3-(Phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives

Abstract

The present invention relates to 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, as well as their use in a method for reducing the virulence of bacteria (preferably Staphylococcus aureus) expressing accessory gene regulator A (AgrA) or an ortholog of AgrA; their use in a method for inhibiting quorum sensing in bacteria, preferably Staphylococcus aureus; and their use in a method for preventing or treating diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus, such as skin or lung infections, for example, atopic dermatitis, Netherton syndrome, or psoriasis in a subject. The compounds have shown excellent ability to inhibit the transcription of genes under the control of the P3 promoter in Staphylococcus aureus, even in the presence of human serum or human serum albumin.

Description

[Technical Field]

[0001] The present invention relates to 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, and their use in methods of reducing the virulence of bacteria (preferably Staphylococcus aureus) expressing accessory gene regulator A (AgrA), or an ortholog of AgrA, their use in methods of inhibiting quorum sensing in bacteria, preferably Staphylococcus aureus, and their use in methods of preventing or treating diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus, including, but not limited to, skin or lung infections, atopic dermatitis, Netherton syndrome and / or psoriasis in a subject. Thus, the present invention relates to anti-pathogenic compositions and methods for the treatment, amelioration and / or prevention of diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus (S. aureus), and more particularly to compositions and methods for reducing the pathogenicity of bacteria expressing AgrA, or an ortholog of AgrA, preferably AgrA. [Background technology]

[0002] Staphylococcus aureus is a human commensal organism and a notorious opportunistic pathogen that causes serious community-acquired and hospital-acquired infections. S. aureus can cause a vast number of infections, ranging from mild superficial skin infections to severe, life-threatening systemic conditions, such as endocarditis, pneumonia, or sepsis (Lee AS, et al. (2018) Nat. Rev. Dis. Primers, Vol. 4, Article 18033 pp. 1-23). Furthermore, S. aureus has also been implicated in atopic dermatitis (Geoghegan JA, et al. (2018) Trends Microbiol. 26(6):484-497) and Netherton syndrome (Williams MR, et al. (2020) Cell reports 30(9):2923-2933). The success of Staphylococcus aureus (S. aureus) in causing such a variety of diseases is the result of the widespread accumulation of virulence factors produced by β-lactam resistance and, for most clones, in combination with resistance to other antibiotic classes. Clinically significant antibiotic resistance has evolved against virtually every antibiotic available, yet the discovery and development of novel antibiotic classes has lagged, contributing to the antibiotic resistance crisis we face today. As a result, alternative strategies for treating or preventing S. aureus-mediated bacterial infections that are effective against multidrug-resistant strains, such as methicillin-resistant S. aureus (MRSA), are needed (Dickey SW, et al. (2017) Nat. Rev. Drug Discov. 16(7):457-471).

[0003] One of these strategies is the antipathogenic approach, which targets only virulence-related traits rather than survival / fitness-related traits. In contrast to common antibiotic therapy, antipathogenic drugs are not bacteriostatic (inhibiting bacterial growth) or bactericidal (killing bacteria) per se. This approach focuses on disarming pathogenic bacteria by blocking or neutralizing their virulence factors, ultimately disrupting bacterial virulence mechanisms and thereby facilitating pathogen clearance by the host immune system. Because antipathogenic drugs do not interfere with essential mechanisms of bacterial growth and survival, they are thought to alleviate the pressure on pathogens to develop resistance. An additional benefit is that specific antipathogenic drugs may preserve a healthy host microbiota and ultimately help counteract microbial dysbiosis by modulating the aggressiveness of pathogens such as Staphylococcus aureus (S. aureus). Importantly, antivirulence approaches offer an increased pool of pharmacological targets and therefore the potential to generate alternative antimicrobial agents with novel modes of action (Muhlen, S. & Dersch, P. (2016) Curr. Top. Microbiol. Immunol. 398:147-183).

[0004] Regulation of virulence factors in Staphylococcus aureus (S. aureus): The agr operon is a bacterial quorum-sensing system that controls cell density-dependent virulence factor expression in S. aureus. It consists of two distinct promoters, P2 and P3. P2 is responsible for the production of quorum-sensing system components (AgrB, AgrD, AgrC, and AgrA; see Figure 1). The precursor peptide AgrD is processed by AgrB to form the mature autoinducing peptide (AIP), which is secreted across the bacterial membrane. AIP binds to the histidine kinase AgrC and activates the transcriptional regulator AgrA by phosphorylation, promoting its expression from P2 and P3. Four allelic variants of agr (types I–IV) exist, each encoding a distinct AIP that functions as a specific ligand for AgrC in its own cell but as an inhibitor of other AgrC variants. P3, together with AgrA, produces the agr effector molecule RNAIII, which is responsible for the transcriptional regulation of approximately 200 genes, including multiple virulence factors and metabolic pathways involved in stationary-phase growth (Khan, BA, et al. (2015) Expert Opin. Investig. Drugs 24(5):689-704). Examples of AgrA-regulated virulence factors include cell surface-associated proteins such as protein A (SpA) and fibronectin-binding proteins, secreted toxins such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble modulins (PSMs), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), or secreted proteases such as SspA or aureolysin. Taken together, the large number of multifunctional virulence determinants makes S. aureus pathogenesis particularly complex, providing the pathogen with an arsenal of mechanisms to inflict damage on the host or to circumvent and evade the host's immune defenses.Notably, most AgrA-regulated virulence factors are responsible for Staphylococcus aureus (S. aureus) virulence in skin and soft tissue infections (SSTIs), lung infections, and chronic inflammatory skin diseases such as atopic dermatitis (Oliveira D. et al. (2018) Toxins 10:252; Geoghegan JA, et al. (2018) Trends Microbiol. 26(6):484-497) and Netherton syndrome (Williams MR, et al. (2020) Cell reports 30(9):2923-2933).

[0005] Preventing virulence factor expression: Inhibition of the expression of the centrally regulated RNAIII, combined with inhibition of PSMα production, is thought to potently reduce virulence factor levels globally (see Figure 1). Current strategies for suppressing RNAIII expression can be divided into different categories: (1) competitive inhibitors of the histidine kinase AgrC; (2) inhibitors of RNAIII transcription (the exact mechanism is unknown); and (3) inhibition of the AgrA-P2 / P3 interaction. Targeting AgrA has the advantage of blocking AgrA-dependent virulence factor expression for all four Agr groups (Gordon CP, et al. (2013) J. Med. Chem. 56(4):1389-404).

[0006] Recently, in a screening of 24,087 compounds selected for inhibition of cyclic thiolactone peptide pheromone (AIP)-induced agrA in connection with a study of acute bacterial infections of the skin and soft tissue caused by Staphylococcus aureus (S. aureus), Sully et al. discovered an AgrA inhibitor called Savirin (Sully EK, et al. (2014) PLoS Pathog. 10(6):e1004174). Savirin was shown to be a potent modulator of AgrA-regulated toxin gene transcription, such as hla, psmα, and pvl, across all four agrA groups without affecting S. aureus viability. Savirin inhibited exotoxin-induced red blood cell (RBC) lysis. Resistance did not develop after multiple passages with Savirin. The molecule was shown to disrupt AgrA-DNA interactions and prevent the upregulation of virulence genes. In mice infected with MRSA USA300, multiple applications of Savirin resulted in a significant reduction in abscess size and skin necrosis.

[0007] Recently, WO 2020 / 109350 described 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4h)-one derivatives that can reduce the pathogenicity of bacteria such as Staphylococcus aureus (S. aureus) by interacting with AgrA and inhibiting the expression of AgrA-regulated virulence factors, and their use in the prevention or treatment of bacterial infections and / or diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus (S. aureus), including skin or lung infections, atopic dermatitis or psoriasis. Summary of the Invention

[0008] The present inventors have surprisingly found that when tested in the presence of human serum (HS) or human serum albumin (HSA; the main component of human serum), the ability of the compounds of WO 2020 / 109350 to inhibit AgrA-associated virulence factors may be affected and reduced. Without wishing to be bound, the reduced ability to inhibit the expression of AgrA-associated virulence factors is believed to be due to non-specific binding of the compounds to serum proteins (e.g., HSA). Such reduced efficacy in the presence of HS or HSA may limit the ability to inhibit AgrA-associated virulence factors when administered (e.g., to animals, preferably mammals, and more preferably humans). The present invention now provides a new class of compounds that overcome this drawback, and thus provides compounds that can reduce the virulence of bacteria, preferably expressing AgrA, and / or inhibit quorum sensing in bacteria, preferably Staphylococcus aureus (S. aureus), in biologically important systems containing human serum or human serum albumin.

[0009] Thus, the present inventors have surprisingly identified a new class of compounds that can interact with AgrA and inhibit the expression of AgrA-regulated virulence factors, even in the presence of human serum (HS) or human serum albumin (HSA). The present inventors transfected Staphylococcus aureus (S. aureus) with a plasmid expressing the reporter gene lacZ under the control of the AgrA-regulated P3 promoter. It was found that the production of the lacZ gene product (i.e., β-galactosidase) was inhibited in the presence of the compounds of the present invention. Surprisingly, the compounds of the present invention retained their AgrA inhibitory activity even when assayed in the presence of HSA.

[0010] Therefore, the compounds of the present invention can inhibit the transcription of genes (preferably virulence factors) under the control of the P3 promoter (for example, in bacteria, preferably in Staphylococcus aureus (S. aureus)) in the presence of HS or HSA. This activity strongly suggests that the compounds of the present invention can be administered to biologically important systems (for example, animals, preferably mammals, and even more preferably humans) while still maintaining efficacy. Additional features and advantages of this technology will be apparent to those skilled in the art upon reading the following detailed description of the invention.

[0011] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof: [ka] (In the formula, R 1 are independently selected from -H, halogen, -C1-C6 alkyl, and -C1-C6 alkoxy, and the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 3 are independently selected from —H, halogen, C1-C6 alkyl, —C1-C6 alkoxy, and —C3-C6 cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are selected from one or more R 11 and each may be replaced by R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10and -C1-C6 alkylene-(5-10 membered heteroaryl), wherein the alkyl is selected from one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or —S(C1-C6 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by one or more R 85 and each independently may be substituted by R 83 and R 84 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; R 85 independently, at each occurrence, represents -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, -C6-C 10 aryl, and oxo; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl having one or more R 86 and optionally substituted by R 86 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkylene-OH, —N(R 83 )(R 84 ), -C1-C6 alkylene-N(R 83 )(R 84 ), —C3-C6 cycloalkyl, and oxo; R 11 is independently at each occurrence a halogen or —OH; m is independently 1 or 2; n is independently 0 or 1).

[0012] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method of reducing the virulence of a bacterium, preferably wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably wherein the bacterium expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacterium expresses AgrA.

[0013] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method of inhibiting quorum sensing in a bacterium, preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA or an orthologue of AgrA, still more preferably the bacterium expresses AgrA.

[0014] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method for the prevention or treatment of a disease caused or exacerbated by a bacterium, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0015] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0016] In one aspect, the present invention provides a compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I), for use as a medicament. [Brief explanation of the drawings]

[0017] [Figure 1]This figure shows quorum-sensing signaling in staphylococci to control virulence factor production. The precursor peptide AgrD is processed by AgrB, and the mature autoinducing peptide (AIP) is secreted across the bacterial membrane. AIP binds to the histidine kinase AgrC in its own cell or on other bacterial cells. AgrC then activates the response regulator AgrA by phosphorylation. Phospho-AgrA binds to and activates transcription from the agr P2 and P3 promoters and the promoter of the psm operon (RNAIII-independent AgrA regulation). Classical targets of AgrA, including several toxins and proteases that are upregulated and several surface-associated proteins such as protein A that are downregulated, are under RNAIII-dependent control. Small molecule inhibitors that bind to the DNA-binding domain of AgrA prevent binding to the P2 and P3 promoters, thus blocking the continuous production of AIP (promoted by P2) and virulence factors (promoted by P3), but also RNAIII-independent AgrA-regulated expression, e.g., production of PSMs. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention relates to compounds capable of inhibiting transcription of genes under the control of the P3 promoter (eg, in bacteria, preferably in S. aureus) and pharmaceutical compositions containing same.

[0019] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The embodiments, preferred embodiments, and highly preferred embodiments described and disclosed herein should apply to all aspects and other embodiments, preferred embodiments, and highly preferred embodiments, whether specifically mentioned again or their repetition is avoided for the sake of brevity.

[0020] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.

[0021] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0022] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can, but need not, be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be attached at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups.

[0023] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. A C1-C6 alkyl group contains 1 to 6 carbon atoms. Examples of -C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, and tert-butyl, isopentyl, and neopentyl.

[0024] The term "alkylene" or "alkylenyl," as used herein, refers to a biradical of a straight or branched hydrocarbon chain derived from an alkyl, as defined herein, in which one hydrogen of the alkyl is cleaved to produce a secondary radical of the alkylene. Examples of alkylene include, by way of illustration, -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-CH-, or -CH(CHCH)-.

[0025] The term "cycloalkyl" means a monocyclic saturated carbocyclic ring containing from 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0026] The term "aryl" refers to cyclic aromatic hydrocarbon groups having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl and naphthyl. 10 An aryl group contains 6 to 10 carbon atoms, preferably 6 or 10 carbon atoms. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be fused (e.g., naphthyl). The aryl group may be substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-C1-C6 alkyl, -C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), and -N(C1-C6 alkyl)2. A substituent (e.g., an alkyl group) may itself be substituted.

[0027] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, S, P, and O, with the remaining ring atoms being C. Preferably, the heteroatoms are selected from N, S, and O, more preferably N and O. The aromatic radical may be independently substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, and pyrazinyl.

[0028] The terms "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refer to a monocyclic or bicyclic saturated or partially saturated 4- to 11-membered ring containing carbon and heteroatoms derived from O, N, and S (preferably O and N), wherein the ring or rings do not contain delocalized π-electrons (aromaticity) shared between ring carbons or ring heteroatoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetazinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, [1,4]diazepane, and [1,2]diazepane. In some embodiments, heterocyclyl rings are present in, for example, but not limited to, compounds 129, 130, and 153, e.g., R 81 and R 82 It is a fused bicyclic heterocycle, such as:

[0029] In some embodiments, the heterocyclyl group or heterocycloalkyl group is a spirocyclic heterocycle. As used herein, a spirocyclic heterocycle or spiroheterocycle is understood to mean a bicyclic ring system in which both rings are connected via a single atom and at least one of the rings is a heterocycle (e.g., at least one of the rings is azetidine, pyrrolidine, morpholine, or piperidine). Exemplary spirocyclic heterocycles include, but are not limited to, compounds 124, 125, 126, 127, 128, 149, 150, 151, and 152, such as R 81 and R 82 There is.

[0030] As used herein, the term "halo" or "halogen" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0031] The term "oxo" refers to a carbonyl functional group consisting of a carbon atom double-bonded to an oxygen atom, which may be abbreviated herein as "oxo," C(O), or C=O.

[0032] The present invention also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. The terms "pharmaceutically acceptable" or "therapeutically acceptable" refer to a material that does not interfere with the effectiveness or biological activity of the active ingredient and that is not toxic to the host. Representative "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, and the like. Examples of suitable salts include water-soluble and water-insoluble salts such as ammonium salts of methylglucamine, ...

[0033] The term "tautomer" refers to a series of compounds having the same number and type of atoms but differing bond connectivity, and which are in equilibrium with each other. A "tautomer" is a single member of this series of compounds. Typically, a single tautomer is depicted, but it is understood that this single structure is meant to represent all possible tautomers that may exist. An example includes enol-ketone tautomerism. When a ketone is depicted, it is understood that both the enol form and the ketone form are part of this disclosure.

[0034] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present invention, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which water is the solvent molecule is typically called a "hydrate." Hydrates include compositions containing stoichiometric amounts of water and compositions containing variable amounts of water.

[0035] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the transfer or transport of a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0036] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0037] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or composition directly to a subject, or administering to a subject a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt of the compound or composition, which can form an equivalent amount of the active compound in the subject's body.

[0038] The term "ortholog" as used herein refers to the well-known meaning of the term. In the art, an ortholog is a gene from a different species that evolved from a common ancestral gene. Although orthologs may diverge due to their separation after a speciation event, they usually share similarities at the sequence and structural levels. Furthermore, orthologs usually have identical functions. Orthology is a type of homology. In this application, the term ortholog is used to include orthologous genes (DNA or RNA) or peptide / protein products of orthologs. Peptide / protein products of orthologs are sometimes referred to as "orthologous products" or simply "orthologs." The meaning is clear from the context (e.g., the antipathogenic composition of the present invention may include an antipathogenic agent capable of reducing the virulence of bacteria expressing a peptide or protein that may be referred to as an ortholog of AgrA, i.e., a product of an orthologous gene of Staphylococcus aureus AgrA from another bacterium, such as Streptococcus pyogenes). In certain embodiments, orthologs of AgrA produce proteins / peptides that share greater than about 70%, about 80%, or about 90% identity with the amino acid sequence of the gene product of AgrA.

[0039] The terms "reduce" and "inhibit" have the commonly understood meaning of lowering or decreasing.

[0040] As used herein, the phrase "reducing the virulence of AgrA-expressing bacteria" typically and preferably refers to inhibiting the synthesis of one or more virulence factors by the bacteria using a compound of formula (I) or a composition of the present invention, preferably a pharmaceutical composition, containing a compound of formula (I). Examples of AgrA-regulated virulence factors include cell surface-associated proteins, such as protein A (SpA) and fibronectin-binding proteins, secreted toxins, such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble modulins (PSMs), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), or secreted proteases, such as SspA or aureolysin. In a preferred example and embodiment of the present invention, reducing the virulence of AgrA-expressing bacteria involves inhibiting the synthesis of one or more virulence factors selected from PSMα, RNAIII, and their downstream targets. In preferred examples and embodiments of the present invention, reducing the pathogenicity of AgrA-expressing bacteria is by inhibiting the synthesis of PSMα. In preferred examples and embodiments of the present invention, reducing the pathogenicity of AgrA-expressing bacteria is by inhibiting the synthesis of RNAIII and / or its downstream targets, preferably RNAIII.

[0041] The term "inhibiting the synthesis of one or more virulence factors" as used herein refers to a complete or partial inhibition (preferably more than 20%, more preferably more than 30%, more preferably more than 50%, more preferably more than 90%, even more preferably more than 95% or even more than 99%) of the synthesis of one or more virulence factors by the bacterium in the absence of the compound of the present invention of formula (I) or the composition of the present invention comprising the compound of formula (I), preferably the pharmaceutical composition, or in comparison to a method of the present invention in which such a compound of the present invention of formula (I) or the composition of the present invention comprising the compound of formula (I), preferably the pharmaceutical composition, is not applied or used.

[0042] Virulence factors contemplated herein include any molecule expressed and secreted by bacteria to promote colonization and / or adhesion in a host subject, promote inflammation in host tissues, promote evasion of the host immune response, and obtain nutrients from the host subject. Virulence factors can also include both exotoxins and endotoxins. Non-limiting examples of virulence factors inhibited by the compounds of the present invention of formula (I) described herein or the compositions of the present invention comprising the compounds of the present invention of formula (I), preferably the pharmaceutical compositions of the present invention, include toxins (e.g., α, β, γ, γ-mutant, and δ-hemolysins, PSMs (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxins E and D (LukED), leukotoxins G and H (LukGH), enterotoxins (e.g., enterotoxin B), exfoliative toxins, proteases (e.g., serine proteases, metalloproteases, and cysteine proteases), nucleases, lipases, coagulase, hyaluronidase, fibronectin binding proteins, clumping factors, pyrogenic toxins, superantigens, and the like. In a preferred embodiment, the virulence factor to be inhibited is RNAIII and / or its downstream target, or PSMα.

[0043] Depending on the severity of the infection, or when used prophylactically, antipathogenic drugs may be administered alone or in combination with therapeutic agents such as antibiotics that are typically and preferably used to prevent and treat infections caused by bacteria such as Staphylococcus, primarily Staphylococcus aureus (e.g., pneumonia, bloodstream infections, acute skin and skin structure infections).

[0044] Antipathogenic drugs may be administered alone or in combination with therapeutic agents typically and preferably used in the prevention and treatment of chronic inflammatory skin diseases (e.g., atopic dermatitis, Netherton syndrome, psoriasis) exacerbated by bacteria such as Staphylococcus, primarily Staphylococcus aureus.

[0045] As used herein, the term "antibiotic" refers to an antimicrobial or anti-infective agent that kills bacteria (bactericidal antibiotics) or inhibits the growth and / or metabolism of bacteria (bacteriostatic antibiotics). Antibiotics are well known to those skilled in the art, and specific and preferred examples thereof include penicillins, cephalosporins, polymyxins, rifamycins, lipiarmycins, quinolones, sulfonamides, macrolides, oxazolidinones, lincosamides, and tetracyclines.

[0046] As used herein, the terms "treating," "treatment," or "therapy" refer to a means of obtaining a desired physiological effect. The effect may be therapeutic in that it partially or completely cures the disease or condition and / or the symptoms caused by the disease or condition. The term refers to inhibiting the disease or condition, i.e., halting its development, or ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0047] As used herein, the term "prophylaxis" refers to a measure of preventing or delaying the onset of a disease or condition and / or symptoms resulting from the disease or condition.

[0048] As used herein, the term "subject" or "animal" or "patient" or "mammal" refers to any subject for whom diagnosis, prognosis, prevention or treatment is desired, particularly a mammalian subject, e.g., a human, or a domestic animal such as a dog, cat or horse, or a food animal such as a cow, sheep or pig, preferably a human. Thus, in a preferred embodiment of the invention, the subject is a human.

[0049] As used herein, the term "for use" as used in "a composition for use in the treatment or prevention of a disease" is intended to also disclose the corresponding method of treatment or prevention, and the corresponding use of the preparation for the manufacture of a medicament for treating or preventing a disease.

[0050] A "therapeutically effective amount" or "effective amount" is the amount of a compound or pharmaceutical composition according to the present invention that elicits the biological or medical response in a subject, preferably a human subject, that is desired by a researcher, veterinarian, physician, or other clinician. As used herein, the term "therapeutic administration" refers to the administration of a therapeutically effective amount. In particular, the terms "effective," "effective amount," and "therapeutically effective amount" as used herein typically and preferably refer to the amount of a compound of the present invention of Formula (I) or a composition of the present invention comprising a compound of the present invention of Formula (I), preferably a pharmaceutical composition of the present invention, that reduces bacterial virulence or results in improved symptoms or prolonged survival in a subject with a bacterial-related disease or disorder. The term "effective amount" is generally used herein to refer to the amount of a given compound, or in the case of a mixture, the total amount of the mixture components that provides a measurable effect on the recited function. It will be understood by those skilled in the art that for a given application, the effective amount can be determined by routine experimentation without undue experimentation using methods described herein or known in the art. The term "therapeutically effective amount" is used generally herein to refer to the amount of a given compound, or, in the case of a mixture, the total amounts of the mixture components, that, when administered to an individual, including a human or non-human animal, provides a measurable therapeutic effect for the recited disease, disorder, or condition, resulting in at least partial improvement of the symptoms of such disease, disorder, or condition. The outcome of treatment can be partial or complete alleviation, inhibition, prevention, amelioration, and / or relief of the disorder, condition, or one or more symptoms thereof.

[0051] Compounds of the Invention In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof: [ka] (In the formula, R 1 are independently selected from -H, halogen, -C1-C6 alkyl, and -C1-C6 alkoxy, and the alkyl and alkoxy are selected from one or more R11 and each may be replaced by R 3 are independently selected from —H, halogen, C1-C6 alkyl, —C1-C6 alkoxy, and —C3-C6 cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are selected from one or more R 11 and each may be replaced by R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 and -C1-C6 alkylene-(5-10 membered heteroaryl), wherein the alkyl is selected from one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or —S(C1-C6 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by one or more R 85 and each independently may be substituted by R 83 and R 84 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; R 85 independently, at each occurrence, represents -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, -C6-C 10 aryl, and oxo; or R 81 and R82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is 86 and optionally substituted by R 86 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkylene-OH, —N(R 83 )(R 84 ), -C1-C6 alkylene-N(R 83 )(R 84 ), —C3-C6 cycloalkyl, and oxo; R 11 is independently at each occurrence a halogen or —OH; m is independently 1 or 2; n is independently 0 or 1).

[0052] In some embodiments, the compound is a compound of formula (IA) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 8A , R 8B , R 81 , R 82 , m and n are as defined in formula (I).

[0053] In some embodiments, the compound is a compound of formula (I-A1) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 , R 82 and m is as defined in formula (I).

[0054] In some embodiments, the compound is a compound of formula (I-A2) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 , R 82 and m is as defined in formula (I).

[0055] In some embodiments, the compound is of formula (I-A3) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 , R 82 and m is as defined in formula (I).

[0056] In some embodiments, the compound is a compound of formula (I-A4) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 , R 82 and m is as defined in formula (I).

[0057] In some embodiments, the compound is of formula (IB) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 3 , R 8A , R 8B , R 81 , R 82 , m and n are as defined in formula (I).

[0058] In some embodiments, the compound is a compound of formula (I-B1) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 3 , R 81 , R 82 and m is as defined in formula (I).

[0059] In some embodiments, the compound is a compound of formula (I-B2) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 3 , R 81 , R 82 and m is as defined in formula (I).

[0060] In some embodiments, the compound is a compound of formula (I-B3) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 3 , R 81 , R 82 and m is as defined in formula (I).

[0061] In some embodiments, the compound is a compound of formula (I-B4) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 3 , R 81 , R 82 and m is as defined in formula (I).

[0062] In some embodiments, the compound is a compound of formula (IC) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 8A , R 8B , R 81 , R 82 and n is as defined in formula (I).

[0063] In some embodiments, the compound is a compound of formula (I-C1) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0064] In some embodiments, the compound is a compound of formula (I-C2) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0065] In some embodiments, the compound is a compound of formula (I-C3) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0066] In some embodiments, the compound is a compound of formula (I-C4) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0067] In some embodiments, the compound is a compound of formula (ID) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 8A , R 8B , R 81 , R 82 and n is as defined in formula (I).

[0068] In some embodiments, the compound is a compound of formula (I-D1) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0069] In some embodiments, the compound is a compound of formula (I-D2) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0070] In some embodiments, the compound is a compound of formula (I-D3) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0071] In some embodiments, the compound is a compound of formula (I-D4) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] In the formula, R 81 and R 82 is as defined in formula (I).

[0072] In some embodiments, R 1 are independently selected from —H, halogen, —C1-C4 alkyl, and —C1-C4 alkoxy, and the alkyl and alkoxy are selected from one or more R 11 and each may be substituted by:

[0073] In some embodiments, R 1 are independently selected from -H, -F, -Cl, -C1-C4 alkyl, and -C1-C4 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more F, Cl, or -OH.

[0074] In some embodiments, R 1 are independently selected from -H, -F, -C1-C2 alkyl, and -C1-C2 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more -F, or -OH.

[0075] In some embodiments, R 1are independently selected from -H, -F, and -C1-C2 alkyl, wherein the alkyl is optionally substituted by one or more -F, or -OH.

[0076] In some embodiments, R 1 are independently selected from -H, -F, and -C1-C2 alkyl.

[0077] In some embodiments, R 1 is independently selected from -H, and -C1-C2 alkyl.

[0078] In a preferred embodiment, R 1 is -CH3.

[0079] In some embodiments, R 3 are independently selected from -H, halogen, -C1-C4 alkyl, -C1-C4 alkoxy, and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are selected from one or more R 11 and each may be substituted by:

[0080] In some embodiments, R 3 are independently selected from -H, halogen, -C1-C3 alkyl, -C1-C3 alkoxy, and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are selected from one or more R 11 and each may be substituted by:

[0081] In some embodiments, R 3 are independently selected from -H, halogen, -C1-C3 alkyl, -C1-C2 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy, and cyclopropyl are selected from one or more R 11 and each may be substituted by:

[0082] In some embodiments, R 3are independently selected from -H, -Cl, -C1-C3 alkyl, -C1-C2 alkoxy, and cyclopropyl, wherein the alkyl is optionally substituted by one or more -F, -Cl, or -OH.

[0083] In some embodiments, R 3 are independently selected from -H, -Cl, -C1-C3 alkyl, -C1-C2 alkoxy, and cyclopropyl, wherein the alkyl is optionally substituted with one or more -F, and preferably the alkyl is unsubstituted or substituted with three -F.

[0084] In some embodiments, R 3 are independently selected from -Cl, -C1-C3 alkyl, -C1-C2 alkoxy, and cyclopropyl, wherein the alkyl is optionally substituted with one or more -F, and preferably the alkyl is unsubstituted or substituted with three -F.

[0085] In some embodiments, R 3 are independently selected from -CH3, -CF3, -Cl, -CH(CH3)2, -OCH3, and cyclopropyl.

[0086] In some embodiments, R 3 is -CF3.

[0087] In some embodiments, R 3 is -Cl.

[0088] In some embodiments, R 3 is -CH(CH3)2.

[0089] In some embodiments, R 3 is -OCH3.

[0090] In some embodiments, R 3 is cyclopropyl.

[0091] In a preferred embodiment, R 3 is —CH3. In a preferred embodiment, R 1 and R 3 are both -CH3.

[0092] In a preferred embodiment, R 8A and R 8B are both -H.

[0093] In some embodiments, R 8A and R 8B are both -H or -CH3.

[0094] In some embodiments, R 8A and R 8B are both -CH3.

[0095] In some embodiments, R 8A is -H and R 8B is -CH3.

[0096] In a preferred embodiment, n is 0 and m is 1.

[0097] In some embodiments, n is 0.

[0098] In some embodiments, n is 1.

[0099] In some embodiments, m is 1.

[0100] In some embodiments, m is 2.

[0101] In some embodiments, n is 0 and m is 2.

[0102] In some embodiments, n is 1 and m is 1

[0103] In some embodiments, n is 1 and m is 2.

[0104] In a preferred embodiment, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl).

[0105] In some embodiments, R 81 and R 82 are both -H.

[0106] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -N(R 83 )(R 84 ), or —S(C1-C4 alkyl).

[0107] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 It may be optionally substituted by -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or -S(C1-C4 alkyl).

[0108] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2)1-2 It may be substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0109] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three halogens, and wherein the alkyl is selected from one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0110] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which alkyl is optionally substituted by one to three -F, -Cl, or -Br, and which alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0111] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which alkyl is optionally substituted by 1 to 3 -F, and which alkyl is optionally substituted by 1 or 2, preferably exactly 1, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0112] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which alkyl is optionally substituted by 1 to 3 -F, and which alkyl is optionally substituted by 1 or 2, preferably exactly 1, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted by -OH, -C1-C2 alkoxy, -NH2, or -S(C1-C2 alkyl).

[0113] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which alkyl is optionally substituted by 1 to 3 -F, and which alkyl is optionally substituted by 1 or 2, preferably exactly 1, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted with -OH, -OCH3, -NH2, or SCH3.

[0114] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which alkyl is optionally substituted by 1 to 3 -F, and which alkyl is optionally substituted by 1 or 2, preferably exactly 1, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be further substituted by -OH, -OCH3, or -NH2.

[0115] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, which is optionally substituted by 1 to 3 -F, and which is optionally further substituted by 1 or 2, preferably exactly 1, -C2 alkynyl, -OH, -OCH3, or -NH2.

[0116] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three halogens, or the alkyl is substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0117] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, -Cl, or -Br, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0118] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl).

[0119] In some embodiments, R 81 and R 82are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be substituted by -OH, -C1-C2 alkoxy, -NH2, or -S(C1-C2 alkyl).

[0120] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It may be substituted by -OH, -OCH3, -NH2, or -SCH3.

[0121] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is substituted by one or two, preferably exactly one, -OH, -(OCH2-CH2) 1-2 It may be substituted by -OH, -OCH3, or -NH2.

[0122] In some embodiments, R 81 and R 82 are each independently at each occurrence selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -OH, -OCH3, or -NH2.

[0123] In some embodiments, R 81is independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), R 82 is -H.

[0124] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C4 alkyl), R 82 is -H.

[0125] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 optionally substituted by -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or -S(C1-C4 alkyl); R 82 is -H.

[0126] In some embodiments, R 81 is independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is selected from one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0127] In some embodiments, R81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three halogens, and the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0128] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, -Cl, or -Br, and wherein the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0129] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, and the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 may be further substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0130] In some embodiments, R 81are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, and the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 may be further substituted by -OH, -C1-C2 alkoxy, -NH2, or -S(C1-C2 alkyl), R 82 is -H.

[0131] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, and the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 may be further substituted by -OH, -OCH3, -NH2, or -SCH3, and R 82 is -H.

[0132] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, and wherein the alkyl is substituted by one or two, preferably exactly one, -OH, -(OCH2-CH2) 1-2 may be further substituted by —OH, —OCH3, or —NH2, and R 82 is -H.

[0133] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, and wherein the alkyl is optionally further substituted by one or two, preferably exactly one, -OH, -OCH3, or -NH2; R 82 is -H.

[0134] In some embodiments, R 81are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three halogens, or the alkyl is substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0135] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, -Cl, or -Br, or the alkyl is substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0136] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 optionally substituted by -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); R 82 is -H.

[0137] In some embodiments, R 81are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 optionally substituted by —OH, —C1-C2 alkoxy, —NH2, or —S(C1-C2 alkyl); R 82 is -H.

[0138] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -(OCH2-CH2) 1-2 may be substituted by -OH, -OCH3, -NH2, or -SCH3, and R 82 is -H.

[0139] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is substituted by one or two, preferably exactly one, -OH, -(OCH2-CH2) 1-2 may be substituted by —OH, —OCH3, or —NH2, and R 82 is -H.

[0140] In some embodiments, R 81 are independently selected from -H, and -C1-C6 alkyl, wherein the alkyl is optionally substituted by one to three -F, or the alkyl is optionally substituted by one or two, preferably exactly one, -OH, -OH, -OCH3, or -NH2; R 82 is -H.

[0141] In some embodiments, R 81 and R82 are each -C1-C6 alkyl.

[0142] In some embodiments, R 81 and R 82 are each -C1-C4 alkyl.

[0143] In some embodiments, R 81 and R 82 are each -C1-C2 alkyl, preferably R 81 is -CH3 and R 82 is -C1-C2 alkyl.

[0144] In a preferred embodiment, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C6 alkylene-(C3-C8 cycloalkyl).

[0145] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C6 alkylene-(C3-C8 cycloalkyl), and R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0146] In some embodiments, R 81 is selected from —C3-C8 cycloalkyl, and —C1-C6 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0147] In some embodiments, R81 is selected from —C3-C8 cycloalkyl, and —C1-C4 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0148] In some embodiments, R 81 is selected from —C3-C8 cycloalkyl, and —C1-C4 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C4 alkyl, halogen, —OH, —C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —C6-C 10 aryl, R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0149] In some embodiments, R 81 is selected from —C3-C8 cycloalkyl, and —C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C-C alkyl, halogen, —OH, —C-C alkoxy, —NH, —NH(C-C alkyl), —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0150] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C3-C7 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C-C alkyl, halogen, —OH, —C-C alkoxy, —NH, —NH(C-C alkyl), —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0151] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C3-C7 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C3 alkyl, —OH, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0152] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl, and -C3-C7 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl, and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is selected from one or two, preferably exactly one, R 85 and R 85is independently, at each occurrence, selected from -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0153] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl, and -C3-C7 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl, and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is selected from one or two, preferably exactly one, R 85 and R 85 is independently, at each occurrence, selected from -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0154] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl, and -C3-C7 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl, and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is selected from one or two, preferably exactly one, R 85 and R 85 is independently, at each occurrence, selected from —OH, —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0155] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C6 alkylene-(C3-C8 cycloalkyl), and R 81 is -C3-C8 cycloalkyl, R81 is one or more R 85 and R 81 is -C1-C6 alkylene-(C3-C8 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0156] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C4 alkylene-(C3-C8 cycloalkyl), and R 81 is -C3-C8 cycloalkyl, R 81 is one or more R 85 and R 81 is -C1-C4 alkylene-(C3-C8 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0157] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C4 alkylene-(C3-C8 cycloalkyl), and R 81 is -C3-C8 cycloalkyl, R 81 is one or more R 85 and R 81is -C1-C4 alkylene-(C3-C8 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, —C1-C4 alkyl, halogen, —OH, —C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —C6-C 10 aryl, R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0158] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl, and -C1-C3 alkylene-(C3-C8 cycloalkyl), and R 81 is -C3-C8 cycloalkyl, R 81 is one or more R 85 and R 81 is -C1-C3 alkylene-(C3-C8 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from —C-C alkyl, halogen, —OH, —C-C alkoxy, —NH, —NH(C-C alkyl), —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0159] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C1-C3 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), and R 81 is -C3-C7 cycloalkyl, or C3-C6 cycloalkyl, R 81 is one or more R 85 and R 81is -C1-C3 alkylene-(C3-C7 cycloalkyl), or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from —C-C alkyl, halogen, —OH, —C-C alkoxy, —NH, —NH(C-C alkyl), —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0160] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C1-C3 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), and R 81 is -C3-C7 cycloalkyl, or C3-C6 cycloalkyl, R 81 is one or more R 85 and R 81 is -C1-C3 alkylene-(C3-C7 cycloalkyl), or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from —C1-C3 alkyl, —OH, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0161] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C1-C3 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), and R 81 is -C3-C7 cycloalkyl, or C3-C6 cycloalkyl, R81 is one or two, preferably exactly one R 85 and R 81 is -C1-C3 alkylene-(C3-C7 cycloalkyl), or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C3 alkyl, preferably R 82 is -H.

[0162] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C1-C3 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), and R 81 is -C3-C7 cycloalkyl, or C3-C6 cycloalkyl, R 81 is one or two, preferably exactly one R 85 and R 81 is -C1-C3 alkylene-(C3-C7 cycloalkyl), or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0163] In some embodiments, R 81 is selected from —C3-C7 cycloalkyl, and —C1-C3 alkylene-(C3-C7 cycloalkyl), preferably —C3-C6 cycloalkyl, and —C1-C3 alkylene-(C3-C6 cycloalkyl), and R 81is -C3-C7 cycloalkyl, or C3-C6 cycloalkyl, R 81 is one or two, preferably exactly one R 85 and R 81 is -C1-C3 alkylene-(C3-C7 cycloalkyl), or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 is unsubstituted and R 85 is independently, at each occurrence, selected from —OH, —N(C-C alkyl), and phenyl; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0164] In a preferred embodiment, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C 1 -C 6 alkylene-(4- to 8-membered heterocycloalkyl).

[0165] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), and R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0166] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0167] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C4 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0168] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C4 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0169] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C4 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, —OH, —C1-C4 alkoxy, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0170] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C4 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C4 alkyl, halogen, -OH, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0171] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, halogen, -OH, and oxo; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0172] In some embodiments, R 81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl contains one or more heteroatoms selected from N and O, preferably one or two heteroatoms selected from N and O, and the heterocycloalkyl contains one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, halogen, -OH, and oxo; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0173] In some embodiments, R81 is selected from 4- to 8-membered heterocycloalkyl, and —C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl contains one or more heteroatoms selected from N and O, preferably one or two heteroatoms selected from N and O, and the heterocycloalkyl contains one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, and oxo; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0174] In some embodiments, R 81 is selected from 4- to 6-membered heterocycloalkyl, and —C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, and morpholine, and wherein the heterocycloalkyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, and oxo; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0175] In some embodiments, R 81 is selected from 4- to 6-membered heterocycloalkyl, and —C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkyl is selected from azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, and morpholine; R 81 When R is a 4- to 6-membered heterocycloalkyl, the heterocycloalkyl may be substituted by one or more, preferably one or two, -C1-C2 alkyl groups; 81When R is -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), the heterocycloalkyl may be substituted by one or more, preferably one or two, -C1-C2 alkyl or oxo; 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0176] In a preferred embodiment, R 81 is -C6-C 10 Aryl, and -C1-C6 alkylene-(C6-C 10 aryl).

[0177] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C6 alkylene-(C6-C 10 aryl), and R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0178] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C6 alkylene-(C6-C 10 aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0179] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C6 alkylene-(C6-C 10aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), and -C6-C 10 aryl, R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0180] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C4 alkylene-(C6-C 10 aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C4 alkyl, halogen, —OH, —C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —C6-C 10 aryl, R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0181] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C4 alkylene-(C6-C 10 aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, —OH, —C1-C4 alkoxy, —NH2, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)2; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0182] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C2 alkylene-(C6-C 10 aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C-C alkyl, halogen, —OH, —C-C alkoxy, —NH, —NH(C-C alkyl), and —N(C-C alkyl), and R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0183] In some embodiments, R 81 is -C6-C 10 Aryl, and -C1-C2 alkylene-(C6-C 10 aryl), wherein the aryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C2 alkyl, halogen, —OH, and —C1-C2 alkoxy; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0184] In some embodiments, R 81 is selected from phenyl, and —C1-C2 alkylene-(phenyl), wherein the phenyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C2 alkyl, halogen, —OH, and —C1-C2 alkoxy; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0185] In some embodiments, R 81is selected from phenyl, and —C1-C2 alkylene-(phenyl), wherein the phenyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, -F, -Cl, -OH, and -C1-C2 alkoxy; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0186] In some embodiments, R 81 is selected from phenyl, and —C1-C2 alkylene-(phenyl), wherein the phenyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -C1-C2 alkyl, -Cl, -OH, and -C1-C2 alkoxy; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0187] In some embodiments, R 81 is selected from phenyl, and —C1-C2 alkylene-(phenyl), wherein the phenyl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from -Cl, -OH, and -C1-C2 alkoxy; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0188] In a preferred embodiment, R 81 is selected from 5-10 membered heteroaryl, and -C1-C6 alkylene-(5-10 membered heteroaryl).

[0189] In some embodiments, R 81 is selected from 5-10 membered heteroaryl, and -C1-C6 alkylene-(5-10 membered heteroaryl), and R 82is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0190] In some embodiments, R 81 is selected from 5-10 membered heteroaryl, and -C1-C6 alkylene-(5-10 membered heteroaryl), wherein the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0191] In some embodiments, R 81 is selected from 5-10 membered heteroaryl, and -C1-C4 alkylene-(5-10 membered heteroaryl), wherein the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0192] In some embodiments, R 81 is selected from 5-10 membered heteroaryl, and -C1-C4 alkylene-(5-10 membered heteroaryl), wherein the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0193] In some embodiments, R 81 is selected from 5-6 membered heteroaryl, and -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0194] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl, and —C1-C4 alkylene-(5- to 6-membered heteroaryl), wherein the heteroaryl contains one or more heteroatoms selected from N, O and S, preferably one or two heteroatoms selected from N, O and S, and the heteroaryl contains one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0195] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl, and —C1-C4 alkylene-(5- to 6-membered heteroaryl), wherein the heteroaryl is each independently selected from pyrrole, furan, thiophene, oxazole, imidazole, pyridine, pyrazole, isoxazole, triazole, and pyrimidine, and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0196] In some embodiments, R 81 is selected from 5-6 membered heteroaryl, and -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryls are each independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine, and the heteroaryls are each independently selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0197] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl, and -C1-C4 alkylene-(5- to 6-membered heteroaryl), each of the heteroaryls is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0198] In some embodiments, R 81 is selected from 5-6 membered heteroaryl, and -C1-C2 alkylene-(5-6 membered heteroaryl), each of which is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0199] In some embodiments, R 81 is -C1-C6 alkylene-(5-10 membered heteroaryl).

[0200] In some embodiments, R 81 is -C1-C6 alkylene-(5-10 membered heteroaryl), and R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0201] In some embodiments, R 81 is -C1-C6 alkylene-(5-10 membered heteroaryl), and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, —C1-C6 alkyl, halogen, —OH, —C1-C6 alkoxy, —N(R 83 )(R 84 ), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C6 alkyl, preferably R 82 is -H.

[0202] In some embodiments, R 81 is -C1-C4 alkylene-(5-10 membered heteroaryl), and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -C6-C 10 aryl, and oxo; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0203] In some embodiments, R 81 is -C1-C4 alkylene-(5-10 membered heteroaryl), and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0204] In some embodiments, R 81 is -C1-C4 alkylene-(5-6 membered heteroaryl), and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0205] In some embodiments, R 81 is -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl contains one or more heteroatoms independently selected from N, O and S, preferably one or two heteroatoms independently selected from N, O and S, and the heteroaryl contains one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0206] In some embodiments, R 81 is -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, pyridine, pyrazole, isoxazole, triazole, and pyrimidine, and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0207] In some embodiments, R 81 is -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine, and the heteroaryl is selected from one or more R 85 and R 85 is independently, at each occurrence, selected from —C1-C4 alkyl, halogen, and —OH; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0208] In some embodiments, R 81 is -C1-C4 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine; R 82 is -H, or -C1-C4 alkyl, preferably R 82 is -H.

[0209] In some embodiments, R 81 is -C1-C2 alkylene-(5-6 membered heteroaryl), wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, and pyridine; R 82 is -H, or -C1-C2 alkyl, preferably R 82 is -H.

[0210] In a preferred embodiment, R 82 is —H, or C1-C6 alkyl, preferably R 82 is —H, or C1-C2 alkyl, and more preferably R 82 is H.

[0211] In some embodiments, R 82 is —H, or —C1-C2 alkyl.

[0212] In some embodiments, R 82 is -H.

[0213] In a preferred embodiment, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is 86 may be substituted by

[0214] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is 86 R may be substituted by 86 is independently at each occurrence selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C4 alkylene-NH2, -C1-C4 alkylene-NH(C1-C4 alkyl), -C1-C4 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl, and oxo.

[0215] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is 86 R may be substituted by 86 is independently at each occurrence selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl, and oxo.

[0216] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, the heterocycloalkyl containing one or more heteroatoms selected from O and N, and the 4- to 11-membered heterocycloalkyl containing one or more R 86 R may be substituted by 86 is independently at each occurrence selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl, and oxo.

[0217] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, the heterocycloalkyl containing one or two heteroatoms selected from O and N, and the 4- to 11-membered heterocycloalkyl containing one or two R 86 R may be substituted by 86 is independently at each occurrence selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl, and oxo.

[0218] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, the heterocycloalkyl containing one or two heteroatoms selected from O and N, and the 4- to 11-membered heterocycloalkyl containing one or two R 86R may be substituted by 86 is independently at each occurrence selected from -C1-C4 alkyl, -F, -Cl, -OH, -C1-C2 alkylene-OH, -NH2, -N(C1-C2 alkyl)2, -C1-C2 alkylene-NH2, -C3-C6 cycloalkyl, and oxo.

[0219] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, the heterocycloalkyl containing one or two heteroatoms selected from O and N, and the 4- to 11-membered heterocycloalkyl containing one or two R 86 R may be substituted by 86 is independently, at each occurrence, selected from —C1-C4 alkyl, —F, —OH, —C1-C2 alkylene-OH, —NH2, —N(C1-C2 alkyl)2, —C1-C2 alkylene-NH2, —C3-C6 cycloalkyl (preferably cyclopropyl), and oxo.

[0220] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl selected from azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azepane, oxazepane (preferably [1,4]oxazepane), diazepane (preferably [1,4]diazepane), 7- to 11-membered spirocyclic heterocycloalkyl, and 8- to 10-membered fused bicyclic heterocycloalkyl, wherein the 4- to 11-membered heterocycloalkyl is selected from one or two R 86 R may be substituted by 86 is independently, at each occurrence, selected from —C1-C4 alkyl, —F, —OH, —C1-C2 alkylene-OH, —NH2, —N(C1-C2 alkyl)2, —C1-C2 alkylene-NH2, —C3-C6 cycloalkyl (preferably cyclopropyl), and oxo.

[0221] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, said heterocycloalkyl being selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, oxazepane (preferably [1,4]oxazepane), diazepane (preferably [1,4]diazepane), 7- to 11-membered spirocyclic heterocycloalkyl, and 8- to 10-membered fused bicyclic heterocycloalkyl, said 4- to 11-membered heterocycloalkyl being selected from one or two R 86 R may be substituted by 86 is independently, at each occurrence, selected from —C1-C4 alkyl, —F, —OH, —C1-C2 alkylene-OH, —NH2, —N(C1-C2 alkyl)2, —C1-C2 alkylene-NH2, —C3-C6 cycloalkyl (preferably cyclopropyl), and oxo.

[0222] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine or morpholine, and the pyrrolidine, piperidine or morpholine is selected from the group consisting of one or two R 86 may be substituted by

[0223] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a pyrrolidine or morpholine, and the pyrrolidine or morpholine is 86 may be substituted by

[0224] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached to form a pyrrolidine, which is 86 may be substituted by

[0225] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a pyrrolidine, which is unsubstituted.

[0226] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached to form an N-linked pyrrolidine, which is an N-linked pyrrolidine having one or two R 86 may be substituted by

[0227] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached to form an N-linked pyrrolidine, which is unsubstituted.

[0228] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached to form a morpholine, which is 86 may be substituted by

[0229] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form a morpholine, which is unsubstituted.

[0230] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached to form an N-linked morpholine, which is an N-linked morpholine having one or two R 86 may be substituted by

[0231] In some embodiments, R 81 and R 82 together with the nitrogen atom to which they are attached form an N-linked morpholine, which is unsubstituted.

[0232] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] (In the formula, R 1 is -CH3, R 3 is -CH3, R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, The 4-8 membered heterocycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84), -C1-C6 alkoxy, phenyl, or oxo, -C6-C 10 Aryl is one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), or -C1-C6 alkoxy, The 5- to 10-membered heteroaryl may be one or more of —C1-C6 alkyl, halogen, —OH, —N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; m is independently 1 or 2; n is independently 0 or 1).

[0233] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] (In the formula, R 1 is -CH3, R 3 is -CH3, R8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, The 4- to 8-membered heterocycloalkyl may each be independently substituted by one or more -C1-C6 alkyl or oxo; -C6-C 10 each aryl is optionally substituted independently with one or more halogen, —OH, or —C1-C6 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; m is independently 1 or 2; n is independently 0 or 1).

[0234] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] (In the formula, R 1 is -CH3, R 3 is -CH3, R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently, at each occurrence, selected from —H, and C1-C2 alkyl, preferably —H, and —CH3; m is independently 1 or 2; n is independently 0 or 1).

[0235] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] (In the formula, R 1 is -CH3, R 3 is -CH3, R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R82 are each independently selected at each occurrence from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, the -C6 aryl is optionally substituted with one or more halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently, at each occurrence, selected from —H, and C1-C2 alkyl, preferably —H, and —CH3; m is independently 1 or 2; n is independently 0 or 1).

[0236] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or tautomer thereof: [ka] (In the formula, R 1 is -CH3, R 3 is -CH3, R 8A and R 8B is each independently in each occurrence -H, or -CH; R 81 and R 82 are each independently selected at each occurrence from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or two, preferably exactly one, -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl has one or two, preferably exactly one, -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted independently by one or two, preferably exactly one, -C1-C2 alkyl or oxo; the -C6 aryl is optionally substituted independently by one or two, preferably exactly one, halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is selected from the group consisting of one or two -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently, at each occurrence, selected from —H, and C1-C2 alkyl, preferably —H, and —CH3; m is independently 1 or 2; n is independently 0 or 1).

[0237] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, The 4-8 membered heterocycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, -C6-C 10 Aryl is one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), or -C1-C6 alkoxy, The 5- to 10-membered heteroaryl may be one or more of —C1-C6 alkyl, halogen, —OH, —N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0238] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, The 4- to 8-membered heterocycloalkyl may each be independently substituted by one or more -C1-C6 alkyl or oxo; -C6-C 10 each aryl is optionally substituted independently with one or more halogen, —OH, or —C1-C6 alkoxy; or R 81 and R 82together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0239] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0240] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently selected at each occurrence from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, the -C6 aryl is optionally substituted with one or more halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0241] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81and R 82 are each independently selected at each occurrence from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or two, preferably exactly one, -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl has one or two, preferably exactly one, -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted independently by one or two, preferably exactly one, -C1-C2 alkyl or oxo; the -C6 aryl is optionally substituted independently by one or two, preferably exactly one, halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is selected from the group consisting of one or two -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0242] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, The 4-8 membered heterocycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo, -C6-C10 Aryl is one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), or -C1-C6 alkoxy, The 5- to 10-membered heteroaryl may be one or more of —C1-C6 alkyl, halogen, —OH, —N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0243] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, The 4- to 8-membered heterocycloalkyl may each be independently substituted by one or more -C1-C6 alkyl or oxo; -C6-C 10 each aryl is optionally substituted independently with one or more halogen, —OH, or —C1-C6 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0244] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C2 alkoxy; or R 81 and R 82together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0245] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H or C1-C2 alkyl, preferably R 82 is H and R 81 is independently selected at each occurrence from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl may be one or more of -OH, -N(R 83)(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, the -C6 aryl is optionally substituted with one or more halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0246] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H or C1-C2 alkyl, preferably R 82 is H and R 81is independently selected at each occurrence from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or two, preferably exactly one, -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl has one or two, preferably exactly one, -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted independently by one or two, preferably exactly one, -C1-C2 alkyl or oxo; the -C6 aryl is optionally substituted independently by one or two, preferably exactly one, halogen, -OH, or -C1-C2 alkoxy; or R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is selected from the group consisting of one or two -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0247] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; The 4-8 membered heterocycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; -C6-C 10 Aryl is one or more of -C1-C6 alkyl, halogen, -OH, -N(R83 )(R 84 ), or -C1-C6 alkoxy, The 5- to 10-membered heteroaryl may be one or more of —C1-C6 alkyl, halogen, —OH, —N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0248] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C6 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0249] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently, at each occurrence, -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0250] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently at each occurrence selected from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, the -C6 aryl is optionally substituted with one or more halogen, -OH, or -C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0251] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 are each independently at each occurrence selected from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or two, preferably exactly one, -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl has one or two, preferably exactly one, -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted independently by one or two, preferably exactly one, -C1-C2 alkyl or oxo; the -C6 aryl is optionally substituted independently by one or two, preferably exactly one, halogen, -OH, or -C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0252] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H, or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; The 4-8 membered heterocycloalkyl may be one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; -C6-C 10 Aryl is one or more of -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), or -C1-C6 alkoxy, The 5- to 10-membered heteroaryl may be one or more of —C1-C6 alkyl, halogen, —OH, —N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0253] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H, or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C6 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C6 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C6 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C6 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C6 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0254] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H, or C1-C2 alkyl, preferably R 82 is H and R 81 is independently, at each occurrence, —H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 8-membered heterocycloalkyl, —C1-C3 alkylene-(4- to 8-membered heterocycloalkyl), —C6-C 10 Aryl, -C1-C3 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C8 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 8-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, -C6-C 10 each aryl is optionally substituted independently by one or more halogen, —OH, or —C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0255] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H, or C1-C2 alkyl, preferably R 82 is H and R 81 is independently selected at each occurrence from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or more of -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl may be one or more of -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted by one or more -C1-C2 alkyl or oxo, the -C6 aryl is optionally substituted with one or more halogen, -OH, or -C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0256] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is —H, or C1-C2 alkyl, preferably R 82 is H and R 81 is independently selected at each occurrence from: -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl); The -C1-C6 alkyl may be one or two, preferably exactly one, -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ), or -S(C1-C2 alkyl), The -C3-C6 cycloalkyl has one or two, preferably exactly one, -OH, -N(R 83 )(R 84 ), or phenyl, the 4- to 6-membered heterocycloalkyl is optionally substituted independently by one or two, preferably exactly one, -C1-C2 alkyl or oxo; the -C6 aryl is optionally substituted independently by one or two, preferably exactly one, halogen, -OH, or -C1-C2 alkoxy; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0257] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which is a 4- to 11-membered heterocycloalkyl group selected from one or more of -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl, or oxo; R 83 and R 84 is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0258] In some embodiments of any of formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 together with the nitrogen atom to which they are attached form a 4- to 11-membered heterocycloalkyl, which 4- to 11-membered heterocycloalkyl may be selected from one or more of -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 ), -C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl), or oxo; R 83 and R 84 is independently at each occurrence selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0259] In a preferred embodiment, the compound is selected from: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0260] In some embodiments, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 1).

[0261] In some embodiments, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-morpholino-2-oxo-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 2).

[0262] Antipathogenic activity of the compounds of the present invention The compounds of the present invention are 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4h)-one derivatives containing an N-linked piperazine or N-linked homopiperazine at the 8-position of the [1,2,3]triazolo[1,5a]quinazolin-5(4h)-one core, further substituted (on the second nitrogen atom) with an (optionally substituted) acetyl or propionyl amide group. As shown in Table 3, the compounds of the present invention were tested in an AgrA reporter assay to evaluate their ability to inhibit the expression of genes under the control of the AgrA-regulated P3 promoter. Specifically, the reporter gene lacZ (encoding the protein product β-galactosidase) was transfected into Staphylococcus aureus (S. aureus) using a plasmid under the control of the P3 promoter. The compounds were serially diluted in lysogeny broth (LB) and incubated with S. aureus. After incubation, S. aureus cells were lysed and treated with 4-methylumbelliferyl galactopyranoside (MUG). β-galactosidase produced by expression of lacZ cleaved MUG into galactopyranose and 4-methylumbelliferone, which were measured by fluorescence. Thus, the fluorescence readout serves as a proxy for the ability of compounds of the invention to inhibit genes under the control of the P3 promoter (e.g., in bacteria, preferably in S. aureus).

[0263] Compounds of the present invention retain activity in the presence of 40 mg / mL HSA and exhibit IC 50The values were as low as 8 μg / mL. Thus, the compounds of the present invention retained their activity in inhibiting the expression of genes regulated by AgrA, even when incubated with physiologically relevant concentrations of HSA. In contrast, as shown in Example 3, although compound 45 of WO 2020 / 109350 inhibited lacZ expression at concentrations below 1 μg / mL in the AgrA reporter assay in the absence of HSA, when incubated with Staphylococcus aureus (S. aureus) in the presence of HSA, the compound was inactive even at the highest concentration of the compound tested, i.e., 128 μg / mL. Without wishing to be bound, a concentration of 40 mg / mL of HSA was selected because this is the same concentration of HSA found in human serum.

[0264] Without wishing to be bound, the ability of the compounds of the present invention to retain their activity even in the presence of HSA allows the compounds of the present invention to be administered (e.g., to a subject, such as a mammal, preferably a human, preferably topically) while still maintaining efficacy. Thus, the compounds of the present invention were surprisingly able to maintain their activity even when incubated in biologically relevant concentrations of HSA.

[0265] Uses of the Compounds of the Invention In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0266] In one aspect, the present invention provides a compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I), for use as a medicament.

[0267] In a further aspect, the present invention provides compounds according to formula (I) as disclosed herein, and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of formula (I), for use in a method for reducing the virulence of bacteria, preferably bacteria expressing AgrA or an orthologue of AgrA, preferably AgrA, more preferably bacteria of a genus selected from Staphylococcus, Streptococcus, or Clostridium, even more preferably Staphylococcus, and even more preferably Staphylococcus aureus. In a further highly preferred embodiment, the bacteria express AgrA or an orthologue of AgrA. In a further highly preferred embodiment, the bacteria express AgrA. In a further highly preferred embodiment, the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium. In a further highly preferred embodiment, the bacterium is of the genus Staphylococcus. In a further highly preferred embodiment, the bacterium is Staphylococcus aureus. The embodiments, preferred embodiments, and highly preferred embodiments described and disclosed herein for compounds of formula (I) shall apply to the methods of the present invention, regardless of whether they are specifically mentioned again or their repetition is avoided for the sake of brevity.

[0268] In a further aspect, the present invention provides a compound according to formula (I) disclosed herein, and a pharmaceutically acceptable salt, stereoisomer, enantiomer, or tautomer of a compound of formula (I), for use in a method for preventing or treating a disease in a subject, preferably an infection or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, wherein the bacterium is selected from the genus Staphylococcus, Streptococcus, or Clostridium, more preferably a Staphylococcus, and even more preferably, the bacterium is Staphylococcus aureus. In a further highly preferred embodiment, the disease is an infection or inflammatory disease. In a further highly preferred embodiment, the disease is an infection. In a further highly preferred embodiment, the disease is a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium. In a further highly preferred embodiment, the disease is a bacterial infection, and the bacterium is selected from the genus Staphylococcus, Streptococcus, or Clostridium. In a further highly preferred embodiment, the disease is exacerbated by a bacterium of the genus Staphylococcus, preferably Staphylococcus aureus. In a further highly preferred embodiment, the disease is an infection caused or exacerbated by a bacterium selected from the genus Staphylococcus. In a further highly preferred embodiment, the disease is an infection caused or exacerbated by Staphylococcus aureus. In a further highly preferred embodiment, the disease is Netherton syndrome or an inflammatory skin disease, preferably atopic dermatitis. In a further highly preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis exacerbated by Staphylococcus aureus.In a preferred embodiment, the disease is Netherton syndrome. The embodiments, preferred embodiments and highly preferred embodiments described and disclosed herein for compounds of formula I shall apply to the methods of the present invention, whether specifically mentioned again or their repetition avoided for the sake of brevity.

[0269] In a further aspect, the present invention provides a compound according to formula (I) for use in a method for inhibiting quorum sensing, preferably AgrA quorum sensing, in a bacterium, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. The embodiments, preferred and highly preferred embodiments described and disclosed herein for compounds of formula I shall apply to the method of the present invention, whether specifically mentioned again or their repetition avoided for the sake of brevity.

[0270] In a further preferred embodiment, the bacterium is selected from Streptococcus pyogenes, Clostridium difficile, or Staphylococcus aureus, and preferably, the bacterium is Staphylococcus aureus. In a highly preferred embodiment, the bacterium is Staphylococcus aureus.

[0271] Therefore, the compositions and compounds of the present invention represent antipathogenic therapeutic agents that can be used as a monotherapy to enhance the self-defense and self-healing capabilities of infected hosts through reduced tissue damage, reduced inflammation, reduced disease transmission, a complete immune response, and a reduced recurrence rate. If the host is unable to fully eliminate the released pathogen, combination therapy with conventional antibiotics (for infections caused by S. aureus) or anti-inflammatory agents (for diseases exacerbated by S. aureus) can be considered, ultimately optimizing the timeliness and / or dosage of treatment (Dickey SW, et al. (2017) Nat Rev Drug Discov 16(7):457-471).

[0272] In a preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the synthesis of one or more bacterial virulence factors, wherein the one or more virulence factors are selected from the group consisting of one or more of toxins (e.g., α, β, γ, γ-mutant, and δ-hemolysin, PSMs (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B), exfoliative toxins), proteases (e.g., serine proteases, metalloproteases, and cysteine proteases), nucleases, lipases, coagulase, hyaluronidase, clumping factors, pyrogenic toxin superantigens (e.g., TSST-1), and combinations thereof. Thus, in a further preferred embodiment of the method of the present invention, the one toxin is selected from α, β, γ, γ-mutant, and δ-hemolysin. In a further preferred embodiment of the method of the present invention, the PSM is PSMα. In a further preferred embodiment of the method of the present invention, the enterotoxin is enterotoxin B or exfoliative toxin. In a further preferred embodiment of the method of the present invention, the protease is selected from serine proteases, metalloproteases and cysteine proteases. In a further preferred embodiment of the method of the present invention, the pyrogenic toxin superantigen is TSST-1. In a further preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the synthesis of one or more bacterial virulence factors, wherein the one or more virulence factors are selected from the group consisting of α, β, γ, γ-mutant, and δ-hemolysin, PSMα, Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxin B, exfoliative toxin, serine proteases, metalloproteases, cysteine proteases, nucleases, lipases, coagulase, hyaluronidase, clumping factor, TSST-1, and any combination of one or more of any specific virulence factor or general group of virulence factors. In a further highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of PSMα, RNAIII, and / or any of their downstream targets.In an even more highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of PSMα. In an even more highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of RNAIII. In an even more highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of a downstream target of RNAIII. In an even more highly preferred embodiment, the method further comprises administering an antibiotic or anti-inflammatory agent to the subject, preferably the human. In an even more highly preferred embodiment, the method further comprises administering an antibiotic to the subject, preferably the human. In an even more highly preferred embodiment, the method further comprises administering an anti-inflammatory agent to the subject, preferably the human.

[0273] In a further aspect, the present invention provides a method for preventing or treating a disease in a subject, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, preferably the bacterium is selected from the genera Staphylococcus, Streptococcus, or Clostridium, more preferably a Staphylococcus, and even more preferably the bacterium is Staphylococcus aureus, the method comprising administering to a subject in need of such prevention or treatment an effective amount of a compound of formula (I), pharmaceutical composition, or combination product, preferably a compound of formula (I). In a further highly preferred embodiment, the disease is an infectious or inflammatory disease. In a further highly preferred embodiment, the disease is an infection. In a further highly preferred embodiment, the disease is a bacterial infection. In a further highly preferred embodiment, the disease is an inflammatory skin disease caused or exacerbated by a bacterium. Preferably, the infection, preferably the bacterial infection, is caused by a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. In a further highly preferred embodiment, the infection, preferably the bacterial infection, comprises an antibiotic-resistant Staphylococcus infection, preferably the antibiotic-resistant Staphylococcus infection comprises a methicillin-resistant Staphylococcus aureus infection.

[0274] Thus, the compounds of formula (I) described herein or compositions of the invention comprising compounds of formula (I), preferably pharmaceutical compositions of the invention, can be administered to a subject to inhibit the activity of AgrA, thereby preventing the production of virulence factors that aid in the development of bacterial infections or disease states or disorders associated with bacterial infections. Examples of diseases and disorders associated with bacterial infections that are responsive to treatment with the compounds and / or compositions of the invention can include, but are not limited to, skin and soft tissue infections, pulmonary infections, or chronic inflammatory skin diseases, such as atopic dermatitis or Netherton syndrome.

[0275] In a further aspect, the present invention provides a method of inhibiting quorum sensing, preferably AgrA quorum sensing, in a bacterium, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, which comprises administering to a subject an effective amount of a compound of formula (I), pharmaceutical composition or combination product, preferably a compound of formula (I).

[0276] In a further preferred embodiment of the present invention, the compound of formula (I) is provided in a topical composition together with a pharmaceutically acceptable carrier and topically administered to a subject, preferably the subject has a disease or disorder associated with bacterial infection, and the bacterial infection is an infection caused or exacerbated by a bacterium, preferably Staphylococcus aureus. In a further preferred embodiment, the infection caused or exacerbated by a bacterium is SSTI, Netherton syndrome or atopic dermatitis. In a further preferred embodiment, the bacterial infection is SSTI, Netherton syndrome or atopic dermatitis.

[0277] Therefore, the compounds of formula (I) of the present invention, or compositions of the present invention, or combination products of the present invention, preferably the compounds of formula (I) of the present invention or pharmaceutical compositions of the present invention comprising the compounds of formula (I) of the present invention, can be used to prevent or treat infection in a subject with any bacterial species that utilizes an AgrA response regulator for quorum sensing and virulence factor production. The compounds and compositions of the present invention are typically and preferably administered to subjects who have or are at risk of having an infection, preferably a bacterial infection such as a Staphylococcus infection and / or a Streptococcus infection. For example, subjects who can benefit from treatment with the compounds or compositions of the present invention described herein may be hospital patients at risk of developing a hospital-acquired infection, or subjects who are known to be infected with or have been exposed to antibiotic-resistant bacteria, such as methicillin-resistant S. aureus, vancomycin-intermediate-sensible S. aureus, and vancomycin-resistant S. aureus. Methods for detecting the presence of a Staphylococcus bacterial infection are well known and can, for example, be used to culture a sample from a subject, such as a blood culture.

[0278] In a further aspect, the present invention provides a method of treating a subject suffering from an infection or an inflammatory disease caused by a bacterium of the genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, preferably a bacterial infection or an inflammatory skin disease, the method comprising administering to the subject a compound of formula (I) according to the present invention and at least one antibiotic active against a bacterium, preferably a bacterium of the genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus.

[0279] In a further aspect, the present invention provides a method of preventing or treating a bacterial infection in a subject, the method comprising the step of administering to said subject in need of such prevention or treatment an effective amount of a compound of formula (I) according to the present invention. Preferably, the bacterial infection is caused by a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus.

[0280] In a further aspect, the present invention provides a method for preventing or treating a disease caused or exacerbated by Gram-positive quorum-sensing bacteria, comprising administering to a subject in need of such prevention or treatment an effective amount of a compound of formula (I) according to the present invention.

[0281] In one aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient.

[0282] In one aspect, the present disclosure provides a compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound according to formula (I), for use as a medicament.

[0283] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method of reducing the virulence of a bacterium, preferably wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably wherein the bacterium expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacterium expresses AgrA.

[0284] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method of inhibiting quorum sensing in a bacterium, preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA or an orthologue of AgrA, still more preferably the bacterium expresses AgrA.

[0285] In one aspect, the invention provides a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, for use in a method for preventing or treating a disease caused or exacerbated by a bacterium in a subject, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0286] In some embodiments, the present invention provides the use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in a method of reducing the virulence of bacteria, preferably in a subject in need thereof, wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA, or an ortholog of AgrA, and even more preferably the bacterium expresses AgrA.

[0287] In some embodiments, the present invention provides the use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in a method of inhibiting quorum sensing in a bacterium, preferably in a subject in need thereof, wherein preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA or an ortholog of AgrA, and even more preferably the bacterium expresses AgrA.

[0288] In some embodiments, the present invention provides use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in a method of preventing or treating a disease caused or exacerbated by a bacterium, preferably in a subject in need thereof, wherein preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the disease is a skin disease or a lung disease, and more preferably the skin disease is atopic dermatitis, Netherton syndrome, or psoriasis.

[0289] In some embodiments, the present invention provides the use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in the manufacture of a medicament for reducing the virulence of a bacterium, preferably in a subject in need thereof, wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA, or an ortholog of AgrA, and even more preferably the bacterium expresses AgrA.

[0290] In some embodiments, the present invention provides the use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in the manufacture of a medicament for inhibiting quorum sensing in a bacterium, preferably in a subject in need thereof, wherein preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the bacterium expresses AgrA or an ortholog of AgrA, and even more preferably the bacterium expresses AgrA.

[0291] In some embodiments, the present invention provides use of a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein, in the manufacture of a medicament for preventing or treating a disease caused or exacerbated by a bacterium, preferably in a subject in need thereof, wherein preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the disease is a skin disease or a lung disease, and more preferably the skin disease is atopic dermatitis, Netherton syndrome, or psoriasis.

[0292] In some embodiments, the present invention provides a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the invention as described herein or a composition of the invention as described herein, preferably wherein the pathogenicity of the bacteria is reduced, preferably wherein the bacteria is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably wherein the bacteria expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacteria expresses AgrA.

[0293] In some embodiments, the present invention provides a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the invention as described herein or a composition of the invention as described herein, preferably wherein quorum sensing of the bacteria is inhibited, preferably wherein the bacteria is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably of Staphylococcus, and even more preferably Staphylococcus aureus, and preferably wherein the bacteria expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacteria expresses AgrA.

[0294] In some embodiments, the present invention provides a method of treating a disease caused or exacerbated by a bacterial infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the present invention as described herein or a composition of the present invention as described herein, preferably the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably the disease is a skin disease or a lung disease, and more preferably the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0295] In some embodiments, the invention provides a method of reducing the pathogenicity of bacteria, preferably wherein the bacteria is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, preferably wherein the bacteria expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacteria expresses AgrA, comprising exposing the bacteria to a compound of the invention described herein or a pharmaceutical composition comprising a compound of the invention described herein.

[0296] In some embodiments, the present invention provides a method of inhibiting quorum sensing in bacteria, preferably wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or an ortholog of AgrA, and even more preferably wherein the bacterium expresses AgrA, comprising exposing the bacterium to a compound of the invention described herein or a pharmaceutical composition comprising a compound of the invention described herein.

[0297] In some embodiments, the present invention provides a method of preventing or treating a disease caused or exacerbated by a bacterium, preferably wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, and preferably wherein the disease is a skin disease or a lung disease, and even more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome, or psoriasis, comprising exposing the bacterium to a compound of the invention as described herein, or a pharmaceutical composition comprising a compound of the invention as described herein.

[0298] The compound of the present invention of formula (I), pharmaceutical compositions containing it, or combination products can be administered to any subject who can experience the beneficial effects of the compound, composition, or product of the present invention described herein.Preferably, the subject is human.The compound of the present invention described herein, compositions containing it, or products can be administered by any means that achieves their intended purpose.For example, administration can be local or systemic, for example, administration can be parenteral, topical, local, subcutaneous, oral, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, buccal, oral mucosal, or ocular, or by inhalation.

[0299] equivalent While the present technology has been described in conjunction with the specific embodiments outlined above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present invention.

[0300] example The present invention will now be described by the following non-limiting examples. Specific embodiments of the present invention are described below, but those skilled in the art will understand that various changes and modifications can be made. References to preparations made in the same way as, or by common methods for, other preparations may include variations in routine parameters, such as slight changes in time, temperature, work-up conditions, reagent amounts, etc.

[0301] Abbreviation The following list provides definitions of certain abbreviations and symbols used herein. It will be understood that the list is not exhaustive, but that the meaning of abbreviations and symbols not defined below will be readily apparent to one of ordinary skill in the art. In describing this invention, elements are identified according to the Periodic Table of the Elements. [Table 2]

[0302] HPLC-MS Unless otherwise specified, the purity and identity of intermediates or example compounds were assessed by state-of-the-art HPLC-MS as described below. HPLC-MS analysis was performed using a Waters Alliance Micromass ZQ 2000 LC-MS system equipped with a Waters 2747 sample manager, a Waters 2695 separation module, a Waters 2996 photodiode array detector (200-800 nm), and a Waters Micromass ZQ2000 detector (scan 100-800 nm). An XBridge C18 column (3.5 μm particle size, 50 × 4.6 mm) was used for HPLC analysis. The injection volume was 20 μL. A mixture of water and acetonitrile was used as the mobile phase for gradient elution. The pH of the mobile phase was adjusted with HCOOH and NH4OH to form a pH 3.8 buffer solution. The analysis time was 5 min (Method A1) or 10 min (Method A2) using a gradient starting from 100% aqueous buffer pH = 3.8 ± 0.3 (NH4OH 0.01%, HCOOH 0.02%) to 100% acetonitrile buffer (NH4OH 0.01%, HCOOH 0.02%). · Within 3.25 minutes at a flow rate of 2 mL / min (5-minute run; Method A1). within 6.5 minutes at a flow rate of 2 mL / min (10-minute run; Method A2).

[0303] Preparation Example 1: 8-Bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one (Intermediate I-1) [ka] To an ice-cooled suspension of 2,4-dimethylbenzenethiol (9.8 ml, 72.46 mmol) and potassium carbonate (20 g, 144.7 mmol) in anhydrous DMF (200 ml) was added 2-bromoacetonitrile (76.09 mmol). The reaction mixture was stirred (on ice) for 1.5 hours. Water (350 ml) was then added, and the product was extracted with EtO (3 × 100 ml). The organic layers were combined, washed with brine (3 × 80 ml), dried over MgSO, filtered, and evaporated to give the intermediate 2-(2,4-dimethylphenyl)-sulfanylacetonitrile as a colorless oil (99.8% yield, >99% purity by HPLC).

[0304] The previous intermediate was solubilized in DCM (250 ml) and cooled using an ice bath. mCPBA (<77%, 33 g, 147.2 mmol) was then added in portions. The reaction mixture was stirred on ice for 40 minutes and left at room temperature overnight. The reaction mixture was then diluted with DCM (250 ml) and washed with 5% aqueous NaSO (2 × 100 ml) and concentrated aqueous NaHCO (8 × 200 ml). The combined aqueous phase was extracted with DCM (2 × 100 ml). The organic phases were combined, dried over MgSO, filtered, and evaporated to give 2-(2,4-dimethylphenyl)-sulfonylacetonitrile as a white powder (92.1% yield, 98% purity by HPLC).

[0305] To a cooled (4 °C) solution of methyl 2-amino-4-bromobenzoate (7 g, 30.4 mmol) in anhydrous acetonitrile under an Ar atmosphere, tert-butylnitrile (1.5 equiv.) was added dropwise. After stirring for 20 min, azidotrimethylsilane (1.2 equiv.) was added dropwise (exothermic reaction—keep the reaction below 15 °C). After the addition was complete, the reaction mixture was stirred in an ice bath for 40 min, then allowed to reach room temperature and stirred for an additional 2 h. Concentrated aqueous NaHCO3 (500 ml) was added to the reaction mixture, giving a suspension, which was extracted with EtOAc (3 × 200 ml). The combined organic layers were washed with brine (200 ml), dried over MgSO4, filtered, and evaporated to give methyl 2-azido-4-bromobenzoate as an orange oil (97% yield, 99% purity by HPLC).

[0306] To an ice-cold solution of 2-(2,4-dimethylphenyl)-sulfonylacetonitrile (11.67 g, 54.65 mmol) in anhydrous EtOH (560 mL) was added dropwise a freshly prepared solution of sodium ethoxide in EtOH (15%, 117 mmol). After 30 min, a solution of methyl 2-azido-4-bromobenzoate (54.13 mmol) in anhydrous EtOH (225 mL) was added dropwise. The resulting mixture was stirred on ice for 1 h and then at room temperature for 1.5 h, and then concentrated in vacuo. The pH was adjusted to 3.1 with aqueous hydrochloric acid (2 M). The precipitate was filtered off. The solid was washed with water (3 × 400 mL) and dried under vacuum. The crude product was triturated several times with cold EtOAc and EtO and dried overnight to give the title intermediate I-1 as a beige solid (86.6% yield, 99.1% purity by HPLC).

[0307] Preparation Example 2: 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazin-1-yl]acetic acid (Intermediate II-1) [ka] Intermediate II-1 was prepared in at least two ways from intermediate I-1 according to the following general scheme: [ka]

[0308] Route A: A 100 ml round-bottom flask was charged with intermediate I-1 (600 mg, 1.38 mmol), tert-butyl piperazine-1-carboxylate (516 mg, 2.77 mmol, 2 equiv.), Pd2dba3 (39.8 mg, 5 mol%), Cs2CO3 (677 mg, 2.08 mmol, 1.5 equiv.), RuPhos (64.6 mg, 0.138 mmol, 10 mol%), and DMF (40 ml). The mixture was degassed with an Ar flush and then stirred at 120 °C in a preheated heating block equipped with a reflux condenser for 3 h. After this time, the mixture was cooled to room temperature, diluted with MeOH, filtered through Celite, and evaporated to dryness. The crude product was purified by flash chromatography with EtOAc-MeOH (100-0 to 95-5) to give 750 mg of a brownish solid, which was triturated with EtO to give 514 mg of tert-butyl 4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazine-1-carboxylate as a beige solid (68% yield, 99% purity by HPLC, Method A1). MS (ES+) m / z 539.

[0309] To a solution of tert-butyl 4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazine-1-carboxylate (500 mg, 0.928 mmol) in 20 mL of dioxane was added 4 M HCl in dioxane (3.45 mL, 15 equiv.), and the mixture was stirred at 80 °C overnight. The precipitate was filtered and triturated with EtO to give 410 mg of 3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one as a beige solid (93% yield, 100% purity by HPLC, Method A1). MS (ES+) m / z 439.

[0310] Intermediate II-1 was then prepared in two additional steps starting from the previous compound (3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one) and methyl bromoacetate in the presence of sodium bicarbonate in acetone, followed by saponification of the ester in the presence of lithium hydroxide as described in Route B below.

[0311] Alternatively, intermediate II-1 was prepared in two additional steps starting from (3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one) and methyl bromoacetate (3.0 equiv.) in the presence of potassium carbonate in DMSO. The mixture was stirred at 120 °C overnight and then cooled to room temperature. DMSO was removed by lyophilization, and the crude product was purified by flash chromatography using ethyl acetate / MeOH (100 to 80:20) to give a beige solid. Subsequent saponification of the ester in the presence of lithium hydroxide was carried out as described in Route B below.

[0312] Route B: A solution of methyl 2-piperazin-1-yl acetate dihydrochloride (80 mg, 0.35 mmol, 1 equiv.) and Cs2CO3 (395 mg, 1.21 mmol, 3.5 equiv.) in anhydrous DMF (9 mL) was stirred for 2 h in a sealed vial. Then, tris(dibenzylideneacetone)dipalladium(0) (9.95 mg, 5 mol%), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (16.2 mg, 10 mol%), and I-1 (150 mg, 0.35 mmol) were added to the vial, which was then flushed with Ar. The vial was then sealed and stirred in a preheated heating block. After 4 h, the mixture was cooled to room temperature and filtered through Celite. The Celite pad was washed with MeOH. The solution was then concentrated to dryness, and the residue was purified by flash chromatography using ethyl acetate / MeOH (100 to 80-20) to give a beige solid (137 mg, 73.9% yield, 95.3% purity by HPLC, LC tR = 2.01 min, MS (ESI + ): m / z=511 [M+H] + ,MS(ESI - ): m / z=509 [M+H] - ).

[0313] In a round-bottom flask, methyl 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazin-1-yl]acetate (159 mg, 0.311 mmol) was dissolved in a solution of THF-HO (50:50, 50 ml), and then LiOH monohydrate (52.3 mg, 1.25 mmol, 4 equiv.) was added. The mixture was stirred at 0°C for 2 hours and then at room temperature overnight. After this time, the THF was removed under reduced pressure, and the mixture was then brought to 0°C and HCl 1N was added dropwise until precipitation. The crude solid was filtered, washed with cold EtOH, and then dried under vacuum overnight. 140 mg of a white solid was obtained, yield 90%.

[0314] Alternatively, the crude solid was filtered, triturated with CHCl3, and then dried under vacuum overnight. Obtained 148 mg of a white solid, yield 95%, purity by HPLC: 100%, LC T R = 1.60 min, MS(ESI + ): m / z=497.2 [M+H] + ,MS(ESI - ): m / z=495.2 [M+H] - .

[0315] Intermediates II-2 to II-11 were prepared following the same procedure as described for intermediate II-1 starting from the corresponding starting materials. [Table 3-1] [Table 3-2] [Table 3-3]

[0316] General reaction conditions for amide formation (using II-1 as an example). [ka] A suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 equiv.) in anhydrous DMF (1 M) and DCM (0.5 M) was treated with intermediate II-1, followed by 1-hydroxybenzotriazole hydrate (1.1 equiv.). After the suspension clarified, the appropriate amine R 81 R 82 A solution of NH (1.5 equiv.) in dichloromethane (2.5 M) was added. The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to remove DMF. If necessary, the residue was purified by chromatography in an appropriate eluent to give the desired product as a solid or tested without further workup.

[0317] Alternatively, a solution of 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazin-1-yl]acetic acid (Intermediate II-1, 2.5 mg, 0.005 mmol) in NMP (0.75 mL) was added to a matrix tube containing TMP (0.004 mL, 0.025 mmol, 5 equiv.) and T3P (0.003 mL, 0.05 mmol, 1 equiv.). After 1 h, the appropriate amine R 81 R 82 NH (0.005 mmol, 1 eq.) and T3P (0.003 mL, 0.005 mmol, 1 eq.) were added to the mixture, which was stirred at room temperature for 16 hours (using a BioShake IQ at 1800 rpm). The crude product was then concentrated to dryness (using a Genevac EZ-2 Plus, medium boiling point, 65°C, 7 hours). The compound was tested without further purification. Alternative methods of acid activation known in the art can also be used.

[0318] General reaction conditions for -Boc protecting group removal Amine R 81 R 82 In cases where the NH contains an additional nitrogen protected by a -Boc group, the following general procedure was used to generate the free amine: A 50 ml flask was charged with a solution of the Boc-protected derivative (1 equivalent) in anhydrous dioxane (0.35 M), then a solution of HCl 4N in dioxane (15 equivalents) was added dropwise and the mixture was stirred at 80° C. Heating was stopped when the reaction was judged complete by LC-MS, and the precipitate was then filtered and triturated in EtO to give the desired product.

[0319] Alternatively, TFA was used: a 50 ml flask was charged with a solution of the Boc-protected derivative (1 equiv.) in anhydrous DCM (1.7 M), then TFA (15 equiv.) was added dropwise and the mixture was stirred at 40° C. Heating was stopped when the reaction was judged complete by LC-MS, and the mixture was then concentrated under reduced pressure and triturated in EtO to give the desired product.

[0320] Alternatively, the matrix tube charged with the Boc-protected derivative was dissolved in anhydrous DCM (0.02 M), then TFA (250 equiv.) was added dropwise and the mixture was stirred at 40° C. (using a BioShake IQ at 1800 rpm). Heating was stopped when the reaction was judged complete by LC-MS, and the mixture was then concentrated to dryness (using a Genevac EZ-2 Plus, medium boiling point, 65° C., 7 h) and left under vacuum for 4 days to give the desired product.

[0321] Alternatively, the matrix tube loaded with the Boc-protected derivative was dissolved in NMP (0.02 M), then aqueous HCl (37%) was added dropwise, and the mixture was stirred at 80° C. Heating was stopped when the reaction was judged complete by LC-MS, and the mixture was then concentrated to dryness (using a Genevac EZ-2 Plus, medium boiling point, 65° C., 7 h) and placed under vacuum for 4 days to give the desired product.

[0322] Example 1: 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 1) [ka] Following the general protocol for amide formation from intermediate II-1 above using pyrrolidine as the amine partner, compound 1 was obtained. The title product was isolated as a beige solid (100% pure by HPLC, Method A2); or A round-bottom flask was charged with intermediate I-1 (30 mg, 0.0692 mmol, 1 equiv.), 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (27.3 mg, 0.138 mmol, 2 equiv.), Pd2dba3 (2 mg, 0.00346 mmol, 5 mol%), Cs2CO3 (34 mg, 0.104 mmol, 1.5 equiv.), and RuPhos (3.23 mg, 0.00692 mmol, 10 mol%), followed by the addition of DMF (0.035 M). The mixture was degassed by Ar flush and then stirred overnight at 120 °C in a preheated heating block equipped with a reflux condenser. After this time, the mixture was cooled to room temperature, diluted with MeOH, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 100% DCM to DCM-MeOH (95-5) to give 13 mg of the title product as a beige solid (34% yield, 100% purity by HPLC, Method A2). LC T R =1.87, [ES+MS] m / z 550.3 (MH+).

[0323] Example 2: 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-morpholino-2-oxo-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 2) [ka] Compound 2 was obtained following the same procedure as described for compound 1, starting from 2-morpholino-1-piperazin-1-yl-ethanone. The title product was isolated as a white solid (100% purity by HPLC, Method A2). LC T R =1.82, [ES+MS] m / z 566.2 (MH+)

[0324] Compounds 3-175 of the present invention were prepared from the corresponding intermediates shown in Table 2 below, following the appropriate general protocol described above. [Table 4-1]

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

[0325] Example 3: AgrA reporter assay A plasmid expressing the reporter gene lacZ under the control of the AgrA-regulated P3 promoter was transformed into S. aureus USA300 strain UAMS-1625. The resulting reporter strain was used to measure AgrA inhibitory activity as follows: Cells from an overnight culture plate were resuspended in 0.9% (w / v) saline, and a bacterial inoculum was added at 5 × 10 5 CFU / ml were prepared in LB medium. Compounds were serially diluted 2-fold in LB, and 50 μL of this 10-fold concentrated sample was added to a 96-deep-well plate. 500 μL of bacterial suspension was finally added to the compound or DMSO control. The plate was covered and incubated with shaking at 37°C. After 18 hours of incubation, 100 μL was transferred to a new clear 96-well plate, and OD was measured using a TECAN Infinite F200 microplate reader to control for growth inhibition. 600An additional 100 μL was transferred to a new black 96-well plate containing 30 μL of lysis buffer (20 mM Tris / HCl, 3 mM MgCl2, 0.5% Tween 20 (v / v), 0.5% NP-40 (v / v)), and the plate was incubated at 37°C for 60 minutes with shaking. 20 μL of the substrate MUG (4-methylumbelliferyl β-D-galactopyranoside) was added at 0.25 mg / ml, and after 3 hours of incubation at 37°C with shaking, fluorescence (excitation: 360 nm, emission: 450 nm) was measured using a TECAN Infinite F200 microplate reader. After normalization to DMSO controls, IC values were calculated using GraphPad PRISM. 50 It was decided that:

[0326] IC in the presence of human serum albumin (HSA, 40 mg / mL) by supplementing the LB medium used for the preparation of the inoculum. 50 It was decided that:

[0327] The activity of compounds of the invention in the absence and presence of human serum albumin is shown below in Table 3. Corresponding data for compound 45 of WO 2020 / 109350 under the same conditions is also shown. [ka] Compound 45 of WO 2020 / 109350 [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

Table 5-5

Claims

1. Compounds of formula (I) or their pharmaceutically acceptable salts, hydrates, or tautomers: 【Chemistry 1】 (In the formula, R １ However, -H, halogen, -C １ -C ６ Alkyl and -C １ -C ６ Independently selected from alkoxys, the alkyl and alkoxys are one or more R １１ They may be substituted by each other, R ３ is independently selected from -H, halogen, C １ -C ６ alkyl, -C １ -C ６ alkoxy, and -C ３ -C ６ cycloalkyl, and the alkyl, alkoxy and cycloalkyl may each be substituted by one or more R １１ s, R ８Ａ and R ８Ｂ However, each independently, at each occurrence, either -H or -CH ３ And, R ８１ and R ８２ However, each independently, when it appears, -H and -C １ -C ６ Alkyl, -C ３ -C ８ Cycloalkyl, -C １ -C ６ Alkylene-(C) ３ -C ８ Cycloalkyl), 4-8 member heterocycloalkyl, -C １ -C ６ Alkylene-(4-8 member heterocycloalkyl), -C ６ -C １０ Ariel, -C １ -C ６ Alkylene-(C) ６ -C １０ aryls), 5-10 member heteroaryls, and -C １ -C ６ Selected from alkylene-(5-10 membered heteroaryl), wherein the alkyl group has one or more -C ２ -C ６ Alkynyl, halogen, -OH, -(OCH) ２ -CH ２ ) １－２ -OH, -C １ -C ６ Alkoxy, -N(R ８３ ) (Caution ８４ ), or -S (C １ -C ６ The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be substituted with one or more R ８５ Each of these may be substituted independently, R ８３ and R ８４ However, independently, at each occurrence, -H and -C １ -C ６ Selected from alkyl groups, R ８５ However, independently, at each occurrence, -C １ -C ６ Alkyl, halogen, -OH, -N(R) ８３ ) (Caution ８４ ), -C １ -C ６ Alkoxy, -C ６ -C １０ Selected from aryl and oxo, or R ８１ and R ８２ However, together with the nitrogen atoms to which they are bonded, they form a 4- to 11-membered heterocycloalkyl group, and the 4- to 11-membered heterocycloalkyl group contains one or more R ８６ It may also be replaced by, R ８６ However, independently, at each occurrence, -C １ -C ６ Alkyl, halogen, -OH, -C １ -C ６ Alkylene-OH,-N(R) ８３ ) (Caution ８４ ), -C １ -C ６ Alkylene-N(R) ８３ ) (Caution ８４ ), -C ３ -C ６ Selected from cycloalkyl and oxo, R １１ However, independently, each occurrence is either a halogen or -OH. m is independently 1 or 2, n is either 0 or 1 independently.

2. R １ ga-CH ３ The compound according to claim 1.

3. R ３ ga-CH ３ The compound according to claim 1.

4. R ８Ａ and R ８Ｂ The compound according to claim 1, wherein all of them are -H.

5. The compound according to claim 1, wherein n is 0 and m is 1.

6. R ８１ and R ８２ are each independently, at each occurrence, -H, and -C １ -C ６ selected from alkyl, wherein said alkyl is one or more -C ２ -C ６ alkynyl, halogen, -OH, -(OCH ２ -CH ２ ) １－２ -OH, -C １ -C ６ alkoxy, -N(R ８３ )(R ８４ ), or -S(C １ -C ６ alkyl) and may be substituted, the compound according to claim 1.

7. R ８１ However, -C ３ -C ８ Cycloalkyl and -C １ -C ６ Alkylene-(C) ３ -C ８ The compound according to claim 1, selected from cycloalkyl.

8. R ８１ However, 4-8 member heterocycloalkyls, and -C １ -C ６ The compound according to claim 1, selected from alkylene-(4-8 membered heterocycloalkyl).

9. R ８１ However, -C ６ -C １０ Aryl, and -C １ -C ６ Alkylene-(C) ６ -C １０ The compound according to claim 1, selected from aryl.

10. R ８１ However, 5-10 member heteroaryls, and -C １ -C ６ The compound according to claim 1, selected from alkylene-(5-10 membered heteroaryl).

11. R ８２ However, -H, or C １ -C ６ It is alkyl, preferably R ８２ However, -H, or C １ -C ２ It is alkyl, and more preferably R ８２ The compound according to claim 1, wherein is H.

12. R ８１ and R ８２ However, together with the nitrogen atoms to which they are bonded, they form a 4- to 11-membered heterocycloalkyl group, and the 4- to 11-membered heterocycloalkyl group contains one or more R ８６ The compound according to claim 1, which may be substituted by

13. The compound according to claim 1, selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 14, for use as a pharmaceutical, preferably for use in a method of preventing or treating a target disease, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by bacteria, wherein the bacteria is preferably selected from the genera Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and more preferably Staphylococcus aureus.

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