquid polyethylene glycols. Additionally, stabilizers may be added. All formulations for oral administration should be formulated in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in the conventional manner.

For administration by inhalation, the compounds can conventionally be delivered as an aerosol spray from pressurized packs or a nebulizer using a suitable nebulizer, eg dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver the metered amount. For use in an inhaler or insufflator, capsules and cartridges of, for example, gelatin can be designed containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, such as a bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as suitable oily injections. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as a polyionic block (co)polymer, sodium carboxymethylcellulose, sorbitol or dextran. The suspension may also optionally contain suitable stabilizers or agents which increase the solubility of the compounds.

Alternatively, the active ingredient may be in the form of a powder for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, prior to use.

The compounds may also be formulated into rectal compositions such as suppositories or retention enemas, for example containing traditional suppository bases such as cocoa butter or other glycerides.

The compounds may also be formulated into a depot formulation. Such long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (eg, emulsified in a suitable oil) or ion exchange resins, or formulated as sparingly soluble derivatives, eg, as a sparingly soluble salt.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, or polymers such as polyethylene glycols.

In some embodiments, the compounds may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be prepared with many acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.; or grounds. Non-limiting examples of pharmaceutically acceptable salts include sodium, potassium, lithium, calcium, magnesium, iron, zinc, hydrochloride, hydrobromide, hydroiodide, acetate, citrate, tartrate and maleate salts, and the like.

Typically, pharmaceutical compositions contain the active compound in an amount effective to achieve the intended purpose. In one embodiment, a therapeutically effective amount means an amount that is effective to prevent or inhibit the development or progression of a disease characterized by mycobacterial infection or activity in a subject being treated. Determining effective amounts is within the ability of those skilled in the art, given the description provided herein.

Any group described in this document, either explicitly designated as a "group" or not so designated (for example, using terms such as "alkyl", "aryl", "aroyl" and the like, separately) may be optional and independently unbranched or branched; may be optionally and independently substituted with one or more independent substituent groups; may optionally and independently attached directly to the corresponding parent structure; may optionally and independently be indirectly attached to the corresponding parent structure via one or more intermediate substituent groups; and/or may have one or more atoms, which are optionally and independently replaced by one or more heteroatoms.

The use of the singular in combination with the term "comprising" in the claims and/or description may mean "one", but it also corresponds to the meaning of "one or more", "at least one" and "one or more than one".

The term "about" is used to indicate that the value includes the standard deviation of the error.

The term "or" means "and/or" unless explicitly stated to mean only alternatives or the alternatives are mutually exclusive, although the description supports a definition that refers only to the alternatives and "and/or".

The words "comprising" (and any form of the word containing, such as "comprise" and "comprises"), "having" (and any form of the word having, such as "having" or "has"), "including" (and any form of the phrase including, such as "includes" and "include") or "comprising" (and any form of the word containing, such as "comprises" and "comprise") are inclusive or non-exhaustive and do not exclude additional unlisted elements or method steps.

Other embodiments of the invention are discussed throughout this application. Any embodiment of the invention that is considered in relation to one aspect of the invention is applicable to other embodiments of the invention, as well as vice versa. It is clear that each embodiment of the invention described in this document, and any obvious variation thereof, is applicable to all embodiments of the invention. Given the description provided herein, in combination with the knowledge of a person skilled in the art to which this invention belongs, any embodiment of the invention described herein can be easily implemented and/or additionally implemented in relation to any application, method, compound, composition, set, their obvious variant, or any combination of them.

EXAMPLES

The examples in this document are provided for illustration and are not intended to be limiting unless otherwise indicated.

The compounds of the present invention have high efficacy, good pharmacokinetic properties and reduced toxicity. For example, ND-10823 has been found to have a dose-limiting toxicity in mice of 100 mg/kg, limiting its potential efficacy as mice will die at doses above 100 mg/kg. However, the addition of fluorine at position 3 increases activity and significantly reduces in vivo toxicity to 250 mg/kg for ND-10890.

MIC MBT=0.3 - 1.3 µM MIC MBT=0.08 - 0.4 µM

MTD=100 mg/kg (mice) MTD=250 mg/kg (mice)

Other compounds containing the 3-fluoro moiety have demonstrated high in vitro activity (nanomolar range) and high in vivo safety (e.g., all ND-11543, ND-11544, ND-11598, ND-11622 have MTD≥250 mg/kg ).

On FIG. 1 depicts the in vivo tolerability of two exemplary compounds ND-11598 and ND-11622 administered orally at 100 mg/kg for two weeks and orally at 250 mg/kg for one week. The mice showed no signs of malaise, weight loss, and all survived after the course of treatment. This indicates that the maximum tolerated dose for these compounds is >250 mg/kg.

The results shown in FIG. 2 confirm the in vivo efficacy of ND-10885 in mice infected with Mycobacterium avium 101 at oral doses of 25 mg/kg and 100 mg/kg. Panel A is the log 10 reduction in colony forming units (CFU) of bacteria in the lungs treated with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg), and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Box B is the log 10 reduction in colony forming units (CFU) of bacteria in the spleen when treated with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg) and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Panel C is the log 10 reduction in liver colony forming units (CFU) of bacteria treated with ND-10885 (at 25 and 100 mg/kg), rifampicin (RMP, 20 mg/kg), and the combination of ND-10885 (100 mg/kg) and rifampicin (20 mg/kg). Statistically confirmed improvement in the effectiveness of the combination of drugs in the lungs and spleen.

The results shown in FIG. 3 demonstrate the in vitro activity of the compounds against various serotypes of Mycobacterium avium and a strain of M. avium resistant to gentamicin. Rifampin is included as a positive control and DMSO as a negative control. MIC values are presented in µg/mL and determined using resazurin dye.

The results shown in FIG. 4 demonstrate the in vitro activity of the compounds against Mycobacterium intracellular (ATCC 13950). Rifampin, clarithromycin, ethambutol and azithromycin are included as positive controls and DMSO as negative controls. MIC values are presented in µg/mL and determined using resazurin dye.

The results shown in FIG. 5 demonstrate in vitro activity of the compounds against clinical strains of Mycobacterium avium and clarithromycin was used as a positive control. MIC values are presented in μg/ml and determined using the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

The results shown in FIG. 6 demonstrate in vitro activity of the compounds against clinical strains of Mycobacterium kansasii; clarithromycin was used as a positive control. MIC values are presented in μg/ml and determined using the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

The results shown in FIG. 7 demonstrate the synergistic effect of ND-11176 and clofazimine against Mycobacterium abscessus as assessed by a "checkerboard analysis" method. Clarithromycin was used as a positive control. MIC values are presented in µg/mL and determined using resazurin dye. In the figure, dark cells represent the dead, lighter cells represent the living.

On FIG. 8 shows a table of compounds and screening results for compounds against Mycobacterium tuberculosis (MBT) H37Rv in various media (GAS, 7H12), low oxygen conditions (LORA), toxicity to Vero cells, and activity against Mycobacterium avium (101 and 2151) and Mycobacterium intracellulare. The dye resazurin was used to determine the MIC values in relation to M. avium and M. intracellular, and MABA was used to determine the MIC in relation to MBT.

Analyzes

In vitro activity against MBT - H37Rv was evaluated both in GAS (glycerol-alanine salt) and in 7H12 medium, while metabolic activity was measured using a microplate assay with Alamar Blue dye (MABA) according to the protocols described by Cho, S.; Lee, H.S.; Franzblau, S.G. See "Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis." Mycobacteria Protocols 2015, 281-292. Activity against non-replicating (latent) MBT was assessed by recording luminescence using a low oxygen survival assay (LORA).

Description of the alamar blue (MABA) microplate assay for TB (GAS, 7H12) to determine MIC ₉₀ values against replicating TB.

The MIC values of the studied compounds in relation to MBT H ₃₇ Rv (ATCC No. 27294) were evaluated using MABA (Cho, S.; Lee, H.S.; Franzblau, SG "Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay ( LORA) for Mycobacterium tuberculosis." Mycobacteria Protocols 2015, 281-292) using rifampin and PA-824 as positive controls. Stock solutions of the compounds were prepared in DMSO at a concentration of 128 μM, and the final test concentrations ranged from 128 μM to 0.5 μM. Two-fold dilutions of compounds were performed in 100 µl glycerol/alanine salt medium in 96-well microplates (BD Optilux™, 96-well microplates, black/clear flat bottom) for GAS analysis (Collins, L., and Franzblau, SG (1997) Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium Antimicrob Agents Chemother 41, 1004-1009), in an iron-deficient medium containing glycerol/alanine salt with 20% added Tween 80 in GAST assay and in Middlebrook 7H12 medium (7H9 broth containing 0.1% w/v casitone, 5.6 μg/ml palmitic acid, 5 mg/ml bovine serum albumin, 4 mg/ml catalase; De Voss , JJ, Rutter, K., Schroeder, B.G., Su, H., Zhu, Y., and Barry, C.E. (2000) The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages Proc. Nat. Acad. Sci. USA 97, 1252-1257). In a volume of 100 µl in 96-well microplates (BD Optilux™, 96-well microplates, black/clear flat bottom) for 7H12 assay. TB cultures (100 μl of 2×10 ⁵ cfu/ml inoculum) were added to the media giving a final assay volume of 200 μl. The plates were incubated at 37°C. On the seventh day of incubation, 12.5 μl of 20% Tween 80 and 20 μl of alamar blue dye (Invitrogen BioSource™) were added to the wells of the test plates. After incubation at 37° C. for 16-24 hours, the fluorescence in the wells was measured at 530 nm (excitation) and 590 nm (emission). MIC values were defined as the lowest concentration causing a ≥90% reduction in fluorescence relative to the mean for controls containing only replicating bacteria.

Description of MDR- and XDR-MBT analysis

MICs were determined as described in Wong et al. (Wong, SY, Lee JS, Kwak, HK, Via, LE, Boshoff, HI, and Barry, C.E. ^3rd . (2011) Antimicrob Agents Chemother. 55, 2515-22).

Briefly, M. tuberculosis strains were grown in Middlebrook 7H9 broth (Becton Dickinson, NJ) supplemented with 10% albumin/dextrose/catalase, 0.05% Tween 80, and 0.2% glycerol such that the absorbance at 650 nm was 0.25. Cells were diluted 1000 times in the above medium. Compounds were added to the first vertical row of a round bottom 96 well plate in triplicate and then serially diluted 2-fold in the remaining rows using Middlebrook 7H9 supplemented medium as diluent. The same volume of the diluted cell suspension was added to each well so that the final volume was 100 μl per well. The plates were incubated at 37°C for 14 days, after which the cell growth was visually studied. The MIC value was defined as the lowest drug concentration that completely inhibits visually detectable growth.

Description (Falzari, K., Zhou, Z, Pan, D., Liu, H., Hongmanee, P., and Franzblau, SG (2005) In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 49, 1447-1454) cytotoxicity assay in the VERO cell line to determine IC ₅₀ values.

Samples were dissolved at a concentration of 12.8 mm in DMSO. Exponential dilutions (three-fold) were performed in MEM growth medium (Gibco, Grand Island, NY) containing 10% fetal bovine serum S5 (HyClone, Logan, UT), 25 mM N-{2-hydroxyethyl)- piperazine-N'-2-ethanesulfonic acid (HEPES, Gibco), 0.2% NaHCO ₃ (Gibco), and 2 mM glutamine (Irvine Scientific, Santa Ana, CA). Final concentrations of DMSO did not exceed 1% v/v. Diluted drug solutions were applied in duplicate to 96-well tissue culture plates (Becton Dickinson Labware, Lincoln Park, NJ) at a volume of 50 μl per well. An equal volume containing 5×10 ⁵ log-phase VERO cells (African green monkey kidney cells, CCL-81; American Type Culture Collection, Rockville, MD) was added to each well and the cultures were incubated at 37° C. in an atmosphere containing 5% _CO2 . After 72 hours, cell viability was determined using an aqueous non-radioactive CellTiter 96 cell proliferation assay (Promega Corp., Madison, Wisconsin) according to the manufacturer's instructions. The absorbance at 490 nm was then recorded using a Victor multimode plate analyzer (PerkinElmer). IC ₅₀ values (50% inhibition concentration) were determined using a point curve fitting program.

In vitro activity against MAC. Eleven M. avium strains were exposed to the compounds for 3 days and metabolic activity and bacteriostatic/bactericidal activity were measured with resazurin. This was carried out in accordance with the methods described in J. Antimicrob. Chemother. (2007) 60(1): 152-155.

The efficacy of ND-10890 type compounds against MAC infections has been demonstrated in a mouse model of infection, see ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995, 39(8), 1647-1654 for a review of the MAC infection model and Antimicrob Agents Chemother. 1992, 36(11): 2413-7 type experiment (performed with clarithromycin). In a two-week experiment with Balb/c infected mice dosed with 25 mg and 100 mg of ND-10890, a >2 log10 CFU reduction in M. avium was observed in the lungs of treated mice. In this case, a greater decrease in the number of bacteria was observed than for the control rifampicin (1.8 log10 cfu). Combination therapy using ND-10890 (100 mg) and rifampicin (20 mg) was even more effective with almost complete elimination of M. avium bacteria (~3 log10 CFU reduction). These data indicate that these compounds will be effective in the treatment of mycobacterial infections.

For a series of key compounds, efficacy was studied against a number of different organisms, which include five gram-positive strains (Bacillus subtilis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus Faecalis (VRE), Mycobacterium vaccae), two gram-negative strains (E. coli, Pseudomonas aeruginosa), yeast (Sporobolomyces salmonicolor) and fungi (Candida albicans and Penicillium notatum). Notably, this class was poorly effective against all control organisms studied, with the exception of good activity against M. vaccae as well as other mycobacteria. It was found that in relation to a number of strains of non-tuberculous mycobacteria (HTM, NTM), this class is a possible inhibitor of M. avium, M. bovis BCG, M. kansasii (<0.08 mm) and most weakly M. abscessus, M. chelonae , M. marinum and M. smegmatis (>10 mM). These compounds are characterized by nanomolar activity against mono-drug resistant, multidrug resistant (MDR) and extended resistance (XDR). MBT, Studies of the mechanism of action (MOA) through the formation of MBT mutants showed a high frequency of spontaneous mutations (>10 ^-8 ) and that these compounds act on the bc1 complex of the respiratory chain (complex III). Key compounds were screened against six mammalian cell lines (PC-3, MCF-7, Huvec, K-562, HeLa and VERO) and showed no toxicity, IC ₅₀ >50 μM.

Synthesis:

The general synthesis scheme involves, firstly, the formation of a heterocyclic backbone in the form of a methyl or ethyl ester by heating 2-aminopyridine 1 or 2-aminothiazole 6 with α-haloketone 2 (i.e. 2-bromoacetoacetate or 2-chloroacetoacetate) in a suitable solvent such as dimethoxyethane or ethanol. Deesterification with a base (LiOH, NaOH, KOH, etc.) in a suitable alcoholic solvent (MeOH, EtOH) followed by acidification with HCl gives the heterocyclic carboxylic acid central moiety (4 and 8). Heterocyclic carboxylic acids (4 or 8) are then coupled with various amines (NH ₂ R") using any method of amide formation, as described in Bodansky, M., "Principles of Peptide Synthesis", Springer-Verlag, 1988, which gives the required amides 5 and 9.

Various structure 2 reagents are commercially available, such as ethyl 2-chloroacetoacetate [CAS: 609-15-4, Sigma-Aldrich] and ethyl 2-bromo-3-oxobutanoate [CAS: 609-13-2, Ark Pharm], while others can be obtained either using the method described in Synthetic Communications, 37(23), 4149-4156; 2007 using N-chlorosuccinimide (NCS, CSI) or N-bromosuccinimide (NBS, BSI) in DMSO;

or using the methods described in Journal of Medicinal Chemistry, 57(12), 5293-5305; 2014 (using BSI or HSI with ammonium acetate in diethyl ether).

More specifically, ethyl 2-bromo-3-oxobutanoate can be obtained by the following procedure:

Ethyl acetoacetate (5.2 ml, 37.7 mmol) was added to N-bromosuccinimide (9.2 g, 49 mmol) followed by 40 ml of dry DMSO. The reaction mixture was stirred for 2 hours at RT or until reaction was complete as determined by TLC (50% hexane:CH ₂ Cl ₂ ). The reaction mixture was diluted with a mixture of hexane isomers and the organic layer was washed with a saturated solution of NH ₄ Cl (2×), water, then the organic layer was dried over sodium sulfate. The drying agent was removed by filtration, and after concentration in vacuo, the crude material was purified on a silica gel column using 50% hexane:CH ₂ Cl ₂ isomer mixture to give ethyl 2-bromo-3-oxobutanoate as a light yellow oil. IR (purified): 1718, 1462, 1227 cm-1; ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.67 (1H, s), 4.28 (2H, q, J=7.0 Hz), 2.43 (3H, s), 1.32 (3H, t, J=7.0 Hz); 13C NMR (50 MHz, CDCl ₃ ): δ 197.6, 167.3, 6.8, 54.6, 27.1, 14.2.

More specifically, methyl 2-bromo-3-oxopentanoate can be prepared by the following procedure:

In a round bottom flask cooled in an ice bath, methyl propionyl acetate (8.7 ml, 69.2 mmol), BSI (13.5 g, 76.1 mmol) and ammonium acetate (53 mg, 0.7 mmol) were mixed together and stirred in the form of a thick suspension for 3 hours. Then 25 ml of diethyl ether was added and the reaction mixture was allowed to warm to room temperature while being stirred for 3 hours until the reaction mixture turned white. After that, the reaction mixture was taken up in 100 ml of diethyl ether, and washed (3×) with water, saturated aqueous sodium chloride solution and dried over sodium sulfate. The drying agent was filtered off and the organic phases were concentrated to give methyl 2-bromo-3-oxopentanoate as a clear oil, 13.45 grams. ¹ H NMR (200 MHz, CDCl ₃ ): δ ppm. 1.12 (t, J=7.2 Hz, 3H, CH ₃ CH ₂ ), 2.79 (c, J=7.2 Hz, 2H, CH ₃ CH ₂ ), 3.82 (s, 3H, OCH ₃ ), 4.81 (s, 1H, CHBr).

The general scheme for the synthesis of the central fragments of imidazo[1,2-α]pyridine-3-carboxylic acids (4a, 4b, 4c, 4d) by coupling with various amines (NH2R") gives in general:

More specifically, imidazo[1,2-α]pyridine-3-carboxylic acid central moieties 4a and 4b can be prepared using the procedures presented in ACS Med. Chem. Lett., 2013, 4 (7), pp 675-679 and ACS Med. Chem. Lett., 2011, 2 (6), pp. 466-470.

As a specific example, 2,7-dimethylimidazo[1,2-α]pyridine-3-carboxylic acid can be prepared as follows. 2-Amino-4-picoline (10.0 g, 91.5 mmol) and ethyl 2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 ml of 1,2-dimethoxyethane (DME) and heated with reflux for 36 hours. The reaction mixture was filtered and the solid (2-amino-4-picoline hydrochloride salt) was collected and washed with a mixture of hexane isomers. The filtrate was concentrated in vacuo and the residue was dissolved in CH ₂ Cl ₂ and washed with 5% acetic acid solution (2×) and saturated aqueous sodium chloride solution. The organic phase was collected, dried over sodium sulfate (Na ₂ SO ₄ ), filtered and then concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography using a solvent system of 20% ethyl acetate:CH ₂ Cl ₂ to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-α]pyridine- 3-carboxylate as a tan solid. T. pl. 59-61°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.14 (d, J=7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J=7.1.1, 7 Hz, 1H), 4.40 (k, J=7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1, 42 (t, J=7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calculated for C ₁₂ H ₁₅ N ₂ O ₂ , 219.1155; found 219.1128.

Ethyl 2,7-dimethylimidazo[1,2-α]pyridine-3-carboxylate (6.64 g, 30.4 g) was dissolved in 75 ml of ethanol (95:5) and 61 ml of 1 N hydrochloric acid was added. LiOH solution (61 mmol). The reaction mixture was stirred at reflux for 36 hours. Upon completion, the reaction mixture was concentrated in vacuo to near dryness and the pH was adjusted to 3 by slowly adding 4N HCl. HCl while cooling in an ice bath. The resulting solids were collected by filtration and dried under vacuum overnight to give 3.86 g (67%) of 2,7-dimethylimidazo[1,2-α]pyridine-3-carboxylic acid as a yellowish solid. T. pl. 180-183°C; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.52 (d, J=7.1 Hz, 1H), 7.73 (td, J=1.8, 0.9, 0.9 Hz, 1H ), 7.48 (dd, J=7.1, 1.3 Hz, 1H), 2.81 (s, 3H), 2.63 (s, 3H). HRMS (EI), M+1 calculated for C ₁₀ H ₁₁ N ₂ O ₂ , 191.0815; found 191.0837.

The central moiety 2-ethyl-6-chloroimidazo[1,2-α]pyridine-3-carboxylic acid 4c can be prepared according to the procedure described in Journal of Medicinal Chemistry, 57(12), 5293-5305; 2014. The central fragment of 2-ethyl-6-methylimidazo[1,2-α]pyridine-3-carboxylic acid 4d (CAS: 1216036-36-0) can be obtained by modifying the above procedure, which includes heating 2-amino- 4-picoline (CAS: 695-34-1) and methyl 2-bromo-3-oxopentanoate (CAS: 117481-97-7) in a suitable solvent (DME, EtOH) followed by hydrolysis of the resulting methyl ester to give the desired carboxylic acids.

Using the same procedures as described above for the synthesis of imidazo[1,2-α]pyridine-3-carboxylic acids (4a-4d), imidazo[2,1-b]thiazole-5-carboxylic acids (8a- 8d).

For example, 2,6-dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (4a) can be prepared by mixing 5-methyl-2-aminothiazole (10 g, 86.7 mmol) and ethyl 2-chloroacetoacetate ( 13.3 ml, 86.7 mmol) and heating the reaction mixture to 60° C. in a minimum amount of 1,2-dichloroethane (15 ml) added to facilitate stirring overnight under argon. Sodium hydrogen carbonate (1 eq.) was then added and the reaction mixture was sparged for 5 minutes. The reaction mixture was concentrated almost to dryness in air. The residue was dissolved in EtOAc and washed with water (2x) followed by 1N. HCl (3×), saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The drying agent was removed and concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ and purified on a silica gel column eluting with CH ₂ Cl ₂ to remove the zone coming out first and then with 20% EtOAc:CH ₂ Cl ₂ to collect the product after concentration as a yellow- orange solid. 4.78 g (25%) ethyl 2,6-dimethylimidazo[2,1-b]thiazole-5-carboxylate. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 7.78 (s, 1H), 4.38 (dc, J=14.0, 7.0 Hz, 2H), 2.59 (s, 3H), 2.44 (s, 3H), 1.40 (t, J=7.0, 7.0 Hz, 3H).

Ethyl 2,6-dimethylimidazo[2,1-b]thiazole-5-carboxylate (4.78 g, 21.3 mmol) was dissolved in 90 ml of EtOH and then 4N was added. aqueous NaOH solution (10.6 ml, 42.6 mmol) and the reaction mixture was stirred over night at 50°C, and until TLC showed a transformation into a more polar spot. The reaction mixture was concentrated to 1/4 volume by blowing air through the reaction mixture. The residue was cooled in an ice bath and then the pH was adjusted to 2-3 by carefully adding conc. HCl (~2 ml), and then 4 N. HCl solution. The product precipitated out of solution and was collected by filtration and dried under vacuum overnight. 1.9 grams of 2,6-dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (4a) was collected as a light yellow solid. ¹ H NMR (300 MHz, CH ₃ OD) δ ppm 7.67 (s, 1H), 2.51 (s, 1H), 2.44 (s, 1H).

In some embodiments of the invention B in general structures:

can be derived from one of the following amines listed below.

In some embodiments, the R3 group, such as "C-group", in the pendant group below:

can be derived from one of the following cyclic amines and substituted cyclic amines shown below:

Piperidinaryl derivatives can be prepared, for example, in accordance with US Patent Application Publication 20070032469, Feb. 8, 2007; PCT International Application 2004058727, July 15, 2004, and PCT International Application 2011028947, March 10, 2011.

Spiropiperidine derivatives can be prepared, for example, according to ACS Medicinal Chemistry Letters, 5(5), 587-591; 2014; Bioorganic & Medicinal Chemistry Letters, 24(10), 2288-2294; 2014; Beilstein Journal of Organic Chemistry, 8, 1700-1704, no. 193; 2012.

Piperazinaryl derivatives can be prepared according to Medicinal Chemistry, 56(24), 10158-10170; 2013; international application PCT 9900386, January 7, 1999; Tetrahedron Letters, 47(15), 2549-2552; 2006; international application PCT 2009095773, August 6, 2009; US Patent Application Publication 20140142114 May 22, 2014; Journal of Medicinal Chemistry, 57(3), 1063-1078; 2014; and international application PCT 2010094126, August 26, 2010

Other cyclic amines and substituted cyclic amines are possible.

The general scheme below shows the procedure for coupling C-groups R3 ("C" in the reaction scheme) with aryl fluoride (11) according to the reaction S _N Ar (see international application PCT 2010097410, September 2, 2010). The S _N AR reaction proceeds at elevated temperatures (typically 100° C. or higher) with non-nucleophilic bases (such as K ₂ CO ₃ ) in polar solvents (such as DMF or DMSO). The resulting intermediate (11) will produce an amine for group B 12 upon reduction of nitrile 11 using any of a number of methods (palladium and hydrogen, PtO ₂ and hydrogen, Raney nickel, Red-Al, lithium aluminum hydride, boranes).

where in the previous scheme in some embodiments of the invention C represents cyclic amines and substituted cyclic amines; and D is hydrogen, halogen, Cl, F, CH ₃ , CF ₃ , OCF ₃ , SF ₅ .

Specific examples of applying a SNAR substitution reaction to a nitrile 11 followed by reduction to an amine 12 include:

which can be prepared by mixing [5-(trifluoromethyl)-2-pyridyl]piperazine [CAS: 132834-58-3] (9 g, 38.9 mmol), potassium carbonate (10.8 g, 77.8 mmol) and 3,4-difluorobenzonitrile (5.4 g, 38.9 mmol) in 50 ml DMF. The reaction mixture was heated to 100° C. overnight.

The reaction mixture was purged with air to dryness and the residue was taken up in EtOAc and washed with water (2×), saturated aqueous sodium chloride solution and then dried over sodium sulfate. The drying agent was removed by filtration and the organic layer was concentrated to a tan solid. The crude solid can be purified on a silica gel column or by recrystallization from hot isopropanol to give 11.95 g of 3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl) benzonitrile as a light yellow solid.

3-Fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzonitrile (4.0 g, 11.4 mmol) was dissolved in 120 ml EtOH. Then 9.5 ml of HCl (114.2 mmol, 10 eq.) and Pd/c (5%, 2.43 g, 1.1 mmol) were added under argon. Hydrogen gas was purged through the solution from three balloons and the reaction mixture was stirred under 1 atm H ₂ for 3 hours. The reaction was monitored by TLC (ninhydrin stain, EtOH eluent) and stopped when complete. Thereafter, the reaction mixture was filtered through glass fiber (or celite) to remove the palladium and washed with CH ₂ Cl ₂ , then the filtrate was concentrated in vacuo. The residue was stirred in 4N. NaOH (100 ml) for 10 min (until it became basic) and was extracted with CH ₂ Cl ₂ (5×). The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated to give 3.85 g of (3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)phenyl)methanamine as yellowish solid.

1-(4-(trifluoromethyl)phenyl)-1,4-diazepane [CAS: 868063-79-0] (2 g, 8.2 mmol) and potassium carbonate (1.7 g, 12.3 mmol) were dissolved in 25 ml DMF and 3,4-difluorobenzonitrile (1.14 g, 8.2 mmol) was added. The reaction mixture was heated to 100° C. overnight. The reaction mixture was purged to dryness and the residue was taken up in EtOAc and washed with water (2×), saturated aqueous sodium chloride solution and then dried over Na ₂ SO ₄ . The drying agent was removed by filtration and the organic phases were concentrated. The residue can be purified using silica gel or by recrystallization from hot isopropanol to give 2 grams of 3-fluoro-4-(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl)benzonitrile as a clear yellowish brown solid.

3-Fluoro-4-(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl)benzonitrile (2 g, 5.5 mmol) was dissolved in 50 ml of MeOH. Then 4.6 ml HCl and Pd/c (5%, 1.2 g, 0.55 mmol) were added under argon. Hydrogen gas was purged through the solution from two balloons and the reaction mixture was stirred under 1 atm H ₂ for 3 hours. The reaction was monitored by TLC (ninhydrin stain, EtOH eluent) and stopped when complete. Thereafter, the reaction mixture was filtered through glass fiber (or celite) to remove the palladium and washed with CH ₂ Cl ₂ , then the filtrate was concentrated in vacuo. The residue was stirred in 4N. NaOH (100 ml) for 10 min (until it became basic) and was extracted with CH ₂ Cl ₂ (5×). The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated to give 1.8 g of (3-fluoro-4-(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl)phenyl)methanamine.

Thiomorpholine (4.9 ml, 48.5 mmol) and potassium carbonate (13.4 g, 96.9 mmol) were dissolved in 50 ml DMF and 3,4-difluorobenzonitrile (6.7 g, 48.5 mmol) was added. The reaction mixture was heated to 100° C. overnight. The reaction mixture was purged to dryness and the residue was taken up in EtOAc and washed with water (2×), saturated aqueous sodium chloride solution and then dried over sodium sulfate. The drying agent was removed by filtration and then the organic phases were concentrated and the residue was recrystallized from hot isopropanol to give 8.74 g of 3-fluoro-4-thiomorpholinobenzonitrile as a light yellow solid. The residue can also be cleaned up using silica gel.

3-Fluoro-4-thiomorpholinobenzonitrile (3 g, 13.5 mmol) was dissolved in 25 ml dry THF and cooled to 0° C. (ice bath temperature) under argon. Red-Al (11.3 mL, 7.9 mmol) was added dropwise to the cooled solution. After completion of the reaction, the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with 1 ml of water while cooling the reaction mixture to 0°C (ice bath temperature). Then 20 ml of 1 N. NaOH solution and the reaction mixture was stirred for 30 min. The solution was filtered through a pad of celite and the pad was washed with THF. The filtrate was concentrated in vacuo and the residue made basic using 50 ml of 4N HCl. NaOH, and was extracted with CH ₂ Cl ₂ (5×). The combined organic phases were washed with saturated aqueous sodium chloride and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated to a yellow semi-solid. The crude material was purified on a silica gel column eluting with 10% EtOH:EtOAc, polarity increased to 100% EtOH to collect 2.2 g of (3-fluoro-4-thiomorpholinophenyl)methanamine as a light solid.

4-(4-(Trifluoromethoxy)phenyl)piperidine [CAS: 180160-91-2] (2 g, 8.2 mmol) and potassium carbonate (2.3 g, 16.3 mmol) were dissolved in 25 ml DMF and added 3,4-difluorobenzonitrile (1.14 g, 8.2 mmol). The reaction mixture was heated to 100° C. overnight. The reaction mixture was purged to dryness and the residue was taken up in EtOAc and washed with water (2×), saturated aqueous sodium chloride solution and then dried over Na ₂ SO 4 . The drying agent was removed by filtration and the organic phases were concentrated. The residue can be purified using silica gel or by recrystallization from hot isopropanol to give 1.75 grams of 3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzonitrile as light yellowish brown solid.

3-Fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzonitrile (1.75 g, 4.8 mmol) was dissolved in 50 ml of MeOH. Then 4 ml of HCl and Pd/c (5%, 1.0 g, 0.48 mmol) were added under argon. Hydrogen gas was purged through the solution from two balloons and the reaction mixture was stirred under 1 atm H ₂ for 3 hours. The reaction was monitored by TLC (ninhydrin stain, EtOH eluent) and stopped when complete. Thereafter, the reaction mixture was filtered through glass fiber (or celite) to remove the palladium and washed with CH ₂ Cl ₂ , then the filtrate was concentrated in vacuo. The residue was stirred in 4N. NaOH (100 ml) for 10 min (until it became basic) and was extracted with CH ₂ Cl ₂ (5×). The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated to give 1.1 g of (3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)phenyl)methanamine.

Alternatively, the preparation of nitrile 11 can be carried out by a Buchwald cross-coupling reaction using palladium as described in PCT International Application 2012113850, Aug. 30, 2012 for the preparation of piperidinylcarbonyl (homo)piperazines, in PCT International Application 2008076243, June 26, 2008 ., and in the international application PCT 2013122897, August 22, 2013

Additionally, obtaining nitrile 12 can be carried out according to other methods. For example, titanium mediated amination of Grignard reagents can be used as described in Angewandte Chemie, International Edition, 2022, 50(36), 8325-8328. This procedure was used to prepare 4-fluoro-3-morpholinobenzonitrile, which can then be reduced to the desired amine.

Nitriles 11 can also be reduced to amines 12 with borane as described in J. Med. Chem. 2007, 50, 3651-3660 for the preparation of (4-(2,6-dimethylmorpholino)-3-fluorophenyl)methanamine hydrochloride.

(4-(2,6-Dimethylmorpholino)-3-fluorophenyl)methanamine hydrochloride

More specifically, 4-(2,6-dimethylmorpholino)-3-fluorobenzonitrile (1.23 g, 3.99 mmol) was taken up in 10 ml of THF and then 1M BH ₃ THF (12.0 ml, 12.0 mmol) was added. and the mixture was heated to reflux. After 2 hours, the solution was cooled to ambient temperature and the reaction was quenched by the careful addition of 3N hydrochloric acid. NaOH solution and stirred for 30 min. The mixture was partitioned between EtOAc and H ₂ O and the separated organic phase was washed with saturated aqueous sodium chloride, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Flash chromatography (5-10% CH ₃ OH/CH ₂ Cl ₂ ) gave the title compound as a colorless oil. (2,5-Difluoro-4-(8-azaspiro[bicyclo[3.2.1]octane-3,2-[1,3]dioxolan]-8-yl)phenyl)methanamine, 73% yield. ¹ H NMR (DMSO-d ₆ ): δ 7.18 (dd, J=14.6, 7.1 Hz, 1H), 6.77 (dd, J=12.6, 7.5 Hz, 1H) , 4.28 (m, 2H), 3.94 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.61 (s, 2H) , 2.03 (m, 2H), 1.64-1.94 (m, 8H).

Nitriles 11 can also be reduced to amines 12 with LiAlH ₄ as described in US Patent Application Publication 20050113576, May 26, 2005, to produce the hydrochloride.

(4-(8-Azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)methanamine

4-(8-Azabicyclo[3.2.1]oct-8-yl)-3-fluorobenzylamine. Lithium aluminum hydride (1.6 g; 43.2 mmol) in THF was treated dropwise with 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-fluorobenzonitrile (2.48 g; 10.8 mmol) . After the addition was complete, the slurry was refluxed for 2 hours, allowed to cool to ambient temperature and quenched with sodium sulfate decahydrate. The mixture was filtered and the filter residue was washed with THF (2×50 ml). The organic phases were combined and concentrated under reduced pressure. The residue was chromatographed (SiO2; 5% methanol in methylene chloride). 4-(8-Azabicyclo[3.2.1]oct-8-yl)-3-fluorobenzylamine. ¹ H NMR (DMSO-d6) δ 7.03 (dd, 1H), 7.92 (dd, 1H), 7.85 (t, 1H), 4.21 (s, 2H), 3.60 (s , 2H), 1.93 (m, 2H), 1.77 (m, 5H), 1.42 (m, 1H), 1.32 (m, 2H).

4-Fluorobenzopentafluorosulfide (CAS: 1063625-86-3, 1.0 g, 13.3 mmol) was dissolved in 6 ml of DMSO and piperazine (2 g, 19.9 mmol) was added and the reaction mixture was heated to 110°C in during the night (12 noon). The reaction mixture was concentrated to dryness and the residue was purified on a silica gel (110 g) column eluting with EtOAc (to remove the zone emerging first, the discoupling product), then the solvent polarity was gradually increased to 100% EtOH to collect 1.1 grams of 1-(4 -(pentafluoro-λ ⁶ -sulfanyl)phenyl)piperazine (most polar zone). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 7.64 (d, J=9.1 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 3.52-3.44 (m, 4H), 3.30-3 .23 (m, 4H).

1-(3-(Pentafluoro-λ ⁶ -sulfanyl)phenyl)piperazine (CAS: 1211581-17-7) can be prepared following the procedures described above, but using 3-fluorobenzopentafluorosulfide (CAS: 1422-41-9).

Alternatively, Boc-protected piperazine (CAS: 57260-71-6) can be heated with 4-fluorobenzopentafluoro sulfide or 3-fluoro-benzopentafluoro sulfide to effect an S _N Ar reaction. The coupling product is then deprotected using trifluoroacetic anhydride (TFAA) or HCl gas to give 1-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)piperazine or 1-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl )piperazine in the case of TFAA or HCl, respectively. These salts can be neutralized with base (NaOH in methanol) to give the free amines.

4-(4-(Pentafluoro-λ ⁶ -sulfanyl)phenyl)piperidine (CAS: 1211590-30-5) and 4-(3-(pentafluoro-λ ⁶ -sulfanyl)phenyl)piperidine (CAS: 1211520-07-8 ) can be obtained by the methods given in J. Med. Chem., 2014, 57 (12), 5293-5305, but using either 4-bromobenzopentafluorosulfide (CAS: 774-93-6), 4-chlorobenzopentafluorosulfide (CAS: 5310-68-9), or 3-bromobenzopentafluorosulfide (CAS : 672-30-0), 3-chlorobenzopentafluorosulfide (CAS: 1462990-45-9) as halides in the Suzuki coupling reaction. The resulting Suzuki coupling product was deprotected with either trifluoroacetic acid (TFA) or nitrogen gas and these salts can then be neutralized with base to give the free amines.

Alternatively, 4-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)piperidine (CAS: 1211590-30-5) can be prepared according to the procedures described in ACS Med. Chem. Lett., 2015, 6(7), 814-818, but using (4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)boronic acid (CAS: 876010-92-3) as boronic acid in the Suzuki coupling reaction. The Suzuki reaction product is then reduced using palladium on carbon and hydrogen followed by Boc deprotection and neutralization to give the free amine.

Coupling of amines 12 with heterocyclic fragments (4a-4d; 8a-8d) is carried out according to standard amide bond formation reactions (as described in "The Practice of Peptide Synthesis," by M. Bodansky and A. Bodansky, Springer-Verlag, New York. 1994, 2nd ed.) or, alternatively, carboxylic acids can be converted to acid chlorides (using oxalyl chloride or thionyl chloride) and then stirred with 12 and a base (trimethylamine, diisopropylethylamine, pyridine) in an aprotic solvent (CH ₃ CN, CH ₂ Cl ₂ , DMF).

Examples of amide coupling to obtain the desired compounds include:

2,6-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (1.17 g, 5.9 mmol) was dissolved in dry CH ₃ CN and then EDA-HCl (1.38 g, 7 2 mmol) and the reaction mixture was stirred for 10 min. Then (3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)phenyl)methanamine (2.29 g, 7.2 mmol) and diisopropylethylamine ( 1.3 ml, 7.2 mmol). The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give N-(3-fluoro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzyl )-2,6-dimethylimidazo[2,1-b]thiazole-5-carboxamide as a yellowish solid, 945 mg. ¹ H NMR (500 MHz, CDCl ₃ ) 8.42 (s, 1H), 7.99 (s, 1H), 7.67 (dd, J=8.9, 1.9 Hz, 1H), 7, 38 (d, J=8.3 Hz, 1H), 7.31 (d, J=12.5 Hz, 1H), 6.95 (t, J=8.5, 8.5 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H), 3.85-3.79 (m, 4H), 3.35-3 .30 (m, 4H).

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (420 mg, 2.2 mmol) was dissolved in dry CH ₃ CN and then EDA-HCl (510 mg, 2.6 mmol) was added and the reaction mixture was stirred for 10 min. Then, (3-fluoro-4-(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl)phenyl)methanamine (878 mg, 2.3 mmol) was added to a round bottom flask under argon atmosphere and DMAP (323 mg, 2.7 mmol). The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give N-(3-fluoro-4-(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl) benzyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide as a yellowish solid, 847 mg.

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.30 (d, J=7.1 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.32 (s, 1H), 6.86 (t, J=8.7, 8.7 Hz, 2H), 6.76 (d, J=7.2, 1H), 6.73 (d, J=8 .8, 2H), 5.98 (br. s., 1H, NH), 4.57 (d, J=5.7 Hz, 2H), 3.75-3.71 (m, 2H), 3 .63 (t, J=6.2, 6.2 Hz, 2H), 3.54-3.50 (m, 2H), 3.30 (t, J=5.7, 5.7 Hz, 2H ), 2.66 (s, 3H), 2.42 (s, 3H), 2.13-2.04 (m, 2H).

6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (900 mg, 4 mmol) was dissolved in dry CH ₃ CN and then EDA-HCl (921 mg, 4.8 mmol) was added and the reaction mixture was stirred for 10 min. Then, (3-fluoro-4-thiomorpholinophenyl)methanamine (998 mg, 4.4 mmol) and DMAP (587 mg, 4.8 mmol) were added to a round bottom flask. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give 6-chloro-2-ethyl-N-(3-fluoro-4-thiomorpholinobenzyl)imidazo[1,2-a]pyridine-3- carboxamide, 777 mg. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.50 (s, 1H), 7.56 (d, J=9.3 Hz, 1H), 7.32 (d, J=9, 2 Hz, 1H), 7.06 (t, J=8.9, 8.9 Hz, 1H), 6.94 (t, J=8.4, 8.4 Hz, 1H), 6.25 ( br.s., 1H, NH), 4.61 (d, J=5.5 Hz, 1H), 3.35-3.26 (m, 4H), 2.99 (q, J=7.4 Hz, 2H), 2.84-2.77 (m, 4H), 1.41 (t, J=7.4, 7.4 Hz, 3H).

2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (814 mg, 3.6 mmol) was dissolved in dry CH ₃ CN and then EDA-HCl (757 mg, 3.9 mmol) was added and the reaction mixture was stirred for 10 min. Then (3-fluoro-4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)phenyl)methanamine (1.19 g, 3.3 mmol) and DMAP (523 mg, 4.3 mmol) were added ) and the reaction mixture was stirred under an argon atmosphere overnight. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give N-(3-fluoro-4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)-2, 6-dimethylimidazo[1,2-a]pyridine-3-carboxamide, 1.1 g.

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (4 g, 21 mmol) and EDA-HCl (4.8 g, 25.2 mmol) were combined together and the reaction mixture was stirred for 10 min. . in dry CH ₃ CN. Then 5-(aminomethyl)-2,3-dihydrobenzo[b]furan (CAS: 55745-74-9, 3.5 g, 23.1 mmol) and DMAP (3.1 g, 25.2 mmol) were added and the reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give N-((2,3-dihydrobenzofuran-5-yl)methyl)-2,7-dimethylimidazo[1,2-a]pyridine- 3-carboxamide as white solid, 4.2 g. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.28 (d, J=7.1 Hz, 1H), 7.37 (s , 1H), 7.21 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.04 (w s, 1H, NH), 4.58 (d, J=7.4 Hz, 1H), 4.55 (apparent t, 2H, latent), 3.19 (t, J=8.6, 8 .6 Hz, 1H), 2.63 (s, 3H), 2.41 (s, 3H). ¹³ C (126 MHz, CDCl ₃ ) δ ppm 161.4, 159.7, 146.3, 138.4, 130.3, 127.7, 127.3, 127.2, 124.7, 115.7, 115.0, 114.9, 109.4, 71.4, 43.2, 29.7, 21.3, 16.7. Melting point = 140-141.5°C. HRMS (EI), M+1 calculated for C ₁₉ H ₂₀ N ₃ O ₂ , 322.1550; found 322.1568. HPLC t _R =1.2-1.4 min (purity 99%).

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (200 mg, 1 mmol) and EDA-HCl (287 mg, 1.5 mmol) were dissolved in 15 ml dry CH ₃ CN (dried using molecular sieves). Then 3-trifluoromethoxybenzylamine (0.15 ml, 1.06 mmol) and DMAP (305 mg, 2.5 mmol) were added. The reaction mixture was stirred under an argon atmosphere at room temperature for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (using 10% EtOAc : CH ₂ Cl ₂ to remove the amine emerging first and the polarity increased to 50% EtOAc : CH ₂ Cl ₂ to collect the product) or by recrystallization from hot CH ₃ CN, which gave 2,7-dimethyl-N-(3-(trifluoromethoxy)benzyl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid, 265 mg. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.24 (d, J=7.1 Hz, 1H), 7.36 (t, J=7.9, 7.9 Hz, 1H) , 7.31-7.20 (m, 3H), 7.13 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.1 Hz, 1H), 6.26 ( br s, 1H, NH), 4.69 (d, J=5.9 Hz, 2H), 2.65 (s, 3H), 2.40 (s, 3H). ¹³ C (126 MHz, CDCl ₃ ) δ ppm 161.2, 149.5, 146.5, 145.5, 140.9, 138.5, 130.1, 127.2, 125.7, 120.7 (k, J=257.4 Hz), 120.0, 119.9, 115.8, 115.0, 114.7, 42.7, 21.3, 16.7. Melting point = 110-111°C. HRMS (EI), M+1 calculated for C ₁₈ H ₁₇ F ₃ N ₃ O ₂ , 364.1267; found 364.1271. HPLC t _R = 2.8 min (purity 99%).

2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (3.5 g, 18.4 mmol) was dissolved in dry CH ₃ CN and then EDA-HCl (4.2 g, 22. 1 mmol) and the reaction mixture was stirred for 10 min. under an argon atmosphere. Then 4-(trifluoromethoxy)benzylamine (3.5 g, 20.2 mmol) and DMAP (2.7 g, 22.1 mmol) were added and the reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column or by recrystallization from hot CH ₃ CN to give 2,6-dimethyl-N-(4-(trifluoromethyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide as white solid, 5.1 grams. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.25 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.55 (d, J=7, 9 Hz, 1H), 7.29 (m, 4H), 6.38 (br.s., 1H, NH), 4.79 (d, J=5.7 Hz, 2H), 2.75 (s , 3H), 2.40 (s, 3H). Melting point = 110.5-111.1°C. HRMS (EI), M+1 calculated for C ₁₈ H ₁₇ F ₃ N ₃ O, 348.1318; found 348.1332. HPLC t _R = 2.7-2.9 min (purity 99%).

2,6-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (250 mg, 1.3 mmol) and EDA-HCl (268 mg, 1.4 mmol) were added together in 12 ml dry CH ₃ CN and the reaction mixture was stirred for 10 min. Then 5-(aminomethyl)-2,3-dihydrobenzo[b]furan hydrochloride salt (CAS: 635309-62-5, 236 mg, 1.4 mmol) and DMAP (342 g, 2.8 mmol) was added and the reaction mixture stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give N-((2,3-dihydrobenzofuran-5-yl)methyl)-2,6-dimethylimidazo[2 ,1-b]thiazole-5-carboxamide as a white solid (ND-11459), 173 mg. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.02 (s, Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=8.0 Hz, 1H) , 6.75 (d, J=8.13 Hz, 1H), 6.02 (br.s., 1H, NH), 4.66-4.49 (m, 4H, overlap) 3.19 (t , J=8.7, 8.7 Hz, 1H), 2.59 (s, 3H), 2.45 (s, 3H).

6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (107 mg, 0.48 mmol) and EDA-HCl (110 mg, 0.57 mmol) were added together in 5 ml dry CH ₃ CN and the reaction mixture were stirred for 10 min. Then 5-(aminomethyl)-2,3-dihydrobenzo[b]furan hydrochloride salt (CAS: 635309-62-5, 100 mg, 0.52 mmol) and DMAP (128 g, 1.0 mmol) was added and the reaction mixture stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO ₃ (×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 6-chloro-N-((2,3-dihydrobenzofuran-5-yl)methyl)-2-ethylimidazo [1,2-a]pyridine-3-carboxamide (ND-11497) as white solid, 81 mg. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.53 (s, 1H), 7.54 (d, J=9.5 Hz, 1H), 7.24 (m, 2H), 7 .11 (d, J=7.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.08 (b.s., 1H, _NH2 ), 4.58 ( m, 4H, overlap), 3.22 (d, J=8.5 Hz, 2H), 2.96 (d, J=7.41 Hz, 2H), 1.39 (t, J=7.2 , 7.2 Hz, 3H).

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (150 mg, 0.79 mmol) was dissolved in 7 ml of dry CH ₃ CN, and then EDA-HCl (181 mg, 0.95 mmol) was added ) and the reaction mixture was stirred for 10 min. 4-(Pentafluorosulfur)benzylamine (CAS: 771573-35-4, 202 mg, 0.87 mmol) and DMAP (116 mg, 0.95 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 180 mg of 2,7-dimethyl-N-(4-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (ND-11857) as a white solid. Melting point = 186-187°C, standard benzoic acid measured at 113-114°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.20 (d, J=7.1 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.40 (s, 1H), 6.77 (d, J=7.1 Hz, 1H), 6.51 (br.s., 1H, NH ₂ ), 4.72 (d, J=5.9 Hz, 2H), 2.69 (s, 3H), 2.41 (s, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.4 (pentet, J=150.0 Hz, 1F), 63.0 (d, J=150.07 Hz, 4F).

6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (150 mg, 0.66 mmol) was dissolved in 7 ml dry CH ₃ CN and then EDA-HCl (153 mg, 0. 80 mmol) and the reaction mixture was stirred for 10 min. 4-(Pentafluorosulfur)benzylamine (CAS: 771573-35-4, 171 mg, 0.73 mmol) and DMAP (98 mg, 0.80 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 115 mg of 6-chloro-2-ethyl-N-(4-(pentafluoro-λ ⁶ -sulfanyl)benzyl )imidazo[1,2-a]pyridine-3-carboxamide (ND-11858) as a white solid. Melting point = 191-192°C, for benzoic acid standard measured at 113-114°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.50 (s, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.55 (d, J=9, 5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.32 (d, J=9.5 Hz, 1H), 6.30 (br.s., 1H, NH ₂ ) 4.74 (d, J=5.9 Hz, 2H), 3.01 (c, J=7.5, 7.5, 7.5 Hz, 2H), 1.43 (t, J= 7.5, 7.5 Hz, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.4 (pentet, J=150.1 Hz, 1F), 63.0 (d, J=150.1 Hz, 4F).

2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (150 mg, 0.79 mmol) was dissolved in 7 ml of dry CH ₃ CN and then EDA-HCl (181 mg, 0.95 mmol) was added ) and the reaction mixture was stirred for 10 min. 4-(Pentafluorosulfur)benzylamine (CAS: 771573-35-4, 202 mg, 0.87 mmol) and DMAP (116 mg, 0.95 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 180 mg of 2,6-dimethyl-N-(4-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (ND-11859) as a white solid. Melting point = 176-177°C, for benzoic acid standard measured at 113-114°C; ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.21 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.46 (d, J=8, 8 Hz, 2H), 7.19 (d, J=8.2 Hz, 1H), 6.33 (b.s., 1H, NH ₂ ), 4.73 (d, J=5.9 Hz, 2H), 2.69 (s, 3H), 2.34 (s, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.5 (pentet, J=150.0 Hz, 1F), 63.0 (d, J=150.05 Hz, 4F).

2,6-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (150 mg, 0.76 mmol) was dissolved in 7 ml of dry CH ₃ CN, and then EDA-HCl (196 mg, 0.92 mmol) was added ) and the reaction mixture was stirred for 10 min. 4-(Pentafluorosulfur)benzylamine (CAS: 771573-35-4, 196 mg, 0.84 mmol) and DMAP (112 mg, 0.92 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 131 mg of 2,6-dimethyl-N-(4-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [2,1-b]thiazole-5-carboxamide (ND-11860) as a white solid. Melting point = 147-148°C, for benzoic acid standard measured at 113-114°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 7.96 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.44 (d, J=8, 3 Hz, 2H), 6.17 (br. s., 1H, NH ₂ ), 4.69 (d, J=6.0 Hz, 2H), 2.59 (s, 3H), 2.42 ( s, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.5 (pentet, J=150.1 Hz, 1F), 63.0 (d, J=150.04 Hz, 4F).

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 0.52 mmol) was dissolved in 5 ml of dry CH ₃ CN, and then EDA-HCl (82 mg, 0.57 mmol) was added ) and the reaction mixture was stirred for 10 min. 3-(pentafluorosulfur)benzylamine (CAS: 771573-34-3, 134 mg, 0.57 mmol) and DMAP (77 mg, 0.63 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 111 mg of 2,7-dimethyl-N-(3-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (ND-11864) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.25 (d, J=7.1 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=8, 1 Hz, 1H), 7.33 (s, 1H), 7.59-7.41 (m, 2H), 6.78 (d, J=7.1, 1H), 6.32 (br. s ., 1H, NH ₂ ), 4.75 (d, J=6.0 Hz, 2H), 2.68 (s, 3H), 2.42 (s, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.4 (pentet, J=149.5 Hz, 1F), 62.9 (d, J=150.00 Hz, 4F).

6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 0.45 mmol) was dissolved in 5 ml dry CH ₃ CN and then EDA-HCl (69 mg, 0.45 mmol) was added. 45 mmol) and the reaction mixture was stirred for 10 min. 3-(pentafluorosulfur)benzylamine (CAS: 771573-34-3, 114 mg, 0.49 mmol) and DMAP (65 mg, 0.53 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 71 mg of 6-chloro-2-ethyl-N-(3-(pentafluoro-λ ⁶ -sulfanyl)benzyl )imidazo[1,2-a]pyridine-3-carboxamide (ND-11865) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.49 (s, 1H), 7.77 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7 .63-7.43 (m, 4H), 7.33 (d, J=9.4 Hz, 1H), 6.36 (b.s., 1H, NH ₂ ), 4.76 (d, J =5.9 Hz, 2H), 3.02 (k, J=7.5, 7.5, 7.5 Hz, 2H), 1.42 (t, J=7.5, 7.5 Hz, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.6 (pentet, J=149.8 Hz, 1F), 62.8 (d, J=150.00 Hz, 4F).

2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 0.52 mmol) was dissolved in 5 ml of dry CH ₃ CN, and then EDA-HCl (82 mg, 0.57 mmol) was added ) and the reaction mixture was stirred for 10 min. 3-(pentafluorosulfur)benzylamine (CAS: 771573-34-3, 134 mg, 0.57 mmol) and DMAP (77 mg, 0.63 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 75 mg of 2,6-dimethyl-N-(3-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (ND-11866) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 9.19 (s, 1H), 7.77 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7 .60-7.45 (m, 3H), 7.21 (d, J=9.1 Hz, 1H), 6.34 (b.s., 1H, NH ₂ ), 4.76 (d, J =6.0 Hz, 2H), 2.70 (s, 3H), 2.36 (s, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ ppm 84.4 (pentet, J=149.5 Hz, 1F), 62.3 (d, J=150.00 Hz, 4F).

2,6-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid (100 mg, 0.51 mmol) was dissolved in 5 ml of dry CH ₃ CN, and then EDA-HCl (72 mg, 0.46 mmol) was added ) and the reaction mixture was stirred for 10 min. 3-(pentafluorosulfur)benzylamine (CAS: 771573-34-3, 118 mg, 0.51 mmol) and DMAP (68 mg, 0.55 mmol) were added to a round bottom flask under argon atmosphere. The reaction mixture was stirred under argon for 12 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (solvent gradient DCM:EtOAc) or by recrystallization from hot CH ₃ CN to give 109 mg of 2,6-dimethyl-N-(3-(pentafluoro-λ ⁶ -sulfanyl)benzyl)imidazo [2,1-b]thiazole-5-carboxamide (ND-11867) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 7.97 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7 .55-7.43 (m, 2H), 6.07 (br. s., 1H, NH ₂ ), 4.72 (d, J=6.0 Hz, 2H), 2.59 (s, 3H ), 2.44 (s, 3H).

2,7-dimethyl-N-((3-oxo-2,3-dihydrobenzofuran-5-yl)methyl)imidazo[1,2-а]pyridine-3-carboxamide

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (1 mmol) and EDA-HCl (1.2 mmol) were added together and the reaction mixture was stirred for 10 min in dry CH ₃ CN. Then 5-(aminomethyl)benzofuran-3(2H)-one (CAS: 1630261-74-3) (1.1 mmol) and DMAP (1.2 mmol) were added and the reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo.

The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (CH ₂ Cl ₂ : EtOAc or EtOAc : EtOH gradient) or by recrystallization from hot CH ₃ CN to give the desired product 2,7-dimethyl-N-((3-oxo-2, 3-dihydrobenzofuran-5-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide.

2,7-Dimethyl-N-((3-oxo-2,3-dihydrobenzofuran-5-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide can be reduced with NaBH ₄ as described in Tetrahedron , 45(5), 1441-6; 1989 or Beilstein Journal of Organic Chemistry, 6, 1061-1069, no. 121; 2010.

The alcohol can be converted to fluoride using DAST (diethylaminosulfur trifluoride) as described in Journal of Heterocyclic Chemistry, 45(3), 887-896; 2008.

2,7-dimethyl-N-((2-oxo-2,3-dihydrobenzofuran-5-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide

2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (1 mmol) and EDA-HCl (1.2 mmol) were combined together and the reaction mixture was stirred for 10 min in dry CH ₃ CN. Then 5-(aminomethyl)benzofuran-2(3H)-one (CAS: 16933726-57-9) (1.1 mmol) and DMAP (1.2 mmol) were added and the reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo.

The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO ₃ (2×), 5% aqueous acetic acid (2×), saturated aqueous sodium chloride, and then dried over sodium sulfate. The drying agent was removed by filtration and the organic phases were concentrated in vacuo. The resulting residue was purified on a silica gel column (CH2Cl2 : EtOAc or EtOAc : EtOH gradient) or by recrystallization from hot CH3CN to give the desired product 2,7-dimethyl-N-((2-oxo-2,3-dihydrobenzofuran-5 -yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide.

2,7-Dimethyl-N-((3-oxo-2,3-dihydrobenzofuran-5-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide can be reduced with NaBH ₄ as described in Tetrahedron , 45(5), 1441-6; 1989 or Beilstein Journal of Organic Chemistry, 6, 1061-1069, no. 121; 2010.

Alcohol can be converted to fluoride using DAST as described in Journal of Heterocyclic Chemistry, 45(3), 887-896; 2008.

Alternatively, the hydroxy compound can be obtained from the synthesis of N-((2-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide with subsequent demethylation using boron tribromide (BBr ₃ ) using the method described in Bioorganic & Medicinal Chemistry Letters, 19(16), 4882-4884; 2009.

N-((2-Methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide is prepared by EDC-mediated coupling of 2,7-dimethylimidazo[ 1,2-a]pyridine-3-carboxylic acid and (2-methoxy-2,3-dihydrobenzofuran-5-yl)methanamine (CAS: 1431851-43-2) according to the general procedure described previously.

Each of the compounds depicted in the figures is included in this document and forms part of this description.

The entire contents of each reference, patent document, article, and the like described herein are independently incorporated herein by reference.

Claims (14)

1. A compound having one of the following formulas:

,

,

,

. 2. The compound according to claim 1 having the formula ND-011544

. 3. The compound according to claim 1 having the formula ND-011598

. 4. The compound according to claim 1 having the formula ND-011622

. 5. The compound according to claim 1 having the formula ND-10885

. 6. Pharmaceutical composition for the treatment of pathological conditions characterized by mycobacterial activity or infection, containing an effective amount of a compound according to any one of paragraphs. 1-5 and a physiologically acceptable carrier.

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