Discovery of BD oxidase inhibitors for the treatment of mycobacteriosis

Abstract

Compounds and compositions that inhibit or target Cyt-bd, and methods for preparing, using, and assaying for the same, are described. Also described are compounds and compositions that inhibit or target Cyt-bd, and one or more Cyt-bc1:aa3 inhibitors, F1F o - Disclosed are compositions, methods and kits comprising an ATP synthesis inhibitor, an NADH dehydrogenase (NDH-2) inhibitor, an NADH dehydrogenase (NDH-2) activator or an antibacterial agent.

Description

[Technical field]

[0001] This invention was made with Government support under Grant No. R37 AI054193 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. This application claims the benefit of U.S. Application No. 62 / 783,984, filed December 21, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] In 2015, there were a record 1.8 million deaths and 10.4 million new cases attributable to Mycobacterium Tuberculosis (Mtb). Historically, TB has claimed the lives of over a billion people, and today, one-third of the world's population is infected with TB. The problem is compounded by the rise in TB / HIV dual infection cases and the spread of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains that are resistant to isoniazid and rifampicin, as well as fluoroquinolones and at least one of the injectable second-line drugs amikacin, kanamycin, and capreomycin. A staggering 5.6% of newly diagnosed cases are multidrug-resistant, with the majority of cases being due to non-compliance with the standard six-month treatment regimen. Therefore, there is an urgent medical need for new drugs that shorten the treatment duration. Rational combinations of synergistic drugs would prevent the emergence of MDR and XDR. The recent approval of bedaquiline (BDQ; Sirturo®) and delamanid (Deltyba®) marked important milestones in the creation of antituberculous drugs. Unfortunately, the initial benefits of BDQ were quickly overshadowed, as resistance emerged less than 3 years after its introduction into clinical practice. This is probably related to the absence of an effective companion diagnostic. Indeed, BDQ is currently administered in combination with weaker second- and third-line drugs, in regimens that are strongly selected for BDQ resistance. The use of synergistic drug combinations with shorter treatment durations is necessary to reduce the incidence of resistance. Summary of the Invention [Problem to be solved by the invention]

[0003] BDQ is a mycobacterial F1F oBDQ is a potent inhibitor of the cytochrome bc1:aa3 complex of M. tuberculosis. The discovery and clinical development of BDQ has established the electron transport system of M. tuberculosis as a viable drug target. Several new drug candidates (e.g., Q203) that inhibit the cytochrome bc1:aa3 complex of M. tuberculosis are in the pipeline. However, all of the bc1 inhibitors are bacteriostatic against M. tuberculosis. The lack of bactericidal activity of this drug class is due to the presence of an alternative terminal oxidase in M. tuberculosis, the so-called cytochrome bd oxidase (Cyt-bd), which is the scientific basis of the present invention. In addition to its role as a terminal oxidase, Cyt-bd is also required as a buffer for intracellular redox reactions that occur in response to redox stressors (e.g., oxidative stress, nitrosative stress, antibiotics).

[0004] Combination therapy is now standard in all TB treatment regimens. Currently, these regimens are mixtures of monotherapies, and the efficacy of combining monotherapies has only been verified at the clinical trial stage. Screening for synthetic lethality at an early stage of drug discovery would dramatically increase the chances of finding more effective synergistic drug cocktails. Developing effective combination therapy could reduce both harmful side effects and the development of antimicrobial resistance in M. tuberculosis. Interference with multiple steps of oxidative phosphorylation has been suggested by us and other groups as a promising anti-TB strategy. [Means for solving the problem]

[0005] In one embodiment, there are compounds described herein that inhibit or target Cyt-bd. Another embodiment includes a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable carrier. Another embodiment includes a compound having any one of formulas (A)-(E), (A'), (A'') and (B') described herein, or a pharma- ceutically acceptable salt thereof. Another embodiment includes a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable carrier. Another embodiment includes a kit comprising: the compound or composition described above; and One or more Cyt-bc1:aa3 inhibitors or F1F o ATP synthase inhibitors, or One or more Cyt-bc1:aa3 inhibitors or F1F o - one or more pharmaceutical compositions comprising an ATP synthase inhibitor, and a pharma- ceutical acceptable carrier. Another embodiment includes a method comprising administering the compound or composition or kit to a subject suffering from a mycobacterial disease or infection. Another embodiment includes a method comprising co-administering to a subject suffering from a mycobacterial disease or infection: the compound or composition described above; and One or more Cyt-bc1:aa3 inhibitors or F1F o ATP synthase inhibitors, or One or more Cyt-bc1:aa3 inhibitors or F1F o - one or more pharmaceutical compositions comprising an ATP synthase inhibitor, and a pharma- ceutical acceptable carrier. Another embodiment includes a method comprising co-administering to a subject suffering from a mycobacterial disease or infection: the compound or composition described above; and One or more Cyt-bc1:aa3 inhibitors, F1F o -ATP synthase inhibitors, NADH dehydrogenase (NDH-2) inhibitors, NADH dehydrogenase (NDH-2) activators or antibacterial agents, or One or more Cyt-bc1:aa3 inhibitors, F1F o - one or more pharmaceutical compositions comprising an ATP synthase inhibitor, an NADH dehydrogenase (NDH-2) inhibitor, an NADH dehydrogenase (NDH-2) activator or an antibacterial agent, and a pharma- ceutical acceptable carrier. Another embodiment includes a kit comprising: the compound or composition described above; and One or more Cyt-bc1:aa3 inhibitors, F1F o -ATP synthase inhibitors, NADH dehydrogenase (NDH-2) inhibitors, NADH dehydrogenase (NDH-2) activators or antibacterial agents, or One or more Cyt-bc1:aa3 inhibitors, F1F o - one or more pharmaceutical compositions comprising an ATP synthase inhibitor, an NADH dehydrogenase (NDH-2) inhibitor, an NADH dehydrogenase (NDH-2) activator or an antibacterial agent, and a pharma- ceutical acceptable carrier.

[0006] The inventors have demonstrated that compounds that inhibit Cyt-bd are also effective as agents that inhibit the oxidative phosphorylation tributary Cyt-bc1:aa3 (partially referred to herein as Cyt-bc1:aa3 inhibitors) and / or mycobacterial F1F o -Drugs that inhibit ATP synthase (some of which are referred to herein as F1F o The inventors have developed a group of compounds that inhibit Cyt-bd, and have found that they are particularly useful in releasing the full potential of Cyt-bc1:aa3 inhibitors and / or F1F o We have found that co-administration of an ATP synthase inhibitor with a cytochrome P450 inhibitor provides therapeutic benefit for MDR-TB and XDR-TB. We have developed an assay / screening protocol to determine compounds that inhibit Cyt-bd. We have found that the cytochrome P450 inhibitors inhibit Cyt-bc1:aa3, Cyt-bd, and / or F1F o We found that a rationally designed combination agent simultaneously targeting ATP synthase could be the cornerstone of a combination microbicide for the treatment of MDR- and XDR-TB.

[0007] The difficulty in identifying drugs that target Cyt-bd lies in the non-essential nature of the target. Indeed, the gene encoding Cyt-bd can be deleted without obvious phenotypic changes in growth, ATP homeostasis, or respiration. However, upon chemical inhibition of the Cyt-bc1:aa3 tributary, respiration via the Cyt-bd tributary becomes essential. For the first time, the inventors have discovered a cell-based drug screen to identify Cyt-bd inhibitors that synergize with known Cyt-bc1:aa3 inhibitors (such as Q203). This screening protocol described herein has yielded inhibitors of a diverse class of compounds that target and inhibit Cyt-bd.

[0008] A number of Cyt-bc1:aa3 inhibitors are known. For example, Abrahams, KA et al. Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS One 7, e52951 (2012); Kang, S. et al. Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a largely multi- and candidate-drug-resistant anti-tuberculosis agent. J Med Chem 57, 5293-305 (2014); Moraski, GC et al. Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity. ACS Med Chem Lett 2, 466-470 (2011); and Pethe, K. et al. Discovery of Q203, a potent clinical candidate for See, for example, U.S. Pat. No. 6,309,238, issued April 12, 2016, U.S. Publication No. 2018 / 0265506, issued September 20, 2018, U.S. Pat. No. 9,605,002, issued March 28, 2017, and U.S. Application No. 62 / 641,668, "Deuterated Imidazopyridines," filed March 12, 2018. Many F1F o-ATP synthase inhibitors are known. See, for example, Reference 2 herein and Riccardi, N. et. al. Bedaquiline: A New Hope for Shorter and Better Anti-Tuberculosis Regimens. Recent Pat Antiinfect Drug Discov. 13(1), 3-11 (2018). Mycobacterial energetics, e.g., ATP synthase, Cyt-bc1:aa3 and Cyt-bd oxidase, are discussed in reference 10 herein and Kumar, A. et. al. Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery. Pathogens 7(1), 24 (2018); doi:10.3390 / pathogens7010024.

[0009] Herein, we show that (1) the combined inhibition of Cyt-bd and Cyt-bc1:aa3 suppresses terminal oxidation of M. tuberculosis even under hypoxic conditions, and (2) inhibition of Cyt-bd enhances the effectiveness of other anti-TB drugs for eradicating infection. The data presented herein show that Cyt-bd allows for the maintenance of respiration in the absence of Cyt-bc1:aa3, while simultaneous inhibition of both oxidases results in rapid killing and elimination of M. tuberculosis during acute infection in mouse lungs. It has now been found that Cyt-bd is used by M. tuberculosis to overcome redox stress under hypoxia and antibiotic challenge, thereby contributing to its extraordinary ability for long-term persistence in the host and drug resistance. This application is accompanied by drawings, which form a part of this specification. [Brief description of the drawings]

[0010] [Figure 1a] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 1b] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 2a] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 2b] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 3a] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 3b] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Figure 4] Screening assay data for representative Cyt-bd inhibitors in mycobacteria. [Diagram 5] A representative 6,6-compound and two comparative compounds (ND-011987 and ND-012030 are comparative compounds). [Figure 6] Minimum inhibitory concentrations (MICs) of representative 6,6-compounds and comparative compounds. [Figure 7] Representative 5,6-compounds and one comparative compound (ND-011986 is the comparative compound). [Figure 8] Minimum inhibitory concentrations (MICs) of representative 5,6-compounds and comparison compounds.

[0011] Each and every compound presented in the drawings is incorporated herein by reference as if fully described. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention provides a series of compounds that target and inhibit Cyt-bd: Quinazoline, quinoline, thieno[3,2-d]pyrimidin-4-amine, furo[3,2-d]pyrimidin-4-amine, 5H-pyrrolo[3,2-d]pyrimidin-4-amine, and 7H-purin-6-amine compounds, methods for their synthesis, compositions thereof, and methods of using such compounds and inhibitors.

[0013] As used herein, quinazoline quinoline compounds may be referred to herein as "6,6-compounds". As used herein, thieno[3,2-d]pyrimidin-4-amine, furo[3,2-d]pyrimidin-4-amine, 5H-pyrrolo[3,2-d]pyrimidin-4-amine, and 7H-purin-6-amine compounds may be referred to herein as "5,6-compounds".

[0014] Strains, diseases, and subjects Various embodiments provide compounds, compositions and methods for killing and / or inhibiting the growth of bacteria, including tuberculous mycobacterium species (such as Mycobacterium tuberculosis) and non-tuberculous mycobacterial species, including but not limited to Mycobacterium avium, Mycobacterium abscessus, Mycobacterium paratuberculosis, Mycobacterium kansasii, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium intracellularae and other species described as causing disease in humans and / or animals. The subject may be a human or an animal.

[0015] BD oxidase assay Targeting respiration and ATP synthesis has attracted strong interest as a new strategy to combat Mycobacterium tuberculosis and other health-related mycobacteria. Mycobacteria use an aerobic respiratory chain that terminates in two branches. One branch is the cytochrome bc1 aa3-type cytochrome c oxidase supercomplex, and the other branch terminates in the cytochrome bd-type quinol oxidase (cytochrome bd oxidase). The assay evaluates the efficacy of compounds against cytochrome bd-type quinol oxidase. The assay principle relies on the fact that when the cytochrome bc1:aa3 branch is inhibited by a specific small molecule inhibitor (Q203), the cytochrome bd oxidase becomes essential for maintaining ATP homeostasis. The putative cytochrome bd oxidase is assessed in a dose-response study by inhibiting the cytochrome bc1:aa3 branch with 100 nM Q203 and its ability to inhibit ATP synthesis after 12-16 h of incubation. IC50 values ​​are measured for test compounds in the presence of Q203 (+Q203) or in the absence of Q203 (-Q203). Validated small molecule inhibitors of cytochrome bd oxidase inhibit ATP homeostasis in the presence of cytochrome bc1:aa3 inhibitors (e.g., Q203, ND-11598, ND-11176, TB47, other compounds shown herein), other cytochrome bc1:aa3 inhibitors, other imidazopyridine carboxamides, or other classes of cytochrome c oxidase inhibitors.

[0016] Formula (A): [ka] (In the formula, X1 is CH, CR6, or N; R1 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R2 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R3 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R4 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R5 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R6 is H, D, halogen, alkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched.

[0017] Optionally, in the compounds of the above formula (A) and the following formulas (A'), (B) to (E), R1, R2, R3, R4, R5, and R6 may each be H. Optionally, R1, R2, R3, R4, R5, and R6 may each be D. Optionally, R1, R2, R3, R4, R5, and R6 may be a combination of H and D. It is also possible that R1, R2, R3, R4, R5, and R6 are not all H or D at the same time, and in such cases, one or more groups of R1, R2, R3, R4, R5, and R6 may be appropriately selected from the given substituents, such as halogen, alkyl, cycloalkyl, F, alkoxy, etc. For example, if R1 is H or D, then R2 can be halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'. As a further example, and not intended to be limiting, if R4 is F or CH3, then R2, R3, and R5 can be H or D, or a combination thereof, and so forth. Also, typically, but not always, only one or two of R1, R2, R3, R4, R5, and R6 are not H or D.

[0018] For example, the compound of formula (A) may have the following formula: [ka] The signal may have one of the following characteristics:

[0019] Other examples of compounds having formula (A) include the following: Formula (A'): [ka] (In the formula, X1 is CH, CR6, or N; R1 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR', nitrile or carboxy; R2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R4 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R5 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R6 is H, D, halogen, alkyl, alkenyl, alkynyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched; With the proviso that when R1 is substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl, Q is not substituted or unsubstituted phenyl.

[0020] Other examples of compounds having formula (A) include the following: Formula (A''): [ka] (In the formula, X1 is CH, CR6, or N; R1 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R3 is a halogen; R4 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R5 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R6 is H, D, halogen, alkyl, alkenyl, alkynyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; n is 0; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is a biaryl ether, said biaryl ether being independently substituted or unsubstituted; With the proviso that when R1 is substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl, Q is not substituted or unsubstituted phenyl.

[0021] Optionally, in the compound of formula (A'') above, R1, R2, R4, R5, and R6 may each be H. Optionally, R1, R2, R4, R5, and R6 may each be D. Optionally, R1, R2, R4, R5, and R6 may be a combination of H and D. It is also contemplated that R1, R2, R4, R5, and R6 are not all H or D at the same time, and in such cases, one or more of R1, R2, R4, R5, and R6 may be appropriately selected from the given substituents, such as halogen, alkyl, cycloalkyl, F, alkoxy, etc.

[0022] Formula (B): [ka] (In the formula, X1 is CH, CR6, or N; R1 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R3 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R4 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R6 is H, D, halogen, alkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched.

[0023] Other examples of compounds having formula (B) include: Formula (B'): [ka] (In the formula, X1 is N; R1 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R3 is a halogen; R4 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; R6 is H, D, halogen, alkyl, alkenyl, alkynyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', NHCOR', NR'COR'', COOR' or nitrile; n is 0; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is either an aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or any of the Q's as set forth herein below, alone or in any combination, wherein any of said aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted; With the proviso that when R1 is substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl, Q is not substituted or unsubstituted phenyl.

[0024] Formula (C): [ka] (In the formula, X1 is CH, CR6, or N; R1 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R3 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R4 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R6 is H, D, halogen, alkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched.

[0025] Formula (D): [ka] (In the formula, R1 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R2 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R3 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R4 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R5 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R6 is H, D, halogen, alkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched.

[0026] Formula (E): [ka] (In the formula, X2 is S, O, CH2, CHR 12 , NH, or NR 13 ;R 12 are independently alkyl, halogen, alkoxy, CF3 or OCF3; R 13 are independently alkyl; Y2 is CH, CR 12 or N;R 12 is independently alkyl, halogen, alkoxy, CF3, or OCF3; R1 is H, D, halogen, alkyl, cycloalkyl, CH3, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; R3 is H, D, halogen, alkyl, cycloalkyl, F, alkoxy, CF3, OCF3, SF3, SF5, PO(CH3)2, COR', CONH2, CONHR', CONR'R'', NH2, NHR', NR'R'', or COOR'; n is 0, 1, 2, 3 or 4; R' is independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; R'' is independent, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 is heteroaryl; Any alkyl, CH, cycloalkyl, alkoxy in any R group is each independently substituted or unsubstituted, branched or unbranched, or any combination thereof; and Q is any of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, or any of Q as set forth herein below, alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched.

[0027] For example, the compound of formula (E) has the following formula: [ka] ; [ka] The signal may have one of the following characteristics:

[0028] Other examples of compounds having formula (E) include: [ka] ; [ka] [ka] [ka] [ka] [ka] [ka]

[0029] Examples of the "Q" moiety of BD oxidase inhibitors

[0030] In any embodiment herein, in any one of the compounds of Formulae (A)-(E), (A'), (A'') and (B'), Q can be any one of alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine, alkynyl, propargyl, triazole, polyethylene glycol, either alone or in any combination, wherein any of said alkyl, alkenyl, aryl, biaryl, biaryl ether, heteroaryl, heterocycle, cyclic amine or combinations thereof are independently substituted or unsubstituted, and any of said alkyl, alkenyl, or combinations thereof are independently branched or unbranched. In an embodiment, Q is independently unsubstituted or C 1-6 Optionally substituted with alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof. In embodiments, Q is independently unsubstituted or substituted with alkyl, alkoxy, halogen, hydroxy, CF3, OCF3, SF5, SF3, sulfate, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, or combinations thereof.

[0031] In any of the embodiments herein, Q can be any of alkyl, alkenyl, terpene, geranyl, geranylgeranyl, and farnesyl. [ka] ; Any of the alkyl, alkenyl, terpene, geranyl, geranylgeranyl, and farnesyl may be substituted or unsubstituted; the alkyl or alkenyl may be branched or unbranched. In an embodiment, Q is independently unsubstituted or C 1-6 Optionally substituted with alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof. In embodiments, Q is independently unsubstituted or substituted with alkyl, alkoxy, halogen, hydroxyl, CF3, OCF3, SF5, SF3, sulfate, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, or combinations thereof.

[0032] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y is independently CH, CR, or N, with up to two Y's being N; each R is independently H, D, alkyl, t-butyl, alkenyl, isopropoxy, cycloalkyl, cyclic amine, CF, OCF, SF, SF, halo, methylsulfone, alkoxy, amine, nitrile, aryl, heteroaryl, heterocycle, furan, thiophene, oxazole, isoxazole, imidazole, pyrrole, pyrrolidine, tetrahydrofuran, pyridine, piperidine, pyrimidine, pyrazine, azepine, 1,4-diazepine, 4H-pyran, tetrahydropyran, indole, quinoline, isoquinoline, chroman, purine, pteridine, benzimidazole, benzothiazole, benzoxazole, benzofuran, benzothiazole, or 1H-imidazole; each R may be independently branched or unbranched, substituted or unsubstituted, or a combination thereof. In embodiments, each R7 may suitably and independently be H, D, alkyl, t-butyl, alkenyl, isopropoxy, cycloalkyl, cyclic amine, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, nitrile, aryl, or heteroaryl; any of the alkyl, t-butyl, alkoxy, and isopropoxy may each independently be substituted or unsubstituted, branched or unbranched, or combinations thereof. In embodiments, each R7 may suitably and independently be H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; any of the alkyl, t-butyl, alkoxy, and isopropoxy are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof. In embodiments, each R7 may independently be H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; any alkyl, t-butyl, alkoxy, isopropoxy in any R7 is each independently substituted or unsubstituted, branched or unbranched, or a combination thereof. In an embodiment, each R7 is independently unsubstituted or C 1-6 Optionally substituted with alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof. In embodiments, each R7 is independently unsubstituted or substituted with alkyl, alkoxy, halogen, hydroxyl, CF3, OCF3, SF5, SF3, sulfate, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, or combinations thereof.

[0033] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y is independently CH, CR, or N, with up to two Y's being N; each R is independently H, D, alkyl, t-butyl, alkenyl, isopropoxy, cycloalkyl, cyclic amine, CF, OCF, SF, SF, halo, methylsulfone, alkoxy, amine, nitrile, aryl, heteroaryl, heterocycle, furan, thiophene, oxazole, isoxazole, imidazole, pyrrole, pyrrolidine, tetrahydrofuran, pyridine, piperidine, pyrimidine, pyrazine, azepine, 1,4-diazepine, 4H-pyran, tetrahydropyran, indole, quinoline, isoquinoline, chroman, purine, pteridine, benzimidazole, benzothiazole, benzoxazole, benzofuran, benzothiazole, or 1H-imidazole; each R may be independently branched or unbranched, substituted or unsubstituted, or a combination thereof. In embodiments, each R7 may suitably and independently be H, D, alkyl, t-butyl, alkenyl, isopropoxy, cycloalkyl, cyclic amine, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, nitrile, aryl, or heteroaryl; any of the alkyl, t-butyl, alkoxy, and isopropoxy may each independently be substituted or unsubstituted, branched or unbranched, or combinations thereof. In embodiments, each R7 may suitably and independently be H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; any of the alkyl, t-butyl, alkoxy, and isopropoxy are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof. In embodiments, each R7 may independently be H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; any alkyl, t-butyl, alkoxy, isopropoxy in any R7 is each independently substituted or unsubstituted, branched or unbranched, or a combination thereof. In an embodiment, each R7 is independently unsubstituted or C 1-6 Optionally substituted with alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof. In embodiments, each R7 is independently unsubstituted or substituted with alkyl, alkoxy, halogen, hydroxyl, CF3, OCF3, SF5, SF3, sulfate, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, or combinations thereof.

[0034] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in Ring A is independently CH, CR7, N, or C-RingB; up to two Y in Ring A are N; up to two Y in Ring A are independently C-RingB; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Each Y in ring B is independently CH, CR8, or N; up to two Y in ring B are N; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any of R7, R8, or combinations thereof are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0035] For example, Q has the formula: [ka] The embodiment may have one of the following:

[0036] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in Ring A is independently CH, CR7, N, or C-(O-Ring B); up to two Y in Ring A are N; up to two Y in Ring A are independently C-(O-Ring B); each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Each Y in ring B is independently CH, CR8, or N; up to two Y in ring B are N; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any of R7, R8, or combinations thereof are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0037] For example, Q has the formula: [ka] The embodiment may have one of the following:

[0038] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in Ring A is independently CH, CR7, N, or C-RingC; up to two Y in Ring A are N; up to two Y in Ring A are independently C-RingC; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Z1 in ring C is CH or N; each W in ring C is independently CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; each m in ring C is independently 0-5; ring C is 3-12 membered; each R 10 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; R7, R 10 Any of the alkyl, t-butyl, alkoxy, isopropoxy in any of the above, or combinations thereof, are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0039] For example, Q has the formula: [ka] [ka] [ka] [ka] The embodiment may have one of the following:

[0040] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in Ring A is independently CH, CR7, N, or C-Ring D; up to two Y in Ring A are N; up to two Y in Ring A are independently C-Ring D; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Z1 in ring D is CH or N; each W in ring D is independently CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; each m in ring D is independently 0-5; ring D is 7-23 membered; each R 10 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; R7, R 10 Any of the alkyl, t-butyl, alkoxy, isopropoxy in any of the above, or combinations thereof, are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0041] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in ring A is independently CH, CR7, N, or C-(ring EB); up to two Y in ring A are N; up to two Y in ring A are independently C-(ring EB); each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Z1 in ring E is CH or N; Z2 in ring E is CH, CR9, or N; each R9 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, nitrile, or hydroxy; each W in ring E is independently CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; each m in ring E is independently 0-5; ring E is 3-12 membered; each R 10 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; Each Y in ring B is independently CH, CR8, or N; up to two Y in ring B are N; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; R7, R8, R9, R 10 Any of the alkyl, t-butyl, alkoxy, isopropoxy in any of the above, or combinations thereof, are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0042] For example, Q has the formula: [ka] [ka] [ka] The embodiment may have one of the following:

[0043] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y in ring A is independently CH, CR7, N, or C-(ring FB); up to two Y in ring A are N; up to two Y in ring A are independently C-(ring FB); each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Z1 in ring F is CH or N; Z2 in ring F is CH, CR9, or N; each R9 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; each W in ring F is independently CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; each m in ring F is independently 0-5; ring F is 7-23 membered; each R 10 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; Each Y in ring B is independently CH, CR8, or N; up to two Y in ring B are N; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; R7, R8, R9, R 10 Any of the alkyl, t-butyl, alkoxy, isopropoxy in any of the above, or combinations thereof, are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0044] For example, Q has the formula: [ka] [ka] The embodiment may have one of the following:

[0045] In any embodiment herein, Q has the formula: [ka]

[0043] In the formula, X4 is CH2, CHR8, CR8R8, S, SO, SO2, O, NH or NR8, [ka] and; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Each W is independent of CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; 10 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any R group are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0046] For example, Q has the formula: [ka] [ka] The embodiment may have one of the following:

[0047] In any embodiment herein, Q has the formula: [ka] The present invention may have one of the following: wherein X5 is CH2, CHR8, CR8R8, S, SO, SO2, O, NH, or NR8; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; R 14 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, nitrile, or [ka] and; each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any R group are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0048] For example, Q has the formula: [ka] [ka] The embodiment may have one of the following:

[0049] In any embodiment herein, Q has the formula: [ka]

[0043] wherein each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Each W is independent of CH2, CHR 10 , C.R. 10 R 10 , N.H., N.R. 10 , S, SO, SO2, or O; 10 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any R group are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0050] In any embodiment herein, Q has the formula: [ka] The present invention may have one of the following: wherein X5 is CH2, CHR8, CR8R8, S, SO, SO2, O, NH, or NR8; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; R 14 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, nitrile, or [ka] and; each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any R group are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0051] For example, Q has the formula: [ka] [ka] The embodiment may have one of the following:

[0052] In any embodiment herein, Q has the formula: [ka] The present invention may have one of the following: In the formula, R 14 are independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, F, methylsulfone, alkoxy, amine, nitrile, or [ka] and; each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Any alkyl, t-butyl, alkoxy, isopropoxy in any R group are each independently substituted or unsubstituted, branched or unbranched, or combinations thereof.

[0053] For example, Q has the formula: [ka] The embodiment may have one of the following:

[0054] In any embodiment herein, Q has the formula: [ka]

[0043] wherein X5 is CH2, CHR8, CR8R8, S, SO, SO2, O, NH, or NR8; each R8 is independently H, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile; Each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; and each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile.

[0055] For example, Q has the formula: [ka] The embodiment may have one of the following:

[0056] In any embodiment herein, Q has the formula: [ka] The present invention may have one of the following: wherein each Y is independently CH, CR7, or N; up to two Y's in any one ring are N; and each R7 is independently H, D, alkyl, t-butyl, isopropoxy, CF3, OCF3, SF5, SF3, halo, methylsulfone, alkoxy, amine, or nitrile.

[0057] In any of the embodiments herein, Q can be an alkynyl, propargyl, triazole or substituted triazole group, or a PEGylated derivative thereof, such as a Q group suitable for the well-known "click" chemistry reaction or a product thereof. For example, Q can include any of the following formulae: [ka] [ka] [ka] (In the formula, o is 1 to 30.) [ka] [ka] (In the formula, R 15 H, C1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, or C 5-6 Heteroaryl) An example of a click reaction is shown below. [ka]

[0058] Other exemplary Cyt-bc1:aa3 inhibitors, F1Fo-ATP synthase inhibitors, and NADH dehydrogenase (NDH-2) activators are shown below. [ka] [ka]

[0059] [ka] [ka] [ka] Other antibacterial agents that can be used in combination with the Cyt-bd inhibitors described herein include rifampicin (RIF), pyrazinamide (PZA), isoniazid (INH), and clarithromycin (CLA).

[0060] overview The following general descriptions are provided for ease of understanding and are not intended to be limiting, unless expressly stated.

[0061] The alkyl group is preferably a monovalent, acyclic, straight-chain or branched, substituted or unsubstituted, saturated or unsaturated hydrocarbon group. The alkyl group has the general formula -C n H 2n+1 In some embodiments, n is 1-6 ((C1-C6) alkyl), which may suitably include C1, C2, C3, C4, C5, and C6 alkyl groups. The alkyl group may be linear or branched, substituted or unsubstituted, saturated or unsaturated, or any combination thereof. One or more hydrogens may be optionally and independently replaced by one or more substituents. 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 is attached to the parent structure through one or more independent divalent intervening substituents. Some examples of alkyl groups include, but are not intended to be limiting, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and the like. The alkyl group may preferably be a monovalent, acyclic, straight-chained or branched, substituted or unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 hydrocarbon group. The alkyl group may preferably be a monovalent, straight-chained, substituted or unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 hydrocarbon group. The alkyl group may preferably be a monovalent, straight-chained, unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 hydrocarbon group.

[0062] One or more hydrogens on the alkyl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0063] Alkenyl groups are preferably monovalent, linear or branched, substituted or unsubstituted unsaturated hydrocarbon groups. Alkenyl groups have the general formula (regardless of any substitution, higher degree of unsaturation, etc.) -C n H 2n-2 In some embodiments, n can have a value of 2-22 ((C 22 ) alkenyl), which is C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , and C 22Alkenyl groups include. Alkenyl groups can be linear or branched, substituted or unsubstituted, with multiple degrees of unsaturation, or any combination thereof. One or more hydrogens can be optionally and independently replaced by one or more substituents. One or more carbon atoms can be optionally and independently replaced by one or more heteroatoms, such as O, S, N, B, or any combination thereof. In some embodiments, an alkenyl group is attached to a parent structure through one or more independent divalent intervening substituents. Some examples of alkenyl groups include, but are not intended to be limiting, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, alkadienes, alkatrienes, terpenes, and the like. Alkenyl groups are preferably monovalent, linear or branched, substituted or unsubstituted, unsaturated C2-C 22 , C2-C 15 , C2-C 10 , C2-C8, or C2-C6 hydrocarbon groups. The alkenyl group is preferably a monovalent, linear or branched, unsubstituted, unsaturated C2-C 22 , C2-C 15 , C2-C 10 , C2-C8, or C2-C6 hydrocarbon groups. The alkenyl group is preferably a monovalent, linear, unsubstituted, unsaturated C2-C 22 , C2-C 15 , C2-C 10 , C2-C8, or C2-C6 hydrocarbon groups. The alkenyl group may preferably be a monovalent, linear, unsubstituted, unsaturated C2-C6 hydrocarbon group. The alkenyl group may preferably be a terpene such as geranyl, farnesyl, geranylgeranyl, etc.

[0064] One or more hydrogens on an alkenyl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0065] Cycloalkyl groups are preferably monovalent, monocyclic or polycyclic, substituted or unsubstituted, saturated or unsaturated hydrocarbon groups. Cycloalkyl groups have the general formula (regardless of any unsaturation, substitution, etc.) -C n H 2n-1In some embodiments, n is 3-8 ((C3-C8)cycloalkyl), which may preferably include C3, C4, C5, C6, C7, or C8 cycloalkyl groups. As noted above, the cycloalkyl group may be substituted or unsubstituted, saturated or unsaturated, monocyclic, bicyclic, tricyclic, or polycyclic, or any combination thereof. One or more hydrogens may be optionally selected and independently replaced by one or more substituents. One or more carbon atoms may be optionally selected 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 connected to the parent structure through one or more independent divalent intervening substituents. Some examples of cyclopropyl groups include, but are not intended to be limiting, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. If polycyclic, one or more of the rings may be linked through a bond or other divalent intervening substituent, fused (e.g., one or more of the rings share two or more carbon atoms or heteroatoms), linked through a single atom (e.g., spiro compounds), or bridged. The cycloalkyl group may be preferably a monovalent, monocyclic or polycyclic, substituted or unsubstituted, saturated or unsaturated C3-C8, C3-C6, C3-C5, or C3-C4 hydrocarbon group. The cycloalkyl group may be preferably a monovalent, monocyclic, substituted or unsubstituted, saturated C3-C8, C3-C6, C3-C5, or C3-C4 hydrocarbon group. The cycloalkyl group is preferably a monovalent, monocyclic, unsubstituted, saturated C3-C8, C3-C6, C3-C5, or C3-C4 hydrocarbon group.

[0066] One or more hydrogens on the cycloalkyl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0067] The alkoxy group is preferably a monovalent group derived from an -O-alkyl group, which may preferably include C1, C2, C3, C4, C5, and C6-O-alkyl groups. In some embodiments, the alkoxy group may be attached to the parent structure via one or more independent divalent intervening substituents. The alkoxy group may preferably be a monovalent, acyclic, straight-chained or branched, substituted or unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkoxy group. The alkoxy group may preferably be a monovalent, straight-chained, substituted or unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkoxy group. The alkoxy group may preferably be a monovalent, straight-chained, unsubstituted, saturated C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkoxy group.

[0068] One or more hydrogens on an alkoxy group can be independently replaced with a C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0069] Cyclic amines are preferably monovalent groups derived from cycloalkyl groups in which one or more of the ring carbons are replaced with nitrogen. Cyclic amines can preferably have a 3-9 member ring in which one or more nitrogens form a ring with 2-8 carbons. For example, cyclic amines can have the following formula: [ka] Here, each x may independently be 1 to 8, and in the case of the second structure, the "N·" group may be filled with hydrogen or other substituents. Each x may independently be 1, 2, 3, 4, 5, 6, 7, or 8. The cyclic amine is a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, including when nitrogen and other heteroatoms are present. In the cyclic amine, one or more additional ring carbons may preferably be replaced with one or more additional heteroatoms, e.g., N, O, P, S, oxidized forms thereof, or combinations thereof. In the cyclic amine, one or more additional ring carbons may preferably be replaced with one or more N, O, or combinations thereof. The cyclic amine may preferably be substituted or unsubstituted, saturated or unsaturated, monocyclic or polycyclic, or any combination thereof. One or more hydrogens may preferably be replaced by one or more substituents. The cyclic amine may preferably be bonded to the parent structure via a ring carbon or nitrogen. In some embodiments, the cyclic amine may be bonded to the parent structure via one or more independent divalent intervening substituents. Non-limiting examples of cyclic amines include aziridine, azetidine, morpholine, thiomorpholine, piperidine, piperazine, and the like.

[0070] One or more hydrogens on the cyclic amine group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0071] Heterocyclic groups are preferably monovalent, substituted or unsubstituted, saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing one or more heteroatoms in one or more rings. Heterocyclic groups can be preferably C3-C20 cyclic groups in which one or more ring carbons are independently replaced with one or more heteroatoms. C3-C20 heterocyclic groups are preferably C3, C4, C5, C6, C7, C8, C9, C10, C12, C14, C16, C18, C19, C20, C21, C22, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C60, C61, C62, C63, C64, C65, C66, C77, C82, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C109, C110, C121, C130, C142, C150, C151, C162, C170, C181, C192, C193, C194, C195, C196, C197, C198, C199, C200, C201, C202, C203, C204, C205, C206, C207, C208, C209, C301, C310, C321, C322, C333, C34, C3 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , and C 20Heterocyclic groups may be cyclic or combinations thereof in which one or more ring carbons are independently replaced by one or more heteroatoms. The one or more heteroatoms may be preferably selected from one or more N, O, or S, or any combination thereof. N or S, or both, may be independently substituted with one or more substituents. N or S, or both, may be independently substituted with hydrogen or other substituents. Heterocyclic groups may be substituted or unsubstituted, saturated or unsaturated, monocyclic, bicyclic, tricyclic, or polycyclic, or any combination thereof. One or more hydrogens of a heterocyclic group may be optionally and independently replaced by one or more substituents. Optionally, a heterocyclic group may include one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, or any combination thereof. Heterocyclic groups may be suitably attached to the parent structure via a ring carbon or heteroatom, such as nitrogen. In some embodiments, a heterocyclic group is attached to the parent structure via one or more independent divalent intervening substituents.Without intending to be limiting, some examples of heterocyclic groups include cyclic amine, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, and the like. Heterocyclic groups include, for example, 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-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholinyl, 1,2-tetrahydrothiazin-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, etc. Heterocyclic groups are preferably C3-C. 12 , C3-C 10 , C3-C8, or C3-C6 saturated cyclic groups, in which one or more ring carbons are independently replaced with one or more N, O, or other heteroatoms. Heterocyclic groups are preferably substituted or unsubstituted C5-C 12 A heteroaryl group is preferably a substituted or unsubstituted C5-C aryl group, in which at most two of the ring carbons are replaced by nitrogen heteroatoms. 12 An aryl group in which one of the ring carbons is replaced with a nitrogen heteroatom.

[0072] One or more hydrogens on a heterocyclic group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0073] The aryl group is preferably a monovalent, substituted or unsubstituted, monocyclic or polycyclic aromatic hydrocarbon group. The aryl group may be a group that is cyclic and contains a delocalized (4n+2) pi-electron system according to Hückel's theory. The aryl group is preferably a C6, C7, C8, C9, C10, C12, C13, C14, C15, C16, C17, C18, C19, C20, C210, C220, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C81, C92, C93, C94, C95, C96, C97, C98, C99, C101, C111, C122, C132, C141, C152, C163, C174, C185, C196, C197, C198, C111, C112, C113, C124, C125, C135, C141, C152, C153, C164, C175, C185, C 10 , C 11 , and C 12 C6-C containing aryl groups 12 It can be an aryl group. The aryl group can be substituted or unsubstituted, and can be substituted with two or more groups that together form a cyclic group, or any combination thereof. In some embodiments, the aryl group is linked to the parent structure via one or more independent divalent intervening substituents. Without intending to be limiting, some examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0074] One or more hydrogens on the aryl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0075] Heteroaryl groups are preferably monovalent, substituted or unsubstituted, monocyclic or polycyclic aromatic hydrocarbon groups in which one or more ring carbons are independently replaced by one or more heteroatoms selected from O, S and N. In addition to the heteroatoms, heteroaryl groups may contain up to 1, 2, 3 or 4 nitrogen atoms in the ring. Heteroaryl groups are aryl groups in which one or more ring carbons are independently replaced by one or more heteroatoms. Heteroaryl groups are preferably aromatic groups, contain one or more heteroatoms, and may be cyclic and contain a delocalized (4n+2) pi-electron system according to Hückel's theory. Heteroaryl groups are preferably C5-C 20 It may be a heteroaryl group. 20 Heteroaryl groups are preferably C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , and C 20The heteroaryl group may be an aryl group, and may be a combination thereof, in which one or more ring carbons are independently replaced with one or more heteroatoms. The heteroaryl group may be substituted or unsubstituted, and may be substituted with two or more groups that together form a cyclic group, or any combination thereof. The heteroaryl group may be suitably bonded to the parent structure through a ring carbon or heteroatom, or through one or more independent divalent intervening substituents. Without intending to be limiting, some examples of heteroaryl groups 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 (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, etc. Heteroaryl groups are preferably substituted or unsubstituted C6-C 12 An aryl group, in which at most two of the ring carbons are replaced by nitrogen heteroatoms. Heteroaryl groups are preferably substituted or unsubstituted C6-C 12 An aryl group in which one of the ring carbons is replaced with a nitrogen heteroatom.

[0076] One or more hydrogens on a heteroaryl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0077] In embodiments, preferred examples of heteroaryls or heterocycles include furan, substituted furan, thiophene, substituted thiophene, oxazole, substituted oxazole, isoxazole, substituted isoxazole, imidazole, substituted imidazole, pyrrole, substituted pyrrole, pyrrolidine, substituted pyrrolidine, tetrahydrofuran, substituted tetrahydrofuran, pyridine, substituted pyridine, piperidine, substituted piperidine, pyrimidine, substituted pyrimidine, pyrazine, substituted pyrazine, azepine, substituted azepine, 1,4-diazepine, substituted 1,4-diazepine, 4H- pyran, substituted 4H-pyran, tetrahydropyran, substituted tetrahydropyran, indole, substituted indole, quinoline, substituted quinoline, isoquinoline, substituted isoquinoline, chroman, substituted chroman, purine, substituted purine, pteridine, substituted pteridine, benzimidazole, substituted benzimidazole, benzothiazole, substituted benzothiazole, benzoxazole, substituted benzoxazole, benzofuran, substituted benzofuran, benzothiazole, substituted benzothiazole, 1H-indazole, and substituted 1H-indazole. Some examples of substituents of these substituted heteroaryl or substituted heterocycles include C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0078] A biaryl group is preferably two aryl groups linked together via a direct covalent bond or via an intervening methylene, ethylene, propylene, etc. The aryl groups may be the same or different. A biaryl group may be connected directly to a parent structure, preferably via one of the ring carbons of an aryl group or via an intervening divalent substituent. A biaryl group may preferably be -CH-CH.

[0079] One or more hydrogens on the biaryl group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0080] A biaryl ether group is preferably two aryl groups linked together through an intervening oxygen. The aryl groups may be the same or different. A biaryl ether group may be connected directly to a parent structure, preferably through one of the ring carbons of one aryl group or through an intervening divalent substituent. A biaryl group may preferably be -C6H4-O-C6H5.

[0081] One or more hydrogens on the biaryl ether group can be independently replaced with C1-C6 alkyl, alkenyl, alkoxy, t-butyl, isopropoxy, amine, nitrile, halogen, F, Cl, hydroxy, CF3, OCF3, SF3, SF5, sulfate, methylsulfone, nitrate, carboxylate, carboxylic acid, carboxamide, aryl, heteroaryl, cyclic amine, cycloalkyl, heterocycle, or combinations thereof.

[0082] A halo group is preferably a monovalent halogen group or halogen-containing substituent, such as or including one or more of F, Br, Cl, I, or combinations thereof. Halo can preferably be F or Cl. In some embodiments, halo is preferably F.

[0083] The pharma- ceutically acceptable carrier is not particularly limited and can be selected from known or common solvents, diluents, dispersions, powders, water, saline, DMSO, ethanol, etc., which can be easily determined by one skilled in the art given the compounds and subject matter disclosed herein. EXAMPLES

[0084] The following examples are intended to illustrate the above invention and should not be construed to narrow its scope.

[0085] The preparation of bd oxidase inhibitors was carried out according to the classical S method, which is described in J. Med. Chem., 1999, 42(22), pp4705-4713. N This can be done by AR and is shown below: [ka] Specific S N AR example: [ka] [ka] Palladium cross-coupling (Buchwald) reaction: [ka] Examples: [ka] According to the phosphonium coupling reaction described by Fu-An Kang in Progress in Heterocyclic Chemistry, Volume 27, 2015, 29-59: [ka] [ka]

[0086] Preparation of Selected Quinazoline Intermediates: [ka] 4-Chloro-7-fluoroquinazoline (CAS:16499-62-0) can be prepared by literature methods, e.g., Bioorganic & Medicinal Chemistry Letters (2017), 27(21), 4885-4888; MedChemComm (2014), 5(9), 1290-1296; PCT International Application 2007071963, 28 June 2007; US Patent Application Publication 20050187231, 25 August 2005. [ka] A general / typical procedure involves: A solution of 18.2 g of CAS:446-32-2 (100 mmol) in 76.5 g (64 ml) of formamide (1.7 mol) was heated to reflux at 120-125° C. for 4 hours. The solvent was removed under reduced pressure, and the crude solid was recrystallized from ethyl alcohol to obtain 12.7 g of compound CAS:16499-57-3 (yield, 87%). To 7.3 g of compound CAS:16499-57-3 (50 mmol), 230 ml of thionyl chloride (2 mol) was added dropwise with stirring at 0° C. 2-3 drops of N,N-dimethylformamide were added to the reaction solution, and the reaction solution was heated under reflux for 3-4 hours. The thionyl chloride was removed under reduced pressure, and the resulting residue was washed with sodium carbonate. The product was extracted with ethyl acetate, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 column chromatography to give 4-chloro-7-fluoroquinazoline (CAS: 16499-62-0).

[0087] [ka] 4-Chloroquinazoline (CAS:5190-68-1) can be prepared by literature methods, e.g., Bioorganic & Medicinal Chemistry Letters, 27(21), 4885-4888; 2017; RSC Advances, 7(54), 34005-34011; 2017; Journal of Heterocyclic Chemistry, 54(4), 2548-2555; 2017; Beilstein Journal of Organic Chemistry, 13, 174-181; 2017; PCT International Application, 2016146074, September 22, 2016.

[0088] Synthesis of biaryl ether anilines: TIFF0007659269000080.tif49424-(4-(Trifluoromethyl)phenoxy)aniline (CAS:57478-19-0) can be prepared by literature methods including Journal of Medicinal Chemistry, 60(13), 5392-5406;2017;MedChemComm, 6(4), 671-676;2015;Journal of Medicinal Chemistry, 56(11), 4811-4815;2013.

[0089] Synthesis of N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine: [ka] Synthesis of N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine. 4-Chloroquinazoline (CAS: 5190-68-1, 700 mg, 4.3 mmol), 4-(4-(trifluoromethyl)phenoxy)aniline (CAS: 57478-19-0, 1.08 g, 4.3 mmol) and potassium carbonate (587 mg, 4.3 mmol) were dissolved in 15 mL of DMSO. The reaction was heated at 110° C. for 12 hours. The reaction was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (twice), water and saturated brine. The organic layers were combined, dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 50% ethyl acetate:CH2Cl2 solvent system to give 1.27 g (78%) of N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine. Recrystallization from hot isopropanol or CH3CN gave pale crystals. 1 H NMR(300 MHz, CDCl3)δ8.75(s, 1H), 7.93(dd, J = 8.3, 1.3 Hz, 2H), 7.87 - 7.74(m, 2H), 7.74(s, 1H), 7.58(dd, J = 8.5, 7.1 Hz, 4H), 7.16 - 7.02(m, 4H). 19 F NMR (282 MHz, CDCl3))δ-61.72(s, 3F). -

[0090] - Synthesis of 7-fluoro-N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine: [ka] Synthesis of 7-fluoro-N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine. 4-Chloro-7-fluoroquinazoline (CAS: 16499-62-0, 480 mg, 2.6 mmol) and 4-(4-(trifluoromethyl)phenoxy)aniline (CAS: 57478-19-0, 662 g, 2.6 mmol) were dissolved in a 3:1 mixture of tetrahydrofuran:isopropanol (total volume 20 mL). Concentrated hydrochloric acid (0.1 mL) was added and the reaction was heated at 70 °C for 10 h. The reaction was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with saturated NaHCO3 solution (twice) and saturated brine. The organic layers were combined, dried over sodium sulfate (Na2SO4), filtered, and then concentrated in vacuo. The crude product was purified by recrystallization from hot CH3CN or isopropanol to give 515 mg (49%) of 7-fluoro-N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine as clear crystals. 1 H NMR (300 MHz, CDCl3) δ8.73(s, 1H), 7.91(dd, J = 9.2, 5.5 Hz, 1H), 7.77 - 7.65(m, 2H), 7.61 - 7.49(m, 3H), 7.45(s, 1H), 7.38 - 7.21(m, 1H), 7.16 - 7.02(m, 4H). 19 F NMR (282 MHz, CDCl3) δ -61.72 (s, 3F), -104.15 - -104.30 (m, 1F).

[0091] protocol: Cyt-bd inhibitor screening assay in mycobacteria (M. bovis BCG and M. tuberculosis): 1. Grow the parental strain M. bovis BCG or M. tuberculosis in 7H9-ADS-tween80 medium supplemented with glycerol. 2. Harvest the medium at mid-logarithmic growth phase (OD 600 0.2~0.5). 3. Wash twice with 7H9-ADS-tween80 medium (without glycerol). 4. Inoculum Size to an OD of 0.05 600 Adjust to. 5. 100X Drug Intermediate Plate in a white 96-well flat-bottom plate * Dispense 1 μL of drug into each well. 6. Dispense 100 μL of culture medium into each well. 7. Place the plate in a humidified incubator at 37°C for 15 hours. 8. Remove the plate and allow to cool to room temperature. 9. Bind BacTiter-Glo according to the manufacturer's instructions TM Reconstruct. 10.25 μL of BacTiter-Glo TM Dispense reagent into each well. 11. Incubate the plate in the dark at room temperature for 12 (10-20) minutes. 12. Read luminescence on a microplate reader (gain: 135; integration time: 1 sec). 13. Plot dose-response curves and ATPIC of test compounds in the presence or absence of Q203 50 Get the value.

[0092] * Drug Intermediate Plate: (200X Plates): Perform two-fold serial dilutions of each test compound in a 96-well round-bottom plate using DMSO as the diluent starting at 5 mM and diluting 10-fold. Prepare a 20 μM Q203 stock. (100X Plates): To prepare the "compound only" dilution plate, transfer 10 μL of each drug dilution (test compound) from the 200X plate to a new plate and add an equal volume of DMSO to each well. To prepare the "Compounds with Q203" dilution plate, transfer 10 µL of each drug dilution (test compound) from the 200X plate to a new plate and add an equal volume of 20 µM Q203 stock to each well.

[0093] Figures 1a-b show data generated with ND-11992 (cpd-21) against H37Rv-Mtb. Figure 2a-b shows data generated with ND-11992 against the N0145-Mtb clinical strain. Figures 3a-b show data generated with ND-11992 (cpd-21) against Mycobacterium bovis BCG.

[0094] ND-11992 (a bd oxidase inhibitor) and Q203 (a cyt-bc1:aa3 inhibitor) were evaluated alone and in combination in an acute mouse model of M. tuberculosis infection. ND-11992 (10 mg / kg PO) + Q203 (5 mg / kg PO) were bactericidal, producing a 1.5 log10 CFU reduction of bacteria when administered orally for 5 days. The combination therapy was superior to ND-11992 at 10 mg / kg (no CFU reduction) or Q203 at 5 mg / kg (0.5 CFU reduction). Both compounds were bacteriostatic when administered alone as single agents. The results are shown in Figure 4. ND-11992 (a bd oxidase inhibitor) and ND-11598 (a cyt-bc1:aa3 inhibitor) were evaluated against a variety of M. abscessus clinical specimens in the checkerboard assay. An additive effect on MICs was observed when both drugs were used in combination. MIC values ​​are given in μg / mL.

[0095] [Table 1] ND-11992 (a bd oxidase inhibitor) and ND-11598 (a cyt-bc1:aa3 inhibitor) were evaluated against various nontuberculous mycobacteria (NTM) clinical isolates of the Mycobacterium avium-intracellular complex (MAIC) in a checkerboard assay. Additive and synergistic effects on MICs were observed when both drugs were used in combination. MIC values ​​are given in μg / mL.

[0096] [Table 2] The entire contents of each reference, patent, publication, patent application, and URL mentioned herein are incorporated by reference as if fully set forth.

Claims

1. Formula (A): 【Chemistry 1】 (In the formula, X １ is N; R １ is H, alkyl or NR′R″; R ２ is H; R ３ is H or a halogen; R ４ is H; R ５ is H; R' is C １－６ is alkyl; R'' is C １－６ is alkyl; n is 0; and Q is, 【Chemistry 2】 (In the formula, Each Y in Ring A is independently CH or C-Ring B; only one Y is C-Ring B; Each Y in Ring B is independently CH or CR 8 ; at least one Y is CR 8 ; each R 8 is independently halogen, CF 3 , amine, C 1-6 alkyl, alkoxy, or OCF 3 . (It is) or a pharma- ceutically acceptable salt thereof.

2. The following: 【Chemistry 3】 2. The compound of claim 1 having a formula selected from the group consisting of:

3. R １ is Me or NMe ２ 2. The compound of claim 1,

4. R 3 The compound of claim 1 , wherein is H or F.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharma- ceutically acceptable carrier.

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