Cytochrome BD oxidase inhibitors and uses thereof

Abstract

The present disclosure relates in part to compounds or pharma- ceutically acceptable salts thereof for modulating the activity of cytochrome BD oxidase or variants thereof. The present disclosure also provides pharma- ceutically acceptable compositions comprising the compounds of the present disclosure, and methods of using the compositions in the treatment of various diseases and disorders associated with cytochrome BD oxidase.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 337,836, filed May 3, 2022, the entire contents of which are incorporated herein by reference.

[0002] Government Licensing Rights This invention was made with Government support under Grant No. R37 AI054193 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] The present disclosure relates in part to compounds or pharma- ceutically acceptable salts thereof for modulating the activity of cytochrome BD oxidase or variants thereof. The present disclosure also provides pharma- ceutically acceptable compositions comprising the compounds of the present disclosure, and methods of using the compositions in the treatment of various diseases and disorders associated with cytochrome BD oxidase. [Background technology]

[0004] Mycobacterial diseases have plagued humanity since ancient times. Most notably, tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the world's leading cause of death from a single infectious agent, surpassing HIV / AIDS in the rankings. Currently, about 2 billion people are infected with tuberculosis. Although the disease remains latent in most people, active disease develops in about 10 million people each year, and more than 1.5 million people die from TB each year. This situation is exacerbated by the increasing number of cases associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. After a drought of nearly 40 years, several new types of anti-TB drugs have been approved for use, but resistance to these new drugs has already become a clinical problem, and new, more effective treatments are needed.

[0005] Compounding this dire situation is the reality that non-tuberculosis mycobacterial (NTM) infections are on the rise. The most difficult to treat NTM infections are Mycobacterium avium complex (or MAC for short, which includes Mycobacterium avium and Mycobacterium intracellulare) and Mycobacterium abscessus (three subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense and M. abscessus subsp. borettii). These NTM infections are extremely difficult to treat. Other examples of atypical pathogenic mycobacteria include Mycobacterium fortuitum and Mycobacterium kansasii.

[0006] The recently approved drug bedaquiline (Sirturo®) inhibits F1F0 ATP synthase in Mtb, indicating that energy metabolism may be a valid target for antimycobacterial drug development. Recently, a series of compounds that inhibit essential oxidative phosphorylation have been reported, including those that inhibit terminal cytochrome bcc:aa3 oxidase (Qcrb inhibitors), such as imidazopyridine carboxamides, which are currently in phase 2 clinical trials (GC Moraski et al., Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculous Activity. ACS Medicinal Chem Try Letters 2, 466-470 (2011); GC Moraski et al., Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis. ACS Medicinal Chem Try Letters 4, 675-679 (2013); and KA Abrahams et al., Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculos like QcrB. PLoS ONE 7, e52951 (2012)) like Q203 (Telecebec) (K. Pethe et al., D is coverage of Q203, a potent clinical candidate for the treatment of M. tuberculos. Nat Med 19, 1157-1160 (2013). However, these compounds are bacteriostatic rather than bactericidal. The most likely reason is that they bind to cytochrome bcc:aa 3This highlights the attractiveness of bd-type terminal oxidases for drug development, as functional redundancy between QcrB and a second terminal oxidase, the cytochrome bd oxidase, protects M. tuberculosis from killing by Q203 (NP Kalia et al., Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci USA 114, 7426-7431 (2017)). Thus, well-designed combinations of synergistic QcrB and bd oxidase (BDO) inhibitors are of particular interest.

[0007] Additionally, observations made in the non-pathogenic mycobacterium Mycobacterium smegmatis revealed that genetic deletion of the gene encoding BDO sensitizes the bacterium to clofazimine, a second-line drug widely used to treat drug-resistant tuberculosis and NTM lung disease (ref). Thus, there is a need to identify cytochrome BD oxidase modulators for the treatment of these and other conditions. The present embodiments described herein fulfill these and other needs.

[0008] Summary of the embodiment The present disclosure provides, in part, a compound or a pharma- ceutically acceptable salt thereof that modulates the activity of cytochrome BD oxidase.The compound may, for example, have a formula as described herein.In some embodiments, the compound is selected from the compounds described herein.In some embodiments, a method for treating a disease, disorder and / or condition as described herein is provided.

[0009] In some embodiments, the present disclosure provides a compound of the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0010] The present disclosure provides a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt.In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0011] The present disclosure also provides a method of using the compounds of the present disclosure, their pharma- ceutically acceptable salts, and their pharma- ceutically acceptable compositions for treating various diseases, disorders, or conditions related to the regulation of the activity of cytochrome BD oxidase.In some embodiments, the disorder, disease, and / or condition is mycobacterial infection.In some embodiments, the method further comprises administering an inhibitor of oxidative phosphorylation process in mycobacteria. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows that compound 12 kills M. abscessus in synergy with clofazimine.

[0013] Detailed Description of Specific Embodiments The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are provided and described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment may also be provided separately or in any subcombination.

[0014] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that embodiments include individual subcombinations of the members of such groups or ranges. For example, the term "C 1-6 Alkyl" or "C 1 -C 6 Alkyl" is methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 It is specifically intended to disclose alkyl individually.

[0015] It is further understood that certain embodiments described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of an embodiment described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination. Moreover, for all purposes, the disclosure encompasses not only the main groups, but also the main groups absent one or more group members. Thus, the disclosure contemplates the explicit exclusion of any one or more of the described group members. Thus, provisos may be applied to any of the disclosed categories or embodiments, thereby excluding any one or more of the implicit elements, species, or embodiments from such categories or embodiments, for example, for use in an express negative limitation.

[0016] All percentages and ratios used herein are by weight unless otherwise specified.

[0017] Compounds of the present disclosure include those generally described herein and further exemplified by the classes, subclasses and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0018] The following definitions are included to provide a clear and consistent understanding of the specification and claims. Terms used herein have the following meanings. All other terms and phrases used herein have their ordinary meanings as understood by those of ordinary skill in the art. Such ordinary meanings are defined in Hawley's Condensed Chemical Dictionary 14 by RJ Lewis, John Wiley & Sons. th Such information can be obtained by consulting technical dictionaries such as those in the US Pat. No. 6,392,312, Published Edition, New York, NY, 2001.

[0019] The term “alkyl” when used alone or as part of a substituent group means a straight or branched chain hydrocarbon group, a spirocyclic group, or a fused or bridged bicyclic group, each group having from 1 to 12 carbon atoms ("C 1 -C 12 "), preferably 1 to 6 carbon atoms ("C 1 -C 6"). Examples of alkyl groups include methyl (Me, C 1 Alkyl), Ethyl (Et, C 2 Alkyl), n-propyl (C 3 Alkyl), isopropyl (C 3 Alkyl), Butyl (C 4 Alkyl), Isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 Alkyl), Pentyl (C 5 Alkyl), isopentyl (C 5 alkyl), tert-pentyl (C 5 Alkyl), Hexyl (C 6 Alkyl), Isohexyl (C 6 The term "spirocyclic group" refers to a spirocyclic compound in which two rings share only one single atom, usually a spiro atom, which is a quaternary carbon. Examples of spirocyclic compounds include spiro[2,3]undecane, spiro[3,3]heptane, and spiro[5,5]undecane. The term "fused bicyclic group" refers to a fused bicyclic compound in which two rings share two adjacent atoms. Examples of fused bicyclic compounds include bicyclo[4.4.0]decane, α-thujene, and decalin. The term "bridged bicyclic group" refers to a bridged bicyclic compound in which two rings share three or more atoms and a bridge containing at least one atom separates the two bridgehead atoms. Examples of bridged bicyclic compounds include bicyclo[2.2.1]heptane, bicyclo[1,1,1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, bicyclo[3.3.3]undecane, and the like. The term "haloalkyl" when used alone or as part of a substituent group means an alkyl group having 1 to 12 carbon atoms ("C 1 -C 12 "), preferably 1 to 6 carbon atoms ("C 1 -C 6"), in which one or more of the hydrogen atoms in the group are replaced by halogen atoms. An example of a haloalkyl group is trifluoromethyl (-CF 3 , C1 haloalkyl), trifluoroethyl-CH 2 CF 3 , C 2 haloalkyl).

[0020] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a single point of attachment to the remainder of the molecule (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a single point of attachment to the remainder of the molecule. 3 -C 6 "a" refers to a hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0021] As used herein, the term "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturated units, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" which requires that one or more heteroatoms are present in one or both of the two rings. Such heteroatoms may be present at the ring junction, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic saturated or partially unsaturated ring system. According to the IUPAC definition, a "bridge" is an unbranched chain of atoms, or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is connected to three or more skeletal atoms (except hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the following groups, each of which is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group may be optionally substituted by one or more of the substituents described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group may be optionally substituted. Exemplary bicyclic rings include: [ka] Examples include:

[0022] Exemplary bridged bicyclic rings include: [ka] Examples include:

[0023] The term "lower alkyl" refers to C 1-4 It means a straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0024] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1-4 It means a straight or branched alkyl group.

[0025] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon, quaternized forms of a basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, such as N (such as 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (such as N-substituted pyrrolidinyl) is meant to include one or more of the following:

[0026] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0027] As used herein, the term "divalent C 1-8 (or C 1-6 ) Saturated or unsaturated straight or branched hydrocarbon chain" means divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0028] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n- (where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3). A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include the substituted aliphatic groups described below.

[0029] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include the substituted aliphatic groups described below.

[0030] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group having the structure: [ka]

[0031] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . + It may be NR (as in the case of N-substituted pyrrolidinyl).

[0032] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties independently may be optionally substituted.

[0033] As used herein, the term "partially unsaturated" means a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to encompass aryl or heteroaryl moieties as defined herein.

[0034] As described herein, the compounds of the present disclosure may include "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at all positions. The combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable compounds or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow its preparation, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein. As used herein, "suitable substituents", "substituents", "optional substituents", or substituents of any optionally substituted group refer to groups that do not abolish the synthetic or pharmaceutical utility of the compounds described herein or intermediates useful for preparing them. Examples of "suitable substituents", "substituents", "optional substituents", or substituents of an optionally substituted group include C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, C 1 -C 6 Alkoxy, Phenyl, C 3 -C 5 Heteroaryl, C 3 -C 10 Cycloalkyl, C 5 -C 6 Aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO 2 , -CO 2 H, -NH 2 , -NH(C 1 -C 8alkyl), -N(C 1 -C 8 Alkyl) 2 , -NH(phenyl), -N(phenyl) 2 , -CHO, -CO(C 1 -C 6 alkyl), -CO(phenyl), -CO 2 (C 1 -C 6 Alkyl) and -CO 2 In some embodiments, a "suitable substituent", "substituent" or "optional substituent" is one or more C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, C 1 -C 6 Alkoxy, Phenyl, C 3 -C 5 Heteroaryl, C 3 -C 10 Cycloalkyl, C 5 -C 6 Aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO 2 , -CO 2 H, -NH 2 , -NH(C 1 -C 8 alkyl), -N(C 1 -C 8 Alkyl) 2 , -NH(phenyl), -N(phenyl) 2 , -CHO, -CO(C 1 -C 6 alkyl), -CO(phenyl), -CO 2 (C 1 -C 6 Alkyl) and -CO 2 (phenyl). One of ordinary skill in the art can readily select appropriate substituents based on the stability, pharmacological activity, and synthetic activity of the compounds described herein.

[0035] The formulas and compounds described herein can be modified using protective groups.Suitable amino and carboxy protective groups are known to those skilled in the art (see, for example, Protecting Groups in Organic Synthesis, Second Edition, Greene, TW, and Wutz, PGM, John Wiley & Sons, New York, and references cited therein; Philip J. Kocienski; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994) and references therein); and Comprehensive Organic Transformations, Larock, RC, Second Edition, John Wiley & Sons, New York (1999) and references therein).

[0036] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or the replacement of one or more isotopically enriched atoms. 13 C- or 14Compounds having this structure include carbon replacement with C-enriched carbon are within the scope of the present disclosure.Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.In certain embodiments, compounds of the present disclosure include one or more deuterium atoms.

[0037] As used herein, the term "inhibitor" is defined as a compound that binds and / or inhibits cytochrome BD oxidase or its variant with measurable affinity.In certain embodiments, the inhibitor has an IC50 and / or binding constant of less than about 100 μM, less than about 50 μM, less than about 20 μM, less than about 10 μM or less than about 5 μM.

[0038] As used herein, the terms "measurable affinity" and "measurably inhibit" refer to a measurable change in the activity of a cytochrome BD oxidase or variant thereof between a sample containing a compound or composition thereof disclosed herein and a cytochrome BD oxidase or variant thereof and an equivalent sample containing a cytochrome BD oxidase or variant thereof in the absence of said compound or composition thereof.

[0039] The term "halo" or "halogen" means chloro, fluoro, bromo or iodo.

[0040] The term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent which forms a carbonyl group (e.g., C=O) when attached to a carbon, and a nitroso, sulfinyl, or sulfonyl group when attached to a nitrogen or sulfur heteroatom.

[0041] The term "cycloalkyl" when used alone or as part of a substituent group means an alkyl group having 3 to 22 carbon atoms ("C 3 -C 22 " ), 3 to 10 carbon atoms (" C 3 -C 10 " ), 3 to 6 carbon atoms (" C 3 -C 6" ), or 3 to 7 carbon atoms ("C 3 -C 7 "). Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopropylmethyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), 1-methylcyclopropyl (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl (C 10 Suitable cycloalkyl groups include: [ka] Examples include:

[0042] The term "heterocycloalkyl" when used alone or as part of a substituent group means a 3-14 membered monocyclic, bicyclic, or tricyclic saturated ring structure that contains at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl groups can be described in terms of the number of atoms in the group or in terms of the number of carbon atoms in the group.

[0043] The term "aryl" when used alone or as part of a substituent group means a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring system. Examples of aryl groups are phenyl and naphthyl.

[0044] The term "heteroaryl", when used alone or as part of a substituent, refers to a monocyclic, bicyclic, or tricyclic aromatic ring structure containing carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can contain a total of 5, 6, 9, 10, or 14 ring atoms. Heteroaryl groups can be described in terms of the number of atoms in the group or in terms of the number of carbon atoms in the group. Thus, the term "5-14 membered heteroaryl" refers to a heteroaryl group containing 5 to 14 ring atoms. The term -C4-C6 heteroaryl, for example, refers to a heteroaryl group containing 4 to 6 carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.

[0045] When a range of carbon atoms is used herein, e.g., C 1 -C 6 includes all ranges, not just individual numbers of carbon atoms. For example, "C 1 -C 3 " is C 1 -C 3 , C 1 -C 2 , C 2 -C 3 , C 1 , C 2 and C 3 The range of carbon atoms may be expressed in alternative ways. For example, the term "C 1 -C 6 " means "C 1 -C 6 " is an alternative expression.

[0046] When a ring system is described herein as having a range of members, such as "5-14 members," all ranges are encompassed, as are the individual atom numbers. For example, "5-14 members" includes 5-6 members, 5-10 members, 6-9 members, 5 members, 6 members, 7 members, 8 members, etc.

[0047] As used herein, "alkoxy" refers to an -O-alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0048] The term “alkenyl” when used alone or as part of a substituent group refers to an alkyl group having 2 to 12 carbon atoms ("C 2 -C 12 "), preferably 2 to 6 carbon atoms ("C 2-6 "), where the group has at least one carbon-carbon double bond, alkenyl group, vinyl (-CH=CH 2 ;C 2 alkenyl), allyl (-CH 2 -CH=CH 2 ;C 3 alkenyl), propenyl (-CH=CHCH 3 ;C 3 Alkenyl; isopropenyl (-C(CH 3 )=CH 2 ;C 3 alkenyl), butenyl (-CH=CHCH 2 CH 3 ;C 4 alkenyl, sec-butenyl (-C(CH 3 )=CHCH 3 ;C4 alkenyl), iso-butenyl (-CH=C(CH 3 ) 2 ;C 4 alkenyl), 2-butenyl (-CH 2 CH=CHCH 3 ;C 4 Alkyl), pentenyl (CH=CHCH 2 CH 2 CH 3or CH 2 =CHCH 2 CH 2 CH 2 -;C 5 alkenyl).

[0049] The term "alkynyl" when used alone or as part of a substituent group refers to an alkynyl group having 2 to 12 carbon atoms ("C 2 -C 12 "), preferably 2 to 6 carbon atoms ("C 2 -C 6 ") and includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH;C 2 alkynyl), propargyl (-CH 2 -CH≡CH;C 3 alkynyl).

[0050] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by separation of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like, may also exist in the compounds described herein, and all such stable isomers are contemplated in the present embodiments. Geometric isomers of the compounds of the present embodiments are described and can be isolated as a mixture of isomers or as separate isomers.

[0051] The compounds provided herein may also include tautomeric forms. All tautomeric forms are included.

[0052] In some embodiments, the compound may exist as a rotamer. In some embodiments, the compound exists as a mixture of rotamers in any ratio. In other embodiments, the compound exists as a specific rotamer substantially free of other rotamers.

[0053] Compounds may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0054] In some embodiments, the compound and its salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition in which the compound is enriched. Substantial separation can include a composition that contains at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or its salt. Methods for separating compounds and their salts are routine in the art.

[0055] Also provided herein are pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; alkali or organic acid salts of acidic residues, such as carboxylic acids. Pharmaceutically acceptable salts include, but are not limited to, conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both, and generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0056] As used herein, the phrase "pharmacologically acceptable" means those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0057] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, biologically suitable for and compatible with administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0058] "Solvate" means a physical association of a compound provided herein with one or more solvent molecules.

[0059] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0060] As used herein, the phrase "in need of" means that an animal or mammal (subject) has been identified as having a need for a particular method or treatment. In some embodiments, the identification can be by any diagnostic means. In any of the methods and treatments described herein, the animal or mammal can be in need of it. In some embodiments, the animal or mammal is in or will be moving to an environment where a particular disease, disorder, or condition is prevalent. In some embodiments, the subject in need of it is suspected of having a condition that needs to be treated.

[0061] As used herein, the term "synergy" or "synergistic effect," when used in connection with describing the effectiveness of a combination of drugs or compounds, refers to a measured combined effect that is greater than that expected from the sum of the effects of the individual drugs or compounds. For example, as described herein, (a) a QcrB inhibitor and (b) a bd oxidase (BDO) inhibitor exhibit synergistic effects in treating mycobacterial infections, meaning that the sum of the inhibitory effects of the combination of (a) and (b) is greater than the sum of the inhibitory effects of (a) and (b) alone.

[0062] As used herein, the term "mycobacterial infection" refers to a group of multisystem infections caused by members of the family Mycobacteriaceae. Mycobacterium is a genus of Actinobacteria referred to as the family Mycobacteriaceae. This genus includes pathogens that cause severe diseases in mammals, such as tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae) in humans.

[0063] As used herein, the phrase "integers from X to Y" refers to any integer, including the endpoints. For example, the phrases "integers from X to Y" or "1 to 5" or "1 to 5", when not modified by the term "integer", refer to 1, 2, 3, 4, 5, or any value therein.

[0064] "Compounds of the disclosure," "compounds described herein," and equivalent phrases are meant to encompass compounds of any formula or structural representation described herein, as well as subgenera thereof, and, where the context permits, the phrases include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the various compounds and formulas provided herein, as well as pharmaceutically acceptable salts or solvates thereof.

[0065] As used herein, the term "isotopic variant" refers to a compound that contains a proportion of an isotope that is greater than the natural abundance at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, i.e., can contain one or more radioactive isotopes, or can be, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen 15-( 15 In compounds where such isotopic substitutions are made, the following atoms, if present, are labeled with non-radioactive isotopes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 2 H / D, any carbon may be 13 C or any nitrogen 15 It is understood that the presence and placement of such atoms may vary, such as may be N, and that determination of such atoms is within the skill of one in the art.

[0066] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers", e.g., diastereomers, enantiomers, and atropisomers. Compounds of the present disclosure may have one or more asymmetric centers, and thus such compounds may be produced as individual (R)- or (S)-stereoisomers at each asymmetric carbon atom, or as mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include all stereoisomers and racemic or other mixtures thereof. Where a single chiral center is present in a structure but no specific stereochemistry is shown at that center, both enantiomers are encompassed by the structure, either alone or as a mixture of enantiomers. Where more than one chiral center is present in a structure but specific stereochemistry is not indicated for those centers, all enantiomers and diastereomers are encompassed by the structure, either individually or as mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0067] Throughout the specification, when a composition is described as having, including, or comprising certain components, or when a process is described as having, including, or comprising certain process steps, it is contemplated that the compositions described herein also consist essentially of or consist of the recited components, and that the processes described herein also consist essentially of or consist of the recited process steps. Further, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the process is operable. Moreover, two or more steps or actions can be performed simultaneously.

[0068] The compounds of the present disclosure and their pharmaceutical compositions are useful as inhibitors of cytochrome BD oxidase or its variants.Without wishing to be bound by any particular theory, it is believed that the compounds of the present disclosure and their pharmaceutical compositions can inhibit the activity of cytochrome BD oxidase or its variants, and thus treat certain diseases, disorders, or conditions related to the regulation of the activity of cytochrome BD oxidase, as described herein.

[0069] In some embodiments, the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, Formula I is [ka] Does not contain compounds of.

[0071] In some embodiments, the disclosure relates to compounds of formula I:

[0072] In some embodiments, the disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula I. In some embodiments, the disclosure relates to a pharma- ceutically acceptable salt of a compound of formula I. In some embodiments, the disclosure relates to a solvate of a compound of formula I.

[0073] In some embodiments, each X is independently N or CR 3 is 。In some embodiments, at least one X is N. In some embodiments, at least two X are N. In some embodiments, at least three X are N. In some embodiments, at least four X are N. In some embodiments, one X is N. In some embodiments, two X are N. In some embodiments, three X are N. In some embodiments, four X are N. In some embodiments, five X are N. In some embodiments, X is CR. 3 is 。

[0074] In some embodiments, each Y is independently N or CR 3 is 。 In some embodiments, at least one Y is N. In some embodiments, at least two Ys are N. In some embodiments, at least three Ys are N. In some embodiments, one Y is N. In some embodiments, two Ys are N. In some embodiments, three Ys are N. In some embodiments, four Ys are N. In some embodiments, five Ys are N. In some embodiments, Y is CR. 4 is 。

[0075] In some embodiments, R 1 , R 2 , R 3 and R 4 are each independently H, D, halogen, or R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 Ra or N(R a )CONR a 2 It is.

[0076] In some embodiments, R 1 H, D, halogen, R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 R a or N(R a )CONR a 2 In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is halogen. In some embodiments, R 1 is R a In some embodiments, R 1 HA-C(O)R a In some embodiments, R 1 HA-CO 2 R a In some embodiments, R 1 -S(O)R a In some embodiments, R 1 -SO 2 R a In some embodiments, R 1 -S(O)NHR a In some embodiments, R 1 -SO 2 NHR a In some embodiments, R 1 -C(O)NHR aIn some embodiments, R 1 -N(R a )CO 2 R a In some embodiments, R 1 is N(R a )CONR a 2 It is.

[0077] In some embodiments, R 2 H, D, halogen, R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 R a or N(R a )CONR a 2 In some embodiments, R 2 is H. In some embodiments, R 2 is D. In some embodiments, R 2 is halogen. In some embodiments, R 2 is R a In some embodiments, R 2 HA-C(O)R a In some embodiments, R 2 HA-CO 2 R a In some embodiments, R 2 -S(O)R a In some embodiments, R 2 -SO 2 R a In some embodiments, R 2 -S(O)NHR a In some embodiments, R 2-SO 2 NHR a In some embodiments, R 2 -C(O)NHR a In some embodiments, R 2 -N(R a )CO 2 R a In some embodiments, R 2 is N(R a )CONR a 2 It is.

[0078] In some embodiments, R 3 H, D, halogen, R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 R a or N(R a )CONR a 2 In some embodiments, R 3 is H. In some embodiments, R 3 is D. In some embodiments, R 3 is halogen. In some embodiments, R 3 is R a In some embodiments, R 3 HA-C(O)R a In some embodiments, R 3 HA-CO 2 R a In some embodiments, R 3 -S(O)R a In some embodiments, R 3 -SO 2 R aIn some embodiments, R 3 -S(O)NHR a In some embodiments, R 3 -SO 2 NHR a In some embodiments, R 3 -C(O)NHR a In some embodiments, R 3 -N(R a )CO 2 R a In some embodiments, R 3 is N(R a )CONR a 2 It is.

[0079] In some embodiments, R 4 H, D, halogen, R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 R a or N(R a )CONR a 2 In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is halogen. In some embodiments, R 4 is R a In some embodiments, R 4 HA-C(O)R a In some embodiments, R 4 HA-CO 2 R a In some embodiments, R4 -S(O)R a In some embodiments, R 4 -SO 2 R a In some embodiments, R 4 -S(O)NHR a In some embodiments, R 4 -SO 2 NHR a In some embodiments, R 4 -C(O)NHR a In some embodiments, R 4 -N(R a )CO 2 R a In some embodiments, R 4 is N(R a )CONR a 2 It is.

[0080] In some embodiments, each R a are independently H, D, halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R a is independently H. In some embodiments, each R a is independently D. In some embodiments, each R a is independently halogen. In some embodiments, each R a are independently optionally substituted C 1 -C 6In some embodiments, each R a is independently 1 -C 6 In some embodiments, each R a is independently 1 -C 6 In some embodiments, each R a are independently optionally substituted C 3 -C 22 In some embodiments, each R a is independently 4 -C 10 In some embodiments, each R a is independently 6 -C 10 In some embodiments, each R a independently or C 5 -C 9 It is heteroaryl.

[0081] In some embodiments, each R a are independently optionally R aa C may be substituted 1 to 3 times by 1 -C 6 Each R aa is independently 1 -C 6 haloalkyl, aryl, where aryl is optionally heterocyclyl, C 1 -C 6 Haloalkyl or C 2 -C 10 It may be further substituted by alkenyl.

[0082] In some embodiments, each R a are independently optionally R aa C may be substituted 1 to 5 times by 3 -C 22 Each R aa are independently halogen, C 1 -C 6Alkyl, C 1 -C 6 haloalkyl, aryl, where aryl is optionally heterocyclyl, C 1 -C 6 Haloalkyl or C 2 -C 10 It may be further substituted by alkenyl. In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, n is 0 to 2 and m is 0 to 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, R 2 is H.

[0083] In some embodiments, the disclosure relates to a compound of formula II.

[0084] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula II. In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, m is 0 to 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, R 2 is H.

[0085] In some embodiments, the disclosure relates to a compound of formula III. In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, R 3 is H. In some embodiments, R 3 is an optionally substituted C 1 -C 6 In some embodiments, C 1 -C 6 The alkyl group may optionally include one or more CF 3 , halogen, C 1 -C 6 Alkoxy, SF 3 and S.F. 5 In some embodiments, C 1 -C 6 The alkyl group may optionally include one or more CF 3 In some embodiments, C 1 -C 6 The alkyl may be optionally substituted with one or more halogens. In some embodiments, C 1 -C 6 Alkyl may optionally include one or more C 1 -C 6In some embodiments, C may be substituted with alkoxy. 1 -C 6 The alkyl group may optionally include one or more SF 3 In some embodiments, C 1 -C 6 The alkyl group may optionally include one or more SF 5 may be replaced by

[0086] In some embodiments, the disclosure relates to a compound of formula IV:

[0087] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula IV. In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, R 1 In some cases, C 3 -C 22 It may be substituted by cycloalkyl.

[0088] In some embodiments, the disclosure relates to a compound of formula V:

[0089] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula V. In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof.

[0090] In some embodiments, R 5 , R 6 and R 7 are each independently H, D, halogen, or R b , -C(O)R b , -CO 2 R b , -S(O)R b , S.O. 2 R b , -S(O)NHR b , -SO 2 NHR b , -C(O)NHR b , -N(R b )CO 2 R b or N(R b )CONR b It is.

[0091] In some embodiments, R 5 H, D, halogen, R b , -C(O)R b , -CO 2 R b , -S(O)R b , S.O. 2 R b , -S(O)NHR b , -SO 2 NHR b , -C(O)NHR b , -N(R b )CO 2 R b or N(R b )CONR b In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is halogen. In some embodiments, R 5 is R b In some embodiments, R 5 HA-C(O)R b In some embodiments, R 5 HA-CO 2 R bIn some embodiments, R 5 -S(O)R b In some embodiments, R 5 SO 2 R b In some embodiments, R 5 -S(O)NHR b In some embodiments, R 5 -SO 2 NHR b In some embodiments, R 5 -C(O)NHR b In some embodiments, R 5 -N(R b )CO 2 R b In some embodiments, R 5 or N(R b )CONR b It is.

[0092] In some embodiments, R 6 H, D, halogen, R b , -C(O)R b , -CO 2 R b , -S(O)R b , S.O. 2 R b , -S(O)NHR b , -SO 2 NHR b , -C(O)NHR b , -N(R b )CO 2 R b or N(R b )CONR b In some embodiments, R 6 is H. In some embodiments, R 6 is D. In some embodiments, R 6 is halogen. In some embodiments, R 6 is R b In some embodiments, R 6 HA-C(O)R bIn some embodiments, R 6 HA-CO 2 R b In some embodiments, R 6 -S(O)R b In some embodiments, R 6 SO 2 R b In some embodiments, R 6 -S(O)NHR b In some embodiments, R 6 -SO 2 NHR b In some embodiments, R 6 -C(O)NHR b In some embodiments, R 6 -N(R b )CO 2 R b In some embodiments, R 6 or N(R b )CONR b It is.

[0093] In some embodiments, R 7 H, D, halogen, R b , -C(O)R b , -CO 2 R b , -S(O)R b , S.O. 2 R b , -S(O)NHR b , -SO 2 NHR b , -C(O)NHR b , -N(R b )CO 2 R b or N(R b )CONR b In some embodiments, R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Rb In some embodiments, R 7 HA-C(O)R b In some embodiments, R 7 HA-CO 2 R b In some embodiments, R 7 -S(O)R b In some embodiments, R 7 SO 2 R b In some embodiments, R 7 -S(O)NHR b In some embodiments, R 7 -SO 2 NHR b In some embodiments, R 7 -C(O)NHR b In some embodiments, R 7 -N(R b )CO 2 R b In some embodiments, R 7 or N(R b )CONR b It is.

[0094] In some embodiments, each R b are independently H, D, halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R b is independently H. In some embodiments, each R bis independently D. In some embodiments, each R b is independently halogen. In some embodiments, each R b are independently optionally substituted C 1 -C 6 In some embodiments, each R b is independently 1 -C 6 In some embodiments, each R b is independently 1 -C 6 In some embodiments, each R b is independently 3 -C 22 In some embodiments, each R b is independently 4 -C 10 In some embodiments, each R b is independently 6 -C 10 In some embodiments, each R b independently or C 5 -C 9 It is heteroaryl.

[0095] In some embodiments, p is 0 to 10. In some embodiments, p is 1 to 10. In some embodiments, p is 2 to 10. In some embodiments, p is 3 to 10. In some embodiments, p is 4 to 10. In some embodiments, p is 5 to 10. In some embodiments, p is 6 to 10. In some embodiments, p is 7 to 10. In some embodiments, p is 8 to 10. In some embodiments, p is 9 to 10. In some embodiments, p is 10. In some embodiments, p is 9. In some embodiments, p is 8. In some embodiments, p is 7. In some embodiments, p is 6. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0096] In some embodiments, the disclosure relates to a compound of formula VI:

[0097] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula VI.

[0098] In some embodiments, the formula: [ka] wherein the variables are as defined herein. or a pharma- ceutically acceptable salt or solvate thereof.

[0099] In some embodiments, the compound has the formula: [ka] has.

[0100] In some embodiments, the compound has the formula: [ka] has. In some embodiments, the compound has the formula: [ka] has.

[0101] In some embodiments, R 5 is H. In some embodiments, R 5 CH 3 In some embodiments, R 5 CO 2 H. In some embodiments, R 5 or CO 2 It's me. 5 is H. In some embodiments, R 5 CH 3 In some embodiments, R 5 CO 2 H. In some embodiments, R 5 CO 2 It's me.

[0102] In some embodiments, the disclosure relates to a compound of formula VII.

[0103] In some embodiments, the disclosure relates to a compound of formula VII-a.

[0104] In some embodiments, the disclosure relates to a compound of formula VII-b.

[0105] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula VII.

[0106] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula VII-a.

[0107] In some embodiments, the present disclosure relates to a pharma- ceutically acceptable salt or solvate of a compound of formula VII-b.

[0108] In some embodiments, R 7 is C 3 -C 22 In some embodiments, R 7 teeth [ka] where the variables are as defined herein. In some embodiments, q is 0 to 8. In some embodiments, q is 1 to 8. In some embodiments, q is 2 to 8. In some embodiments, q is 3 to 8. In some embodiments, q is 4 to 8. In some embodiments, q is 5 to 8. In some embodiments, q is 6 to 8. In some embodiments, q is 7 to 8. In some embodiments, q is 8. In some embodiments, q is 7. In some embodiments, q is 6. In some embodiments, q is 5. In some embodiments, q is 4. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, r is 0 to 8. In some embodiments, r is 1 to 8. In some embodiments, r is 2 to 8. In some embodiments, r is 3 to 8. In some embodiments, r is 4 to 8. In some embodiments, r is 5 to 8. In some embodiments, r is 6 to 8. In some embodiments, r is 7 to 8. In some embodiments, r is 8. In some embodiments, r is 7. In some embodiments, r is 6. In some embodiments, r is 5. In some embodiments, r is 4. In some embodiments, r is 3. In some embodiments, r is 2. In some embodiments, r is 1. In some embodiments, R 8 H, D, halogen, R c , -C(O)R c , -CO 2 R c , -S(O)R c , S.O. 2 R c , -S(O)NHR c , -SO 2 NHR c In some embodiments, R 8 -C(O)NHR cIn some embodiments, R 8 -N(R c )CO 2 R c In some embodiments, R 8 or N(R c )CONR c In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is halogen. In some embodiments, R 8 is R c In some embodiments, R 8 HA-C(O)R c In some embodiments, R 8 HA-CO 2 R c In some embodiments, R 8 -S(O)R c In some embodiments, R 8 SO 2 R c In some embodiments, R 8 -S(O)NHR c In some embodiments, R 8 -SO 2 NHR c In some embodiments, R 8 -C(O)NHR c In some embodiments, R 8 -N(R c )CO 2 R c In some embodiments, R 8 is N(R c )CONR c In some embodiments, each R c are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R c is independently H. In some embodiments, each R c is independently D. In some embodiments, each R c is independently 3 In some embodiments, each R c is independently 3 In some embodiments, each R c is independently CN. In some embodiments, each R c is an independent SF 3 In some embodiments, each R c is an independent SF 5 In some embodiments, each R c is independently halogen. In some embodiments, each R c are independently optionally substituted C 1 -C 6 In some embodiments, each R c is independently 1 -C 6 In some embodiments, each R c is independently 1 -C 6 In some embodiments, each R c is independently 3 -C 22 In some embodiments, each R c is independently 4-C 10 In some embodiments, each R c is independently 6 -C 10 In some embodiments, each R c is independently 5 -C 9 It is heteroaryl.

[0109] In some embodiments, R 7 teeth, [ka] It is.

[0110] In some embodiments, R 7 teeth, [ka] It is.

[0111] In some embodiments, R 7 teeth, [ka] It is.

[0112] In some embodiments, R 7 teeth, [ka] It is.

[0113] In some embodiments, R 7 teeth, [ka] It is.

[0114] In some embodiments, R 7 teeth, [ka] It is.

[0115] In some embodiments, R 7 teeth, [ka] wherein the variables are as defined herein. It is.

[0116] In some embodiments, R d H, D, halogen, R e , -C(O)R e , -CO 2 R e , -S(O)R e , S.O. 2 R e , -S(O)NHR e , -SO 2 NHR e , -C(O)NHR e , -N(R e )CO 2 R e or N(R e )CONR e In some embodiments, R d is H. In some embodiments, R d is D. In some embodiments, R d is halogen. In some embodiments, R d is R e In some embodiments, R d HA-C(O)R e In some embodiments, R d HA-CO 2 R e In some embodiments, R d -S(O)R e In some embodiments, R d SO 2 R e In some embodiments, R d -S(O)NHR eIn some embodiments, R d -SO 2 NHR e In some embodiments, R d -C(O)NHR e In some embodiments, R d -N(R e )CO 2 R e In some embodiments, R d is N(R e )CONR e In some embodiments, each R e are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R e is independently H. In some embodiments, each R e is independently D. In some embodiments, each R e is independently 3 In some embodiments, each R e is independently 3 In some embodiments, each R e is independently CN. In some embodiments, each R e is an independent SF 3 In some embodiments, each R e is an independent SF 5In some embodiments, each R e is independently halogen. In some embodiments, each R e are independently optionally substituted C 1 -C 6 In some embodiments, each R e is independently 1 -C 6 In some embodiments, each R e is independently 1 -C 6 In some embodiments, each R e is independently 3 -C 22 In some embodiments, each R e is independently 4 -C 10 In some embodiments, each R e is independently 6 -C 10 In some embodiments, each R e independently or C 5 -C 9 It is heteroaryl.

[0117] In some embodiments, t is 0 to 12. In some embodiments, t is 1 to 12. In some embodiments, t is 2 to 12. In some embodiments, t is 3 to 12. In some embodiments, t is 4 to 12. In some embodiments, t is 5 to 12. In some embodiments, t is 6 to 12. In some embodiments, t is 7 to 12. In some embodiments, t is 8 to 12. In some embodiments, t is 9 to 12. In some embodiments, t is 10 to 12. In some embodiments, t is 11 to 12. In some embodiments, t is 10. In some embodiments, t is 11. In some embodiments, t is 12. In some embodiments, t is 9. In some embodiments, t is 8. In some embodiments, t is 7. In some embodiments, t is 6. In some embodiments, t is 5. In some embodiments, t is 4. In some embodiments, t is 3. In some embodiments, t is 2. In some embodiments, t is 1.

[0118] In some embodiments, R 7 teeth, [ka] It is.

[0119] In some embodiments, R 7 teeth, [ka] It is.

[0120] In some embodiments, R 7 teeth, [ka] It is.

[0121] In some embodiments, R 7 teeth, [ka] It is.

[0122] In some embodiments, R 7 teeth, [ka] It is.

[0123] In some embodiments, R 7 teeth, [ka] It is.

[0124] In some embodiments, R 7 teeth, [ka] It is.

[0125] In some embodiments, R 7 teeth, [ka] It is.

[0126] In some embodiments, R 7 teeth, [ka] It is.

[0127] In some embodiments, R 7 teeth, [ka] It is.

[0128] In some embodiments, R 7 teeth, [ka] where the variables are as defined herein. In some embodiments, R f H, D, halogen, R g , -C(O)R g , -CO 2 R g , -S(O)R g , S.O. 2 R g , -S(O)NHR g , -SO 2 NHR g , -C(O)NHR g , -N(R g )CO 2 R g or N(R g )CONR g In some embodiments, R f is H. In some embodiments, R f is D. In some embodiments, R f is halogen. In some embodiments, R f is R g In some embodiments, R f HA-C(O)R g In some embodiments, R f HA-CO 2 R g In some embodiments, R f -S(O)R g In some embodiments, R f SO 2 R g In some embodiments, R f -S(O)NHR g In some embodiments, R f -SO 2 NHR g In some embodiments, R f -C(O)NHR gIn some embodiments, R f -N(R g )CO 2 R g In some embodiments, R f or N(R g )CONR g In some embodiments, each R g are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R g is independently H. In some embodiments, each R g is independently D. In some embodiments, each R g is independently 3 In some embodiments, each R g is independently 3 In some embodiments, each R g is independently CN. In some embodiments, each R g is an independent SF 3 In some embodiments, each R g is an independent SF 5 In some embodiments, each R g is independently halogen. In some embodiments, each R g are independently optionally substituted C 1 -C 6In some embodiments, each R g is independently 1 -C 6 In some embodiments, each R g is independently 1 -C 6 In some embodiments, each R g is independently 3 -C 22 In some embodiments, each R g is independently 4 -C 10 In some embodiments, each R g is independently 6 -C 10 In some embodiments, each R g independently or C 5 -C 9Heteroaryl. In some embodiments, u is 0-12. In some embodiments, u is 1-12. In some embodiments, u is 2-12. In some embodiments, u is 3-12. In some embodiments, u is 4-12. In some embodiments, u is 5-12. In some embodiments, u is 6-12. In some embodiments, u is 7-12. In some embodiments, u is 8-12. In some embodiments, u is 9-12. In some embodiments, u is 10-12. In some embodiments, u is 11-12. In some embodiments, u is 10. In some embodiments, u is 11. In some embodiments, u is 12. In some embodiments, u is 9. In some embodiments, u is 8. In some embodiments, u is 7. In some embodiments, u is 6. In some embodiments, u is 5. In some embodiments, u is 4. In some embodiments, u is 3. In some embodiments, u is 2. In some embodiments, u is 1.

[0129] In some embodiments, R 7 teeth, [ka] where the variables are as defined herein. In some embodiments, R h H, D, halogen, R j , -C(O)R j , -CO 2 R j , -S(O)R j , S.O. 2 R j , -S(O)NHR j , -SO 2 NHR j , -C(O)NHR j , -N(R j )CO 2R j or N(R j )CONR j In some embodiments, R h is H. In some embodiments, R h is D. In some embodiments, R h is halogen. In some embodiments, R h is R j In some embodiments, R h HA-C(O)R j In some embodiments, R h HA-CO 2 R j In some embodiments, R h -S(O)R j In some embodiments, R h SO 2 R j In some embodiments, R h -S(O)NHR j In some embodiments, R h -SO 2 NHR j In some embodiments, R h -C(O)NHR j In some embodiments, R h is -N(R j )CO 2 R j In some embodiments, R h is N(R j )CONR j In some embodiments, each R j is independently H. In some embodiments, each R j is independently D. In some embodiments, each R j is independently 3 In some embodiments, each R j is independently 3 In some embodiments, each R jis independently CN. In some embodiments, each R j is an independent SF 3 In some embodiments, each R j is an independent SF 5 In some embodiments, each R j is independently halogen. In some embodiments, each R j are independently optionally substituted C 1 -C 6 In some embodiments, each R j is independently 1 -C 6 In some embodiments, each R j is independently 1 -C 6 In some embodiments, each R j is independently 3 -C 22 In some embodiments, each R j is independently 4 -C 10 In some embodiments, each R j is independently 6 -C 10 In some embodiments, each R j is independently 5 -C 9Heteroaryl. In some embodiments, v is 0 to 7. In some embodiments, v is 1 to 7. In some embodiments, v is 2 to 7. In some embodiments, v is 3 to 7. In some embodiments, v is 4 to 7. In some embodiments, v is 5 to 7. In some embodiments, v is 6 to 7. In some embodiments, v is 7. In some embodiments, v is 6. In some embodiments, v is 5. In some embodiments, v is 4. In some embodiments, v is 3. In some embodiments, v is 2. In some embodiments, v is 1.

[0130] In some embodiments, R 7 teeth, [ka] In some embodiments, R h are H, F, CN, and NH 2 , COOH, SO 2 Cl, CH 2 NH 2 , C.H. 2 OH, CH 2 COOH, C≡CH, CH 2 In some embodiments, R h is H. In some embodiments, R h is F. In some embodiments, R h is CN. In some embodiments, R h NH 2 In some embodiments, R h is COOH. In some embodiments, R h SO 2 In some embodiments, R h CH 2 NH 2 In some embodiments, R h CH 2 In some embodiments, Rh CH 2 In some embodiments, R h is C≡CH. In some embodiments, R h CH 2 This is COOMe.

[0131] In some embodiments, R 7 teeth, [ka] where the variables are as defined herein. In some embodiments, R k H, D, halogen, R m , -C(O)R m , -CO 2 R m , -S(O)R m , S.O. 2 R m , -S(O)NHR m , -SO 2 NHR m , -C(O)NHR m , -N(R m )CO 2 R m or N(R m )CONR m In some embodiments, R k H, D, halogen, R m , -C(O)R m , -CO 2 R m , -S(O)R m , S.O. 2 R m , -S(O)NHR m , -SO 2 NHR m , -C(O)NHR m , -N(R m )CO 2 R m or N(R m )CONR m In some embodiments, R k is H. In some embodiments, Rk is D. In some embodiments, R k is halogen. In some embodiments, R k is R m In some embodiments, R k HA-C(O)R m In some embodiments, R k HA-CO 2 R m In some embodiments, R k -S(O)R m In some embodiments, R k SO 2 R m In some embodiments, R k -S(O)NHR m In some embodiments, R k -SO 2 NHR m In some embodiments, R k -C(O)NHR m In some embodiments, R k -N(R m )CO 2 R m In some embodiments, R k or N(R m )CONR m In some embodiments, R k is R k is H. In some embodiments, R k is D. In some embodiments, R k is halogen. In some embodiments, R k is R m In some embodiments, R k HA-C(O)R m In some embodiments, R k HA-CO 2 R m In some embodiments, R k -S(O)R mIn some embodiments, R k SO 2 R m In some embodiments, R k -S(O)NHR m In some embodiments, R k -SO 2 NHR m In some embodiments, R k -C(O)NHR m In some embodiments, R k -N(R m )CO 2 R m In some embodiments, R k or N(R m )CONR m In some embodiments, each R m are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R m is independently H. In some embodiments, each R m is independently D. In some embodiments, each R m is independently 3 In some embodiments, each R m is independently 3 In some embodiments, each R mis independently CN. In some embodiments, each R m is an independent SF 3 In some embodiments, each R m is an independent SF 5 In some embodiments, each R m is independently halogen. In some embodiments, each R m are independently optionally substituted C 1 -C 6 In some embodiments, each R m is independently 1 -C 6 In some embodiments, each R m is independently 1 -C 6 In some embodiments, each R m is independently 3 -C 22 In some embodiments, each R m is independently 4 -C 10 In some embodiments, each R m is independently 6 -C 10 In some embodiments, each R m independently or C 5 -C 9 It is heteroaryl. In some embodiments, y is 1 to 12. In some embodiments, y is 2 to 12. In some embodiments, y is 3 to 12. In some embodiments, y is 4 to 12. In some embodiments, y is 5 to 12. In some embodiments, y is 6 to 12. In some embodiments, y is 7 to 12. In some embodiments, y is 8 to 12. In some embodiments, y is 9 to 12. In some embodiments, y is 10 to 12. In some embodiments, y is 11 to 12. In some embodiments, y is 10. In some embodiments, y is 11. In some embodiments, y is 12. In some embodiments, y is 9. In some embodiments, y is 8. In some embodiments, y is 7. In some embodiments, y is 6. In some embodiments, y is 5. In some embodiments, y is 4. In some embodiments, y is 3. In some embodiments, y is 2. In some embodiments, y is 1. In some embodiments, x is 0 to 12. In some embodiments, x is 1 to 12. In some embodiments, x is 2 to 12. In some embodiments, x is 3 to 12. In some embodiments, x is 4 to 12. In some embodiments, x is 5 to 12. In some embodiments, x is 6 to 12. In some embodiments, x is 7 to 12. In some embodiments, x is 8 to 12. In some embodiments, x is 9 to 12. In some embodiments, x is 10 to 12. In some embodiments, x is 11 to 12. In some embodiments, x is 10. In some embodiments, x is 11. In some embodiments, x is 12. In some embodiments, x is 9. In some embodiments, x is 8. In some embodiments, x is 7. In some embodiments, x is 6. In some embodiments, x is 5. In some embodiments, x is 4. In some embodiments, x is 3. In some embodiments, x is 2. In some embodiments, x is 1.

[0132] In some embodiments, R k is F.

[0133] In some embodiments, R k is Me.

[0134] In some embodiments, the compound has the formula: [ka] [In the formula, R 3 and y is as defined above, R 00 is C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6Alkynyl, C 1 -C 6 Alkoxy, Phenyl, C 3 -C 5 Heteroaryl, C 3 -C 10 Cycloalkyl, C 5 -C 6 Aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO 2 , -CO 2 H, -NH 2 , -NH(C 1 -C 8 alkyl), -N(C 1 -C 8 Alkyl) 2 , -NH(phenyl), -N(phenyl) 2 , -CHO, -CO(C 1 -C 6 alkyl), -CO(phenyl), -CO 2 (C 1 -C 6 Alkyl) or -CO 2 (phenyl), and zz is between 0 and 5. In some embodiments, R 3 is H or optionally substituted C 1 -C 6 In some embodiments, y is 0 to 6. In some embodiments, R 00 is halo or haloalkyl. In some embodiments, zz is 0-2.

[0135] In some embodiments, R 7 teeth, [ka] where the variables are as defined herein. In some embodiments, R o H, D, halogen, R p , -C(O)R p , -CO 2 R p , -S(O)R p, S.O. 2 R p , -S(O)NHR p , -SO 2 NHR p , -C(O)NHR p , -N(R p )CO 2 R p or N(R p )CONR p In some embodiments, R o is H. In some embodiments, R o is D. In some embodiments, R o is halogen. In some embodiments, R o is R p In some embodiments, R o HA-C(O)R p In some embodiments, R o HA-CO 2 R p In some embodiments, R o -S(O)R p In some embodiments, R o SO 2 R p In some embodiments, R o -S(O)NHR p In some embodiments, R o -SO 2 NHR p In some embodiments, R o -C(O)NHR p In some embodiments, R o -N(R p )CO 2 R p In some embodiments, R o is N(R p )CONR p In some embodiments, each R p are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 In some embodiments, each R p is independently H. In some embodiments, each R p is independently D. In some embodiments, each R p is independently 3 In some embodiments, each R p is independently 3 In some embodiments, each R p is independently CN. In some embodiments, each R p is an independent SF 3 In some embodiments, each R p is an independent SF 5 In some embodiments, each R p is independently halogen. In some embodiments, each R p are independently optionally substituted C 1 -C 6 In some embodiments, each R p is independently 1 -C 6 In some embodiments, each R p is independently 1 -C 6 In some embodiments, each R p is independently 3 -C 22In some embodiments, each R p is independently 4 -C 10 In some embodiments, each R p is independently 6 -C 10 In some embodiments, each R p independently or C 5 -C 9 It is heteroaryl.

[0136] In some embodiments, z is 0 to 5. In some embodiments, z is 0 to 4. In some embodiments, z is 1 to 4. In some embodiments, z is 2 to 4. In some embodiments, z is 0 to 4. In some embodiments, z is 3 to 4. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5.

[0137] In some embodiments, R o H, D, CF 3 , OCF 3 , CN or NR q 2 In some embodiments, each R q is independently H. In some embodiments, each R q is independently D. In some embodiments, each R q is independently 3 In some embodiments, each R q is independently 3 In some embodiments, each R q is independently CN. In some embodiments, each R q is an independent SF 3 In some embodiments, each R qis an independent SF 5 In some embodiments, each R q is independently halogen. In some embodiments, each R q are independently optionally substituted C 1 -C 6 In some embodiments, each R q is independently 1 -C 6 In some embodiments, each R q is independently 1 -C 6 In some embodiments, each R q is independently 3 -C 22 In some embodiments, each R q is independently 4 -C 10 In some embodiments, each R q is independently 6 -C 10 In some embodiments, each R q independently or C 5 -C 9 In some embodiments, two R q Together, C 4 -C 10 Forms a heterocycle.

[0138] In some embodiments, R 7 is an optionally substituted C 1 -C 6 In some embodiments, R 7 teeth, [ka] It is. In some embodiments, R 7 teeth, [ka] It is. In some embodiments, R 7 teeth, [ka] It is.

[0139] In some embodiments, R 7 teeth, [ka] It is.

[0140] In some embodiments, the compounds provided herein have the formula: [ka] [ka] [ka] has.

[0141] In some embodiments, the compound has the formula: [ka] has.

[0142] In some embodiments, the compound has the formula: [ka] has.

[0143] In some embodiments, the compound has the formula: [ka] has.

[0144] In some embodiments, the compound has the formula: [ka] has.

[0145] In some embodiments, the compound has the formula: [ka] has.

[0146] In some embodiments, the compound has the formula: [ka] has.

[0147] In some embodiments, the compound has the formula: [ka] has.

[0148] In some embodiments, the compound has the formula: [ka] has.

[0149] In some embodiments, the compound has the formula: [ka] has.

[0150] In some embodiments, the compound has the formula: [ka] has.

[0151] In some embodiments, the compound has the formula: [ka] has.

[0152] In some embodiments, the compound has the formula: [ka] has.

[0153] In some embodiments, the compound has the formula: [ka] has.

[0154] In some embodiments, the compound has the formula: [ka] has.

[0155] In some embodiments, the compound has the formula: [ka] has.

[0156] In some embodiments, the compound has the formula: [ka] has.

[0157] In some embodiments, the compound has the formula: [ka] It is.

[0158] In some embodiments, the compound has the formula: [ka] has.

[0159] In some embodiments, the compound has the formula: [ka] has.

[0160] In some embodiments, the compound has the formula: [ka] has.

[0161] In some embodiments, the compound has the formula: [ka] has.

[0162] In some embodiments, the compound has the formula: [ka] has.

[0163] In some embodiments, the compound has the formula: [ka] It is.

[0164] In some embodiments, the compound has the formula: [ka] has.

[0165] In some embodiments, the compound has the formula: [ka] has.

[0166] In some embodiments, the compound has the formula: [ka] has.

[0167] In some embodiments, the compound has the formula: [ka] has.

[0168] In some embodiments, the compound has the formula: [ka] has.

[0169] In some embodiments, the compound has the formula: [ka] has.

[0170] In some embodiments, the compound has the formula: [ka] has.

[0171] In some embodiments, the compound has the formula: [ka] has.

[0172] In some embodiments, the compound has the formula: [ka] has.

[0173] In some embodiments, the compound has the formula: [ka] has.

[0174] In some embodiments, the compound has the formula: [ka] has.

[0175] In some embodiments, the compound has the formula: [ka] has.

[0176] In some embodiments, the compound has the formula: [ka] has.

[0177] In some embodiments, the compound has the formula: [ka] It is.

[0178] In some embodiments, the compound has the formula: [ka] has.

[0179] In some embodiments, the compound has the formula: [ka] has.

[0180] In some embodiments, the compound has the formula: [ka] has.

[0181] Exemplary compounds of the present disclosure are shown in Table 1 below.

[0182] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0183] Uses, Formulation and Administration: Pharmaceutically acceptable compositions In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharma- ceutically acceptable salt thereof. According to another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable derivative thereof and a pharma- ceutically acceptable carrier, adjuvant or vehicle. In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, adjuvant or vehicle. In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable adjuvant. In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable vehicle.

[0184] The amount of compound in the composition of the present disclosure is effective to measurably inhibit cytochrome BD oxidase or its variant in biological sample or patient.In certain embodiments, the amount of compound in the composition of the present disclosure is effective to measurably inhibit cytochrome BD oxidase or its variant in biological sample or patient.In certain embodiments, the composition of the present disclosure is formulated for administration to a patient who needs such composition.In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0185] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0186] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that it is formulated with.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the composition of the present disclosure includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0187] "Pharmaceutically acceptable derivatives" means non-toxic salts, esters, salts of esters, or other derivatives of the disclosed compounds which, upon administration to a recipient, are capable of directly or indirectly providing a compound of the disclosure, or an inhibitory active metabolite or residue thereof.

[0188] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of cytochrome BD oxidase or a variant thereof.

[0189] The compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0190] For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially those polyoxyethylated. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. For formulation purposes, other commonly used surfactants, such as Tween, Span, and other emulsifiers, or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used.

[0191] The pharma- ceutically acceptable composition of the present disclosure may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0192] Alternatively, the pharma- ceutically acceptable composition of the present disclosure can be administered in the form of suppositories for rectal administration.These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycol.

[0193] The pharma- ceutically acceptable compositions of the present disclosure may also be administered topically, especially when the subject of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0194] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches can also be used.

[0195] For topical application, the provided pharma- ceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharma-ceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.In some embodiments, the compound can be applied in pure form for topical administration, for example when it is a liquid.However, it will generally be desirable to administer the active agent to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which may be, for example, a solid, liquid, gel, etc. For example, suitable solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Suitable liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol / glycol blends, which can dissolve or disperse the compound at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, impregnated into bandages or other dressings, or sprayed onto the affected area using pump or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified minerals can also be used with the liquid carriers to form spreadable pastes, gels, ointments, soaps, etc., for direct application to the user's skin.

[0196] For ophthalmic use, the provided pharma- ceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharma-ceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0197] The pharma- ceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0198] Most preferably, the pharmaceutically acceptable composition of the present disclosure is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present disclosure is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present disclosure is administered with food.

[0199] The amount of the compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions provided should be formulated so that a dose of 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions. In some embodiments, a suitable dosage is in the range of about 0.5-100 mg / kg, e.g., about 10-75 mg / kg body weight / day, e.g., 3-50 mg / kg body weight of the recipient per day, preferably in the range of 6-90 mg / kg / day, and most preferably in the range of 15-60 mg / kg / day. The compounds are conveniently formulated into a unit dosage form, e.g., formulated to contain 5-1000 mg, conveniently 10-750 mg, and most conveniently 50-500 mg of active ingredient per unit dosage form. In one embodiment, the present invention provides a composition comprising the compounds of the present invention, which is formulated into such a unit dosage form.

[0200] The compounds described herein are conveniently administered in a dosage form of, for example, 5 to 1000 mg / m 2 , advantageously 10 to 750 mg / m 2 , most conveniently 50-500 mg / m 2 The desired dose can be conveniently presented in a single dose or as a divided dose administered at appropriate intervals, for example, two, three, four or more subdoses per day. The subdoses themselves can be further divided, for example, into a number of discrete loosely spaced administrations.

[0201] The desired administration can conveniently be effected in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided into a number of discrete loosely spaced administrations, such as, for example, multiple inhalations from an insufflator or multiple drops into the eye.

[0202] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend on the particular compound in the composition.

[0203] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting cytochrome BD oxidase or a mutant thereof.

[0204] The activity of the compounds utilized in the present disclosure as inhibitors of cytochrome BD oxidase or its variants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of cytochrome BD oxidase or its variants. Alternative in vitro assays quantify the ability of inhibitors to bind to cytochrome BD oxidase or its variants. Detailed conditions for assaying the compounds utilized in the present disclosure as inhibitors of cytochrome BD oxidase or its variants are described in the following examples.

[0205] The term "treatment", "treat" or "treating" of any disease or disorder as used herein means, in some embodiments, improving the disease or disorder (i.e., preventing or reducing the occurrence of the disease or at least one of its clinical symptoms). In another embodiment, "treating", "treat" or "treatment" means improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treatment", "treat" or "treating" means modulating the disease or disorder, either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treatment", "treat" or "treating" means delaying the onset of the disease or disorder.

[0206] The provided compounds are inhibitors of cytochrome BD oxidase or its variants, and are therefore useful for treating various diseases, disorders, or conditions associated with the regulation of the activity of cytochrome BD oxidase.Thus, in certain embodiments, the present disclosure provides a method for treating low hepcidin disorders, diseases, and / or conditions, comprising administering to a patient in need thereof a compound of the present disclosure or a pharma-ceutically acceptable composition thereof.

[0207] In some embodiments, the disclosure provides a method of treating an infectious disease in a mammal, comprising administering to a mammal having an infectious disease an effective amount of a compound or pharmaceutical composition described herein, including primates, humans, rodents, dogs, cats, cattle, sheep, horses, pigs, goats, cows, etc.

[0208] Without wishing to be bound by any particular theory, it has been found that inhibition of cytochrome BD oxidase leads to the death of mycobacteria.Thus, in some embodiments, the present disclosure provides a method for treating mycobacterial infection in a subject, comprising administering to the subject one or more of the compounds provided herein or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject one or more compounds described and provided herein. In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharma- ceutically acceptable salt of a compound described and provided herein. In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharma- ceutically acceptable salt of two or more compounds described and provided herein.

[0210] In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more compounds as described and provided herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more compounds as described and provided herein. In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound as described and provided herein. In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising two or more compounds as described and provided herein.

[0211] In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharma- ceutically acceptable salt of a compound described and provided herein.In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharma- ceutically acceptable salt of two or more compounds described and provided herein.

[0212] In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to a subject a compound of the formula: [ka] [ka] or a pharma- ceutically acceptable salt, or a pharmaceutical composition thereof, to the subject. In some embodiments, the present invention provides a method of treating a mycobacterial infection in a subject, the method comprising administering to the subject a compound having the formula: [ka] The method includes administering to the subject a compound having the formula:

[0213] In some embodiments, the disclosure provides a method of treating a mycobacterial infection described herein, comprising administering to a subject a compound described or provided herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the compound is present in a therapeutically effective amount.

[0214] In some embodiments, the present disclosure provides a method of treating a mycobacterial infection described herein, further comprising administering an inhibitor of oxidative phosphorylation in mycobacteria. In some embodiments, the inhibitor of oxidative phosphorylation in mycobacteria is a QcrB inhibitor. In some embodiments, the QcrB inhibitor is an imidazopyridine. In some embodiments, the QcrB inhibitor is Q203 or clofazimine, etc. In some embodiments, the compound described herein and the inhibitor described herein 2 exhibit synergistic effects. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered in a synergistically therapeutically effective amount. In some embodiments, the inhibitor described herein or a pharmaceutically acceptable salt thereof can be administered in a synergistically therapeutically effective amount.

[0215] In some embodiments, the present disclosure provides a method of treating a mycobacterial infection in a subject, comprising administering to the subject a pharmaceutical composition described herein. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. In some embodiments, the compound described herein and the inhibitor described herein exhibit a synergistic effect. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered in a synergistic therapeutically effective amount. In some embodiments, the inhibitor described herein or a pharmaceutically acceptable salt thereof is administered in a synergistic therapeutically effective amount.

[0216] In some embodiments, the present disclosure provides a method of treating a mycobacterial infection in a subject as described and provided herein, wherein the mycobacterial infection is caused by bacteria from the Mycobacterium tuberculosis complex.

[0217] In some embodiments, the disclosure provides a method of treating a mycobacterial infection in a subject, wherein the mycobacterial infection is caused by a nontuberculous mycobacterium (NTM), such as one belonging to the Mycobacterium abscessus complex or the Mycobacterium avium complex.

[0218] In some embodiments, the present disclosure provides a method of treating a mycobacterial infection in a subject, wherein the subject is in need thereof, as described and provided herein.

[0219] Although the present embodiment has been described in connection with certain specific embodiments for illustrative purposes, the present embodiment is not limited thereto. Thus, various modifications, adaptations, and combinations of the various features of the described embodiment may be made without departing from the scope of the presently claimed subject matter, as defined in the claims. Furthermore, the following examples are illustrative, but not limiting, of the compounds, compositions, and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. Any journal articles, patent applications, issued patents, or other references are incorporated by reference in their entirety. EXAMPLES

[0220] synthesis The compounds of the present disclosure, including their salts, may be prepared using known organic synthesis techniques, and may be synthesized according to any of a number of possible synthetic routes.

[0221] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, the solvent suitable for the specific reaction step can be selected by those skilled in the art.

[0222] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups.The necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art.The chemistry of protecting groups is described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0223] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H NMR or 13 The activity of the compound may be monitored by spectroscopy, such as 1C NMR), infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry, or chromatography, such as high performance liquid chromatography ("HPLC") or thin layer chromatography, or liquid chromatography-mass spectrometry ("LC-MS").

[0224] Unless otherwise indicated, work-up included partitioning the reaction mixture between the organic and aqueous phases indicated in parentheses, separating the layers, drying the organic layer over anhydrous sodium sulfate, filtering, and distilling off the solvent under reduced pressure. Purification, unless otherwise noted, included purification by silica gel chromatographic techniques, typically using an appropriately polar ethyl acetate / petroleum ether mixture as the mobile phase.

[0225] The compounds of the present disclosure can be prepared using a number of preparation reactions known in the literature.The following scheme provides general guidance in relation to the preparation of the compounds provided herein.Those skilled in the art will understand that they can use their general knowledge of organic chemistry to modify or optimize the preparation methods shown in the scheme to prepare various compounds.The exemplary synthetic methods for preparing compounds are described in the following scheme.

[0226] General scheme The general synthetic methods used in each of the general schemes are set out below, including illustrations of compounds synthesized using the designated general schemes. Any specific conditions and reagents described herein should not be construed as limiting the scope of the disclosure, but are provided for illustrative purposes only.

[0227] The following abbreviations have the following definitions:

[0228] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and generally refer to a temperature that is about the temperature of the room in which the reaction is carried out, e.g., from about 20° C. to about 30° C.

[0229] ACN - acetonitrile;br - broad;℃ - degrees Celsius;CHCl 3 -Chloroform; CD 3 OD-deuterated methanol; DMSO-d 6-deuterated dimethyl sulfoxide;DCM-dichloromethane;DIPEA-diisopropylethylamine;DMF-N,N-dimethylformamide;d-doublet;dd-doublet;EDC.HCl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;mg-milligram;g-gram;h: hour; 1 H-proton;HCl-hydrochloric acid;HPLC-high performance liquid chromatography;H 2 -Hydrogen;HOBt-1-hydroxybenzotriazole;K 2 CO 3 - Potassium carbonate; LCMS - Liquid Chromatography-Mass Spectrometry; LiOH.H 2 O-Lithium hydroxide monohydrate; M-Molar concentration; MHz-Megahertz (frequency); MeOH-Methanol; mL-Milliliter; min-Minute; mol-Mole; M + - molecular ion; M- multiplet; N 2 -Nitrogen;NH 3 - ammonia; NBS-N-bromosuccinimide; NCS-N-chlorosuccinimide; NMR-nuclear magnetic resonance; NaOH-sodium hydroxide; RT-room temperature; s: singlet; t-triplet; TLC-thin layer chromatography; TFA-trifluoroacetic acid; TEA-triethylamine; THF-tetrahydrofuran; %-percentage; μ-micron; and δ-delta; Zn-zinc; mmol-millimolar.

[0230] Analyses of the compounds of the present disclosure were carried out by common methods well known to those skilled in the art, unless otherwise stated. The present disclosure has been described with reference to certain preferred embodiments, but other embodiments will become apparent to those skilled in the art from consideration of this specification. The present disclosure is further defined by reference to the following examples, which detail the analyses of the compounds of the present disclosure.

[0231] It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of this disclosure.

[0232] Materials and Methods Unless otherwise stated, all reagents were obtained from commercial sources and used without further purification. The NMR spectrometer utilized was a Bruker instrument operating at a frequency of 400 MHz.

[0233] General Scheme 1: Method A [ka]

[0234] As shown in General Scheme 1, the compounds described herein can be prepared from classical nucleophilic aromatic substitution (SNAr) reactions of the corresponding halogenated core (e.g., 5-chloro-2-methylpyrazolo[1,5-a]quinazoline, CAS:885525-06-4) and the desired amine with an appropriate non-nucleophilic base (triethylamine, N,N-diisopropylethylamine, potassium carbonate) and non-nucleophilic solvent (acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc.). Variables are as defined and provided herein.

[0235] Example 1: Synthesis of N-cycloheptyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (Compound 12) by Method A [ka]

[0236] 5-Chloro-2-methylpyrazolo[1,5-a]quinazoline (CAS: 885525-06-4, 80 mg, 0.37 mmol), cycloheptanamine (CAS: 5452-35-7, 42 mg, 0.37 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) were combined in 5 mL acetonitrile. The reaction was heated at 80° C. for 24 h. The reaction was then cooled and concentrated under reduced pressure. The resulting residue was purified by HPLC using HPLC. 2 Cl 2 The organic phase was taken up in ethyl acetate and washed with 2% aqueous acetic acid (2x), water and brine. 2 SO4 The organic solvent was evaporated, filtered, and the resulting residue was dissolved in CH 2 Cl 2 Purification by flash chromatography on silica gel eluting with ethyl acetate gave N-cycloheptyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (compound 12). 1 H NMR (400 MHz, CDCl3) δ8.30 (1H, dd, J = 8.4, 0.7 Hz), 7.72 (1H, ddd, J = 8.4, 7.3, 1.2 Hz), 7.62 (1H, dd, J = 8.1, 0.6 Hz), 7.34 (1H, ddd, J = 8.4, 7.3, 1.2 Hz), 6.03 (1H, s), 5.29 (1H, bd, J = 7.5 Hz), 4.41 (1H, dquin, J = 7.7, 3.8 Hz), 2.45 (3H, s), 2.21 - 2.06 (2H, m), 1.75 - 1.58 (10H, m). 13 C NMR (125 MHz, CDCl3) δ 152.5, 150.9, 146.9, 136.7, 132.7, 123.4, 122.1, 115.3, 111.2, 94.5, 51.3, 34.9, 28.3, 24.1, 14.6 Hz. HRMS (ESI-TOF, positive mode) m / z ([M+1]); C 18 H 22 N 4 Calculated value: 295.192; Measured value: 295.196.

[0237] General Scheme 2: Method B [ka]

[0238] The compounds described herein can be prepared by a palladium cross-coupling reaction, ie, a Buchwald-Hartwig amination reaction, as shown in general Scheme 2.

[0239] Example 2: Synthesis of N-cycloheptyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (Compound 12) by Method B [ka]

[0240] In a vial, methanesulfonato-2'-methylamino-1,1'-biphenyl-2-yl-palladacycle 4th generation (CAS: 1599466-85-9, 15 mg, 0.017 mmol), sodium tert-butoxide (34 mg, 0.36 mmol), 5-chloro-2-methylpyrazolo[1,5-a]quinazoline (CAS: 885525-06-4, 42 mg, 0.19 mmol) and cycloheptanamine (CAS: 5452-35-7, 22 mg, 0197 mmol) were combined in anhydrous toluene (2 mL) to form a suspension. This suspension was stirred for 5 min with argon degassing. The reaction vial was sealed and heated to 110 °C for 48 h. The reaction was then cooled and filtered through Celite to form a pad, which was then separated by HCl. 2 Cl 2 (20 mL). The filtrate was washed with 2% aqueous acetic acid (2x), water and brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtered organics were concentrated to dryness. The resulting residue was purified by silica gel flash chromatography to give N-cycloheptyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (compound 12).

[0241] Example 3: Synthesis of N-cyclopentyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (Compound 8) [ka]

[0242] 5-Chloro-2-methylpyrazolo[1,5-a]quinazoline (CAS: 885525-06-4, 55 mg, 0.25 mmol), cyclopentylamine (22 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) were combined in 5 mL acetonitrile. The reaction was heated at 80° C. for 24 h. The reaction was then allowed to cool and concentrated under reduced pressure. The resulting residue was purified by HPLC using HPLC. 2 Cl 2 The organic phase was taken up in ethyl acetate and washed with 2% aqueous acetic acid (2x), water and brine. 2 SO 4 The organic solvent was evaporated, filtered, and the resulting residue was dissolved in CH 2 Cl 2 Purification by silica gel flash chromatography eluting with ethyl acetate gave N-cyclopentyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (ND-14445). 1 H NMR (400 MHz, CDCl3) δ 8.30 (1H, dd, J = 8.4, 0.6 Hz), 7.72 (1H, ddd, J = 8.4, 7.3, 1.1 Hz), 7.61 (1H, dd, J = 8.3, 1.0 Hz), 7.34 (1H, ddd, J =8.3, 7.3, 1.1 Hz), 6.05 (1H, s), 5.31 (1H, bd, J = 6.1 Hz), 4.59 (1H, dquin, J = 6.9, 6.9 Hz), 2.46 (3 H, s), 2.28 - 2.17 (2H, m), 1.85 - 1.66 (4H, m), 1.61 - 1.50 (2H, m). 13 C NMR (125 MHz, CDCl3) δ 152.5, 151.7, 146.9, 136.6, 132.7, 123.4, 122.2, 115.3, 111.1, 94.6, 52.7, 33.4, 23.9, 14.6 Hz. HRMS (ESI-TOF, positive mode) m / z ([M+1]); C 16 H 19 N 4 Calculated value: 267.161; measured value: 267.160.

[0243] Example 4: Synthesis of N-cyclooctyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (Compound 9) [ka]

[0244] 5-Chloro-2-methylpyrazolo[1,5-a]quinazoline (CAS: 885525-06-4, 55 mg, 0.25 mmol), cyclooctylamine (32 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) were combined in 5 mL acetonitrile. The reaction was heated at 80° C. for 24 h. The reaction was then allowed to cool and concentrated under reduced pressure. The resulting residue was purified by HPLC using HPLC. 2 Cl 2 The organic phase was taken up in ethyl acetate and washed with 2% aqueous acetic acid (2x), water and brine. 2 SO 4 The organic solvent was evaporated, filtered, and the resulting residue was dissolved in CH 2 Cl 2 Purification by flash chromatography on silica gel eluting with ethyl acetate gave N-cyclooctyl-2-methylpyrazolo[1,5-a]quinazolin-5-amine (ND-14446). 1 H NMR (400 MHz, CDCl3) δ 8.29 (1H, dd, J = 8.4, 0.8 Hz), 7.72 (1H, ddd, J = 8.4, 7.3, 1.1 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.34 (1H, ddd, J = 8.3, 7.3, 1.1 Hz), 6.03 (1H, s), 5.29 (1H, bd, J = 7.5 Hz), 4.49 - 4.38 (1H, m), 2.45 (3H, s), 2.09 - 1.98 (2H, m), 1.84 - 1.54 (12H, m). 13C NMR (125 MHz, CDCl3) δ 152.5, 150.9, 147.0, 136.7, 132.7, 123.4, 122.1, 115.3, 111.2, 94.5, 50.4, 31.9, 27.4, 25.5, 23.7, 14.6 Hz. HRMS (ESI-TOF, positive mode) m / z ([M+1]); C 19 H 24 N 4 Calculated value: 309.208; Measured value: 309.213.

[0245] Biological assays Compounds described and provided herein were evaluated for their potential to inhibit cytochrome BD oxidase in Mycobacterium abscessus, where M. abscessus ATCC 19977T wild type (WT) and cyt-bcc:aa3 expression-deficient (ΔqcrCAB) strains were treated with a two-fold dose response of drugs (starting at 40 μM). ATP levels were measured after 6–15 h of incubation using a commercially available kit. Compounds that specifically target bd oxidase (BDO) to inhibit oxidative phosphorylation (and thus ATP levels) are expected to be active only in the ΔqcrCAB mutant strain.

[0246] The potency of the test compounds provided herein in Mycobacterium abscessus is shown in Table 2. M. abscessus ATCC 19977T wild type (WT) and cyt-bcc:aa 3 (ΔqcrCAB) expression-deficient strains were treated with a two-fold dose response of drugs (starting at 40 μM). ATP levels were measured after 6-15 h of incubation using a commercial kit. Compounds that specifically target BDO to inhibit oxidative phosphorylation (ATP levels) are expected to be active only in the ΔqcrCAB mutant strain.

[0247] [Table 2]

[0248] As shown in Figure 1, compound 12 was demonstrated to synergize with clofazimine to kill M. abscessus. This result is unexpected and surprising in that clofazimine is bactericidal in the presence of compound 12, whereas clofazimine is bacteriostatic when tested alone. Therefore, the combination of BDO inhibitors and clofazimine is expected to be effective in treating mycobacterial infections.

[0249] This work was supported by the National Research Foundation (NRF) Singapore Investigatorship Program: NRF-NRFI 06-2020-0004.

[0250] While numerous embodiments of the present disclosure have been described, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be appreciated that the scope of the present disclosure is defined by the appended claims, rather than by the specific embodiments shown by way of example.

Claims

1. formula: 【Chemistry 1】 [In the formula, Each X is independently N or CR 3 and; Each Y is independently N or CR 4 and; R 1 , R 2 , R 3 and R 4 are each independently H, D, halogen, or R a , -C(O)R a , -CO 2 R a , -S(O)R a , -SO 2 R a , -S(O)NHR a , -SO 2 NHR a , -C(O)NHR a , -N(R a )CO 2 R a or N(R a )CONR a 2 and; Each R a are independently H, D, halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl. or a pharma- ceutically acceptable salt thereof; 【Chemistry 2】 Except.

2. The compound has the formula: 【Chemistry 3】 wherein n is 0 to 2 and m is 0 to 4.

2. The compound of claim 1, having the formula: or a pharma- ceutically acceptable salt thereof.

3. R 2 The compound according to claim 1 or 2, wherein is H.

4. The compound has the formula: 【Chemistry 4】 4. The compound of claim 3, having the formula:

5. 5. The compound of claim 4, wherein m is 1.

6. The compound has the formula: 【Chemistry 5】 6. The compound of claim 5, having the formula:

7. R 3 is H or optionally substituted C 1 -C 6 alkyl, where C 1 -C 6 The alkyl group may optionally include one or more CF 3 , halogen, C 1 -C 6 Alkoxy, SF 3 and S.F. 5 7. The compound of claim 6, optionally substituted by:

8. The compound has the formula: 【Chemistry 6】 8. The compound of claim 7, having the formula: or a pharma- ceutically acceptable salt thereof.

9. R 1 may be optionally substituted C 3 -C 22 9. The compound of claim 8, which is cycloalkyl.

10. The compound has the formula: 【Chemistry 7】 [In the formula, R 5 , R 6 and R 7 are each independently H, D, halogen, or R b , -C(O)R b , -CO 2 R b , -S(O)R b , S.O. 2 R b , -S(O)NHR b , -SO 2 NHR b , -C(O)NHR b , -N(R b )CO 2 R b or N(R b )CONR b and; Each R b are independently H, D, halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; and p is 0 to 10.

10. The compound of claim 9, having the formula: or a pharma- ceutically acceptable salt thereof.

11. 11. The compound of claim 10, wherein p is 0.

12. 11. The compound of claim 10, wherein p is 1.

13. The compound is 【Chemistry 8】 13. The compound of claim 12, wherein:

14. R 5 But, H, CH 3 , CO 2 H or CO 2 14. The compound of claim 13, wherein said compound is Me.

15. R 7 But, C 3 -C 22 The compound of any one of claims 10 to 14, which is cycloalkyl.

16. R 7 but, 【Chemistry 9】 [In the formula, q is 0 to 8; r is 0 to 8; R 8 H, D, halogen, R c , -C(O)R c , -CO 2 R c , -S(O)R c , S.O. 2 R c , -S(O)NHR c , -SO 2 NHR c , -C(O)NHR c , -N(R c )CO 2 R c or N(R c )CONR c and Each R c are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl.

16. The compound of claim 15,

17. R 7 but, 【Chemistry 10】 17. The compound of claim 16,

18. R 7 but, 【Chemistry 11】 [In the formula, R d H, D, halogen, R e , -C(O)R e , -CO 2 R e , -S(O)R e , S.O. 2 R e , -S(O)NHR e , -SO 2 NHR e , -C(O)NHR e , -N(R e )CO 2 R e or N(R e )CONR e and; Each R e are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; and t is between 0 and 12.

16. The compound of claim 15,

19. R 7 but, 【Chemistry 12】 20. The compound of claim 18, wherein

20. R 7 but, 【Chemistry 13】 [In the formula, R f H, D, halogen, R g , -C(O)R g , -CO 2 R g , -S(O)R g , S.O. 2 R g , -S(O)NHR g , -SO 2 NHR g , -C(O)NHR g , -N(R g )CO 2 R g or N(R g )CONR g and; Each R g are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; and u is between 0 and 12.

16. The compound of claim 15,

21. R 7 but, 【Chemistry 14】 [In the formula, R h H, D, halogen, R j , -C(O)R j , -CO 2 R j , -S(O)R j , S.O. 2 R j , -S(O)NHR j , -SO 2 NHR j , -C(O)NHR j , -N(R j )CO 2 R j or N(R j )CONR j and; Each R j are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; and v is between 0 and 7.

16. The compound of claim 15,

22. 20. The compound of claim 18, wherein v is 1.

23. R 7 but, 【Chemistry 15】 20. The compound of claim 19,

24. R h H, F, CN, NH 2 , COOH, SO 2 Cl, CH 2 NH 2 , C.H. 2 OH, CH 2 COOH, C≡CH, CH 2 21. The compound of claim 20, which is COOMe.

25. R 7 but, 【Chemistry 16】 [In the formula, R k H, D, halogen, R m , -C(O)R m , -CO 2 R m , -S(O)R m , S.O. 2 R m , -S(O)NHR m , -SO 2 NHR m , -C(O)NHR m , -N(R m )CO 2 R m or N(R m )CONR m and; Each R m are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; y is 1 to 12; and x is between 0 and 12.

16. The compound of claim 15,

26. The compound is 【Chemistry 17】 [In the formula, R 3 is H or optionally substituted C 1 -C 6 is alkyl, y is 0 to 6; R 00 is halo or haloalkyl, and zz is between 0 and 5.

26. The compound of claim 25, having the formula: or a pharma- ceutically acceptable salt thereof.

27. 26. The compound of claim 25, wherein y is 4 or 5.

28. R k The compound according to any one of claims 25 to 27, wherein is H.

29. 29. The compound of any one of claims 25 to 28, wherein x is 2.

30. R k The compound of claim 29, wherein is F.

31. 29. The compound of any one of claims 25 to 28, wherein x is 4.

32. R k The compound of claim 31 , wherein is Me.

33. The compound of claim 10, wherein p is 0 to 3.

34. R 7 but, 【Chemistry 18】 [In the formula, R o H, D, halogen, R p , -C(O)R p , -CO 2 R p , -S(O)R p , S.O. 2 R p , -S(O)NHR p , -SO 2 NHR p , -C(O)NHR p , -N(R p )CO 2 R p or N(R p )CONR p and; Each R p are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 is heteroaryl; and z is 0 to 5.

34. The compound of claim 33, wherein

35. R o But H, D, CF 3 , OCF 3 , CN or NR q 2 where each R q are independently H, D, and CF 3 , OCF 3 , C.N., S.F. 3 ,SCIENCE FICTION 5 , halogen, optionally substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkyl, C 3 -C 22 Cycloalkyl, C 4 -C 10 Heterocycle, C 6 -C 10 Aryl or C 5 -C 9 Heteroaryl or two R q Together, C 4 -C 10 35. The compound according to claim 34, which forms a heterocycle.

36. R 7 may be optionally substituted C 1 -C 6 12. The compound of claim 11, wherein said compound is alkyl.

37. R 7 but, 【Chemistry 19】 37. The compound of claim 36,

38. The compound has the formula: 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 2. The compound of claim 1, having the formula:

39. 39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof.

40. formula: 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof.

41. 41. The pharmaceutical composition of claim 39 or 40, further comprising an inhibitor of the oxidative phosphorylation process in mycobacteria.

42. 42. The pharmaceutical composition of claim 41, wherein the inhibitor of the oxidative phosphorylation process in mycobacteria is a QcrB inhibitor.

43. 43. The pharmaceutical composition of claim 42, wherein the QcrB inhibitor is an imidazopyridine.

44. The pharmaceutical composition of claim 42, wherein the QcrB inhibitor is Q203 or clofazimine, etc.

45. 45. The pharmaceutical composition of any one of claims 39 to 44, further comprising a pharma- ceutically acceptable carrier, adjuvant or vehicle.

46. 40. A method of treating a mycobacterial infection in a subject, comprising administering to the subject a compound according to any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof.

47. 1. A method of treating a mycobacterial infection in a subject, comprising administering to the subject a compound of the formula: 【Chemistry 26】 【Chemical 27】 or a pharma- ceutically acceptable salt thereof.

48. 48. The method of claim 46 or 47, wherein the compound or a pharma- ceutically acceptable salt thereof is present in a therapeutically effective amount.

49. 49. The method of any one of claims 46 to 48, further comprising administering an inhibitor of the oxidative phosphorylation process in mycobacteria.

50. 50. The method of claim 49, wherein the inhibitor of the oxidative phosphorylation process in mycobacteria is a QcrB inhibitor.

51. The method of claim 50, wherein the QcrB inhibitor is an imidazopyridine.

52. The method of claim 51, wherein the QcrB inhibitor is Q203 or clofazimine, etc.

53. The method of any one of claims 49 to 52, wherein said compound and said inhibitor exhibit a synergistic effect.

54. 54. The method of claim 53, wherein the compounds or pharma- ceutically acceptable salts thereof are administered in synergistic therapeutically effective amounts.

55. 55. The method of claim 53 or 54, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is administered in a synergistic therapeutically effective amount.

56. A method for treating a mycobacterial infection in a subject, comprising administering to said subject a pharmaceutical composition according to any one of claims 39 to 40.

57. 46. ​​A method for treating a mycobacterial infection in a subject, comprising administering to said subject a pharmaceutical composition according to any one of claims 41 to 45.

58. 58. The method of claim 56 or 57, wherein the compound or a pharma- ceutically acceptable salt thereof is present in a therapeutically effective amount.

59. 59. The method of claim 57 or 58, wherein the compound and the inhibitor exhibit a synergistic effect.

60. 60. The method of claim 59, wherein the compound or a pharma- ceutically acceptable salt thereof is present in a synergistic therapeutically effective amount.

61. 61. The method of claim 59 or 60, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is present in a synergistic therapeutically effective amount.

62. 62. The method of any one of claims 46 to 61, wherein the mycobacterial infection is caused by bacteria from the Mycobacterium tuberculosis complex.

63. 62. The method of any one of claims 46 to 61, wherein the mycobacterial infection is caused by a non-tuberculosis mycobacteria (NTM), such as an NTM belonging to the Mycobacterium abscessus complex or the Mycobacterium avium complex.

64. The method of any one of claims 46 to 63, wherein the subject is in need of treatment.

65. The compound has the formula: 【Chemistry 28】 48. The compound of claim 38, the pharmaceutical composition of claim 40, or the method of claim 47, wherein

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