8-Heterocyclic-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5A]quinazolin-5(4H)-one derivatives as antibacterial agents

Abstract

The present invention relates to 8-heterocyclic-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, as well as their use in methods for reducing the virulence of bacteria (preferably Staphylococcus aureus) expressing accessory gene regulator A (AgrA) or an ortholog of AgrA, their use in methods for inhibiting quorum sensing in bacteria, preferably Staphylococcus aureus, and their use in methods for preventing or treating diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus, such as skin or lung infections, atopic dermatitis, Netherton syndrome, or psoriasis in a subject. The compounds have demonstrated excellent ability to inhibit transcription of genes under the control of the P3 promoter in S. aureus, even in the presence of human serum or human serum albumin.

Description

[Technical Field]

[0001] The present invention relates to 8-heterocycle-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, and their use in a method for reducing the virulence of bacteria (preferably Staphylococcus aureus) expressing accessory gene regulator A (AgrA), or an orthologue 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 a disease caused or exacerbated by bacteria, preferably S. aureus, such as a skin or lung infection, atopic dermatitis, Netherton syndrome, 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 causing 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] In a study of acute bacterial infections of the skin and soft tissue caused by Staphylococcus aureus (S. aureus), screening 24,087 compounds selected for inhibition of cyclic thiolactone peptide pheromone (AIP)-induced agrA, 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 agr 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 for preventing or treating bacterial infections and / or diseases caused or exacerbated by bacteria, preferably Staphylococcus aureus (S. aureus), such as 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 systemically (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. In the presence of the compounds of the present invention, production of the lacZ gene product (i.e., β-galactosidase) was found to be inhibited. Surprisingly, the compounds of the present invention retained AgrA inhibitory activity even when assayed in the presence of HS or HSA.

[0010] Thus, in the presence of HS or HSA, the compounds of the present invention can inhibit the transcription of genes (preferably virulence factors) under the control of the P3 promoter (e.g., in bacteria, preferably in Staphylococcus aureus (S. aureus)). This activity strongly suggests that the compounds of the present invention can be administered systemically (e.g., orally or parenterally) to biologically important systems (e.g., 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 disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, 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, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82, C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R 81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH; R 86 -H, -COOH, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87 are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11is independently at each occurrence a halogen, or —OH).

[0012] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, 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, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R 81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, or -OH; R 86 -H, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87 are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11 is independently at each occurrence a halogen, or —OH).

[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 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.

[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 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.

[0015] 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.

[0016] 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.

[0017] 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. [Brief explanation of the drawings]

[0018] [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

[0019] The present invention relates to compounds and pharmaceutical compositions comprising same that are capable of inhibiting transcription of genes under the control of the P3 promoter (e.g., in bacteria, preferably in S. aureus), even in the presence of HS or HSA.

[0020] 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.

[0021] 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.

[0022] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0023] 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.

[0024] 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.

[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] Unless otherwise specifically defined, "heteroaryl" refers to a monovalent monocyclic aromatic radical of 5 to 6 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. The heteroaryl group can be fused to a partially saturated heterocycle, as in, for example, compound 54. Additional exemplary ring systems of such heterocycle-aryl or heterocycle-heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine, and dihydrobenzoxanyl.

[0027] 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. Heterocyclyl or heterocycloalkyl rings can be bridged, as shown, for example, in compound 50.

[0028] As shown in compounds 3 to 21, Y 3 is CR 84 R 85 If R 8 forms a spirocyclic heterocycle with the ring of formula (A). As used herein, spirocyclic heterocycle or spiroheterocycle is understood to mean a bicyclic ring system in which both rings are connected through 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).

[0029] As used herein, the term "halo" or "halogen" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0030] 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.

[0031] 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, ...

[0032] The term "tautomer" refers to a series of compounds having the same number and type of atoms but differing in connectivity and in equilibrium with one another. 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.

[0033] 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.

[0034] 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.

[0035] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0036] 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.

[0037] 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.

[0038] The terms "reduce" and "inhibit" have the commonly understood meaning of lowering or decreasing.

[0039] 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.

[0040] 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.

[0041] 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 formula (I) described herein or the compositions of the present invention comprising the compounds of formula (I), preferably the pharmaceutical compositions of the present invention, include one or more of 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, and pyrogenic toxin superantigens (e.g., TSST-1). In a preferred embodiment, the virulence factor inhibited is RNAIII and / or its downstream targets, or PSMα.

[0042] 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).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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 the disease."

[0049] 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.

[0050] Compounds of the Invention In a first aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof: [ka] (In the formula, R 1are 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, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH; R 86 -H, -COOH, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11 is independently at each occurrence a halogen, or —OH).

[0051] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, 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 3are independently selected from -H, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; However, Y 1 is CR 81 R 82 and Y 2 is CR 81A R 82A and Y 3 CHR 86 and R 81 , R 82 , R 81A , R 82A and R 86 are each -H, then the sum of m and n is 4, 5, or 6; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R 81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH; R 86 -H, -COOH, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11 is independently at each occurrence a halogen, or —OH).

[0052] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, 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 3are independently selected from -H, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R 81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH; R 86 is -COOH or -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11 is independently at each occurrence a halogen, or —OH).

[0053] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, 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 3are independently selected from -H, -C1-C6 alkyl, and -C1-C6 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be replaced by R 7 is independently selected from -H, and -OH; R 8 is a group of formula (A): [ka] In the formula, n is independently an integer of 0 to 3, m is independently an integer from 0 to 3; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O; Y 2 independently, at each occurrence, 81A R 82A and O, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 or O, then the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 81 and R 81A can combine with the carbon atoms to which they are attached to form a bridged ethylene, R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C7 cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, or -OH; R 86 -H, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, R 87are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively; R 11 is independently at each occurrence a halogen, or —OH).

[0054] 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:

[0055] 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 optionally substituted with one or more F, Cl, and -OH, respectively.

[0056] In some embodiments, R 1 are independently selected from -H, -F, -C1-C2 alkyl, and -C1-C2 alkoxy, wherein the alkyl and alkoxy are optionally substituted with one or more -F, and -OH, respectively.

[0057] In some embodiments, R 1 are independently selected from -H, -F, and -C1-C2 alkyl, wherein the alkyl is optionally substituted with one or more -F, and -OH, respectively.

[0058] In some embodiments, R 1 are independently selected from -H, -F, and -C1-C2 alkyl.

[0059] In some embodiments, R 1 is independently selected from -H, and -C1-C2 alkyl.

[0060] In some embodiments, R 1 is -CH3.

[0061] In some embodiments, R 3 are independently selected from -H, -C1-C4 alkyl, and -C1-C4 alkoxy, wherein the alkyl and alkoxy are selected from one or more R 11 and each may be substituted by:

[0062] In some embodiments, R 3 is independently selected from —H, —C1-C4 alkyl, and —C1-C4 alkoxy, wherein the alkyl and alkoxy are each optionally substituted by one or more —F, —Cl, or —OH.

[0063] In some embodiments, R 3 is independently selected from -H, and -C1-C4 alkyl, wherein the alkyl is optionally substituted by one or more -F, -Cl, or -OH.

[0064] In some embodiments, R 3 is independently selected from —H, and —C1-C4 alkyl.

[0065] In some embodiments, R 3 is independently selected from -H, and -C1-C2 alkyl.

[0066] In some embodiments, R 3 is independently —C1-C2 alkyl.

[0067] In some embodiments, R 3 is —CH3. In some embodiments, R 1 and R 3 is -CH3.

[0068] In some embodiments, R 7 is —H. In some embodiments, R 7 is -OH.

[0069] In some embodiments, Y 3 is CR 84 R 85 ;CHR 86 ;NR 87 are independently selected from, and O; Y 3 is CR 84 R 85 If m and n are at least 2, then Y 3 CHR 86 , N.R. 87 , or O, then the sum of m and n is at least 3; However, Y 1 is CR 81 R 82 and Y 2 is CR 81A R 82A and Y 3 CHR 86 and R 81 , R 82 , R 81A , R 82A and R86 When each is —H, the sum of m and n is 4, 5, or 6.

[0070] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 is selected from Y 2 independently, at each occurrence, 81A R 82A is selected from Y 3 is CR 84 R 85 ;CHR 86 ; and NR 87 are independently selected from

[0071] In some embodiments, Y 3 is CR 84 R 85 is.

[0072] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH, respectively.

[0073] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, or -OH, respectively.

[0074] In some embodiments, Y 3 is CR84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, -OH, or -COOH, respectively.

[0075] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, or -OH, respectively.

[0076] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0077] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0078] In some embodiments, Y 3is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0079] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0080] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0081] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0082] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl, -OH, or -COOH, respectively, and preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3, or -OH, respectively.

[0083] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl or -OH, respectively, preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3 or -OH, respectively.

[0084] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, -OH, or -COOH, preferably each cycloalkyl, C4 heterocycle, and C6 heterocycle is each optionally substituted by one or two -CH3, or -OH.

[0085] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, or -OH, preferably each cycloalkyl, C4 heterocycle, and C6 heterocycle is each optionally substituted by one or two -CH3, or -OH.

[0086] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl, -OH, or -COOH; preferably, each of which may be substituted by one or two -CH3, or -OH.

[0087] In some embodiments, Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl or -OH, preferably each of which may be substituted by one or two -CH3 or -OH.

[0088] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH, respectively.

[0089] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, or -OH, respectively.

[0090] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, -OH, or -COOH, respectively.

[0091] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, or -OH, respectively.

[0092] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0093] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0094] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing a heteroatom selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0095] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing a heteroatom selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0096] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0097] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82Aare each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0098] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl, -OH, or -COOH, respectively, and preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3, or -OH, respectively.

[0099] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl or -OH, respectively, preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3 or -OH, respectively.

[0100] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, -OH, or -COOH, preferably the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or two -CH3, or -OH.

[0101] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, or -OH, preferably the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or two -CH3, or -OH.

[0102] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82Aare each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl, -OH, or -COOH; preferably, each of which may be substituted by one or two -CH3, or -OH.

[0103] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A independently, at each occurrence, is H and Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl or -OH, preferably each of which may be substituted by one or two -CH3 or -OH.

[0104] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH, or -COOH, respectively.

[0105] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, or -OH, respectively.

[0106] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, -OH, or -COOH, respectively.

[0107] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, or -OH, respectively.

[0108] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0109] In some embodiments, Y 1 independently, at each occurrence,81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0110] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing a heteroatom selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0111] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing a heteroatom selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0112] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, -OH, or -COOH, respectively.

[0113] In some embodiments, Y 1 independently, at each occurrence, 81 R 82or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, and the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C3 alkyl, or -OH, respectively.

[0114] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81Aindependently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl, -OH, or -COOH, respectively, and preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3, or -OH, respectively.

[0115] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82Ais independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85 together with the carbon atoms to which they are attached form a -C4-C6 cycloalkyl, or a 4- to 6-membered heterocycle, the heterocycle containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocycle optionally being substituted by one or more -C1-C2 alkyl or -OH, respectively, preferably the cycloalkyl or heterocycle optionally being substituted by one or two -CH3 or -OH, respectively.

[0116] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, -OH, or -COOH, preferably the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or two -CH3, or -OH.

[0117] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atoms to which they are attached form a -C4 cycloalkyl, -C4 heterocycle, or -C6 heterocycle, wherein the C4 heterocycle and C6 heterocycle each contain one or two heteroatoms selected from O and N, and the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or more -C1-C2 alkyl, or -OH, preferably the cycloalkyl, C4 heterocycle, and C6 heterocycle are each optionally substituted by one or two -CH3, or -OH.

[0118] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl, -OH, or -COOH; preferably, each of which may be substituted by one or two -CH3, or -OH.

[0119] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 or O, preferably Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A or O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 and R 81A independently, at each occurrence, is H and R 82 and R 82A are each independently at each occurrence H, or -C1-C3 alkyl, preferably R 82 and R 82A is independently, at each occurrence, H; m and n are each independently 0, 1, 2, or 3; the sum of m and n is 2, 3, or 4; Y 3 is CR 84 R 85 and R 84 and R 85together with the carbon atom to which they are attached form a cyclobutane, azetidine, oxetane, piperidine or morpholine, each of which may be substituted by one or more -C1-C2 alkyl or -OH, preferably each of which may be substituted by one or two -CH3 or -OH.

[0120] In some embodiments, Y 3 is CHR 86 is.

[0121] In some embodiments, Y 3 is CHR 86 and R 86 -H, -COOH, and -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocyclic ring, However, Y 1 is CR 81 R 82 and Y 2is CR 81A R 82A and Y 3 CHR 86 and R 81 , R 82 , R 81A , R 82A and R 86 When each is —H, the sum of m and n is 4, 5, or 6.

[0122] In some embodiments, Y 3 is CHR 86 and R 86 is -H or -COOH.

[0123] In some embodiments, Y 3 is CHR 86 and R 86 is H.

[0124] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH.

[0125] In some embodiments, Y 3 is CHR 86 and R 86 is H, where Y 1 is CR 81 R 82 and Y 2 is CR 81A R 82A and R 81 , R 82 , R 81A , R 82A When each is —H, the sum of m and n is 4, 5, or 6.

[0126] In some embodiments, Y 3 is CHR 86 and R 86 is H and the sum of m and n is 3 or 4.

[0127] In some embodiments, Y 3 is CHR86 and R 86 is H and the sum of m and n is 4, 5, or 6.

[0128] In some embodiments, Y 3 is CHR 86 and R 86 is H and the sum of m and n is 4.

[0129] In some embodiments, Y 3 is CHR 86 and R 86 is H and the sum of m and n is 5.

[0130] In some embodiments, Y 3 is CHR 86 and R 86 is H, and the sum of m and n is 6.

[0131] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H and the sum of m and n is 3 or 4.

[0132] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H and the sum of m and n is 4, 5, or 6.

[0133] In some embodiments, Y 1 independently, at each occurrence, 81 R 82and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H and the sum of m and n is 4.

[0134] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H and the sum of m and n is 5.

[0135] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, and the sum of m and n is 6.

[0136] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, the sum of m and n is 3 or 4, and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, preferably R 81 , R 82 , R 81A and R82A is independently H at each occurrence.

[0137] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, the sum of m and n is 4, 5, or 6, and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, preferably R 81 , R 82 , R 81A and R 82A is independently H at each occurrence.

[0138] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, the sum of m and n is 4, and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, preferably R 81 , R 82 , R 81A and R 82A is independently H at each occurrence.

[0139] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, the sum of m and n is 5, and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, preferably R 81 , R 82 , R 81A and R 82A is independently H at each occurrence.

[0140] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is H, the sum of m and n is 6, and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, preferably R 81 , R 82 , R 81A and R 82A is independently H at each occurrence.

[0141] In some embodiments, R 86 Ha-NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocycle.

[0142] In some embodiments, R 86 is -COOH or -NR 88 R 89 or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, which is optionally substituted by one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 88 Or R 89 One of them, together with the nitrogen atom to which they are attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocycle.

[0143] In some embodiments, Y3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, which is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH.

[0144] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, which is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH.

[0145] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle, which may be substituted by one or more -C1-C6 alkyl or -OH, preferably -C1-C2 alkyl or -OH.

[0146] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R81 , R 81A , R 82 or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle, which may be substituted by one or more -C1-C6 alkyl or -OH, preferably -C1-C2 alkyl or -OH.

[0147] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0148] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0149] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N.

[0150] In some embodiments, Y 3is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N.

[0151] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 heteroatoms selected from O and N.

[0152] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 heteroatoms selected from O and N.

[0153] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0154] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0155] In some embodiments, Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0156] In some embodiments, Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0157] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82Awherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, which is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH.

[0158] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, which is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH.

[0159] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle, which may be substituted by one or more -C1-C6 alkyl or -OH, preferably -C1-C2 alkyl or -OH.

[0160] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle, which may be substituted by one or more -C1-C6 alkyl or -OH, preferably -C1-C2 alkyl or -OH.

[0161] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81, R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0162] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0163] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N.

[0164] In some embodiments, Y 1 independently, at each occurrence,81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more heteroatoms selected from O and N.

[0165] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 heteroatoms selected from O and N.

[0166] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 heteroatoms selected from O and N.

[0167] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0168] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0169] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 is -COOH, or R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0170] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A wherein the sum of m and n is 2, 3 or 4, preferably the sum of m and n is 3, and Y 3 is CHR 86 and R 86 together with the carbon atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0171] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R89 is.

[0172] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 is.

[0173] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0174] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0175] In some embodiments, Y 3 is CHR 86 and R 86-COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N.

[0176] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N.

[0177] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N.

[0178] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N.

[0179] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N.

[0180] In some embodiments, Y 3 is CHR86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N.

[0181] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0182] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0183] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0184] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0185] In some embodiments, Y 3 is CHR 86and R 86 -COOH, or NR 88 R 89 wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0186] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0187] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0188] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0189] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0190] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0191] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0192] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0193] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0194] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0195] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0196] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0197] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0198] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0199] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0200] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0201] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0202] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0203] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0204] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0205] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0206] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C3 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0207] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0208] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0209] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0210] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0211] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0212] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 88 and R 89 One of the groups, together with the nitrogen atom to which it is attached, forms R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0213] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl.

[0214] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl.

[0215] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0216] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0217] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -CH3.

[0218] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -CH3.

[0219] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0220] In some embodiments, Y 3 is CHR 86 and R 86is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0221] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C2 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0222] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C2 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0223] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -CH3, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0224] In some embodiments, Y 3 is CHR 86 and R86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -CH3, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0225] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82A are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0226] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C3 alkyl, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0227] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82 are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C2 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0228] In some embodiments, Y 1 independently, at each occurrence, 81 R82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82 are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -C1-C2 alkyl; and m and n are each independently 1 or 2; preferably, m is 2 and n is 1 or 2.

[0229] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82 are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 and R 89is independently at each occurrence selected from -H, and -CH3, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0230] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 81A , R 82 and R 82 are each independently at each occurrence selected from -C1-C2 alkyl, and -H, preferably R 81 , R 81A , R 82 and R 82 are each independently, at each occurrence, H and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 and R 89 is independently at each occurrence selected from -H, and -CH3, and m and n are each independently 1 or 2, preferably m is 2 and n is 1 or 2.

[0231] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0232] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle.

[0233] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N.

[0234] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N.

[0235] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocyclic ring, the heterocyclic ring containing 1 or 2 atoms selected from O and N.

[0236] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocyclic ring, the heterocyclic ring containing 1 or 2 atoms selected from O and N.

[0237] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0238] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5-6 membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine.

[0239] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0240] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A, R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine.

[0241] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0242] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0243] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0244] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0245] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0246] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0247] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0248] In some embodiments, Y 3 is CHR86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0249] In some embodiments, Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0250] In some embodiments, Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0251] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0252] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0253] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0254] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing one or more atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0255] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0256] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81, R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle, the heterocycle containing 1 or 2 atoms selected from O and N, and m and n each independently being 1 or 2, preferably 2 and n being 1 or 2.

[0257] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0258] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached form a 5- to 6-membered heterocycle, the heterocycle being selected from piperidine, morpholine, piperazine and pyrrolidine, and m and n are each independently 1 or 2, preferably 2 and n is 1 or 2.

[0259] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 -COOH, or NR 88 R 89 and R 88 are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0260] In some embodiments, Y 1 independently, at each occurrence, 81 R 82 and Y 2 independently, at each occurrence, 81A R 82A and Y 3 is CHR 86 and R 86 is NR 88 R 89 and R 88are independently -H, or -C1-C2 alkyl, and R 89 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form pyrrolidine, wherein m and n are each independently 1 or 2, and preferably m is 2 and n is 1 or 2.

[0261] In some embodiments, Y 3 is NR 87 is.

[0262] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively.

[0263] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C6 alkyl or —OH, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, and the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl or -OH, respectively.

[0264] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C6 alkyl or —OH, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl.

[0265] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle is each optionally substituted by one or more —C1-C6 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl each contains one or more atoms selected from O and N.

[0266] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C4 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, each alkyl optionally substituted by one or more —C1-C4 alkoxy, —OH, —NH2, —NHC1-C4 alkyl, or N(C1-C4 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle each optionally substituted by one or more —C1-C4 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81, R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl contains 1 or 2 atoms selected from O and N, respectively.

[0267] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, each alkyl optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle each optionally substituted by one or more —C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0268] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle containing one or more atoms selected from O and N, each alkyl optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle optionally substituted by one or more -C1-C2 alkyl, or R87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0269] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle containing 1 or 2 atoms selected from O and N, each alkyl optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle optionally substituted by one or more -C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0270] In some embodiments, Y 3 is NR 87 and R 87are independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, wherein each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0271] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82Aand C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively.

[0272] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C6 alkyl or —OH; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82Aand C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, and the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl may be substituted by one or more -C1-C6 alkyl or -OH, respectively.

[0273] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C6 alkyl or —OH; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl.

[0274] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, each alkyl optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle is each optionally substituted by one or more —C1-C6 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C6 alkyl; or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form a 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl.

[0275] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C4 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, each alkyl optionally substituted by one or more —C1-C4 alkoxy, —OH, —NH2, —NHC1-C4 alkyl, or N(C1-C4 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle is each optionally substituted by one or more —C1-C4 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C4 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R81A , R 82 Or R 82A and the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl each contains one or more atoms selected from O and N.

[0276] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, each alkyl optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the cycloalkyl or 4- to 6-membered heterocycle is each optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heterocycle or the 5- to 6-membered heteroaryl contains 1 or 2 atoms selected from O and N, respectively.

[0277] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains one or more atoms selected from O and N, and each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82Aand the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0278] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle contains 1 or 2 atoms selected from O and N, and each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle is optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0279] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, wherein each alkyl is optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the 4- to 6-membered heterocycle is optionally substituted by one or more -C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl, or R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 Or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0280] In some embodiments, Y 3 is NR 87 and R 87together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, respectively.

[0281] In some embodiments, Y 3 is NR 87 and R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted by one or more -C1-C6 alkyl or -OH, preferably -C1-C2 alkyl or -OH, respectively.

[0282] In some embodiments, Y 3 is NR 87 and R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl.

[0283] In some embodiments, Y 3 is NR 87 and R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82Aand the carbon atoms to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl contains one or more atoms selected from O and N.

[0284] In some embodiments, Y 3 is NR 87 and R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl contains 1 or 2 atoms selected from O and N.

[0285] In some embodiments, Y 3 is NR 87 and R 87 together with the nitrogen atom to which it is attached, R 81 , R 81A , R 82 or R 82A and the carbon atom to which they are attached to form piperidine, morpholine, piperazine, pyrrolidine, or imidazole.

[0286] Y 3 NR 87 In some embodiments, R 87are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH.

[0287] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the heterocycle is optionally substituted by one or more halogen, —C1-C6 alkyl, or —OH.

[0288] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C6 alkyl.

[0289] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C4 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C4 alkoxy, —OH, —NH2, —NHC1-C4 alkyl, or N(C1-C4 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C4 alkyl.

[0290] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C2 alkyl.

[0291] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle contains one or more atoms selected from O and N, and each alkyl is optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more -C1-C2 alkyl.

[0292] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle contains 1 or 2 atoms selected from O and N, and each alkyl is optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more -C1-C2 alkyl.

[0293] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, wherein each alkyl is optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more -C1-C2 alkyl.

[0294] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, wherein each alkyl is optionally substituted with one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted with one or more -C1-C2 alkyl.

[0295] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C2 alkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, and the heterocycle is optionally substituted with one or more -C1-C2 alkyl groups.

[0296] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted with one or more halogen, —C1-C6 alkoxy, —OH, —O(CH2)2—OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH, and wherein the heterocycle is optionally substituted with one or more halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, or —OH; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82Ais independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0297] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, wherein the cycloalkyl is optionally substituted by one or more —C1-C6 alkyl or —OH, and wherein the heterocycle is optionally substituted by one or more —C1-C6 alkyl or —OH; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0298] In some embodiments, Y 3 is NR 87 and R 87is independently selected from —H, —C1-C6 alkyl, —C(O)C1-C6 alkyl, —S(O)2NH2, —S(O)2C1-C6 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C6 alkoxy, —OH, —NH2, —NHC1-C6 alkyl, or N(C1-C6 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C6 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C6 alkyl.

[0299] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C4 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C4 alkoxy, —OH, —NH2, —NHC1-C4 alkyl, or N(C1-C4 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C4 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C4 alkyl.

[0300] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the cycloalkyl or heterocycle is each optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0301] In some embodiments, Y 3 is NR 87 and R 87 is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle contains one or more atoms selected from O and N, and each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0302] In some embodiments, Y 3 is NR 87 and R 87is independently selected from —H, —C1-C4 alkyl, —C(O)C1-C4 alkyl, —S(O)2NH2, —S(O)2C1-C2 alkyl, —C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle contains 1 or 2 atoms selected from O and N, and each alkyl is optionally substituted by one or more —C1-C2 alkoxy, —OH, —NH2, —NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more —C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0303] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, -C(O)C1-C4 alkyl, -S(O)2NH2, -S(O)2C1-C2 alkyl, -C3-C6 cycloalkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, wherein each alkyl is optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, and the heterocycle is optionally substituted by one or more -C1-C2 alkyl; Y 1independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 independently, at each occurrence, 81A R 82A and C(O), and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C2 alkyl.

[0304] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C4 alkyl, and a 4- to 6-membered heterocycle, the heterocycle being selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, each alkyl being optionally substituted by one or more -C1-C2 alkoxy, -OH, -NH2, -NHC1-C2 alkyl, or N(C1-C2 alkyl)2, the heterocycle being optionally substituted by one or more -C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 is CR 81A R 82A and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R82A is independently at each occurrence selected from -H, and -C1-C2 alkyl, m is 2, and n is 2.

[0305] In some embodiments, Y 3 is NR 87 and R 87 are independently selected from -H, -C1-C2 alkyl, and a 4- to 6-membered heterocycle, wherein the heterocycle is selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine, and oxetane, and the heterocycle is optionally substituted with one or more -C1-C2 alkyl; Y 1 independently, at each occurrence, 81 R 82 , C(O), and O, preferably Y 1 is CR 81A R 82A and Y 2 independently, at each occurrence, 81A R 82A and O, preferably Y 2 independently, at each occurrence, 81A R 82A and R 81 , R 82 , R 81A and R 82A is independently at each occurrence selected from -H, and -C1-C2 alkyl, m is 2, and n is 2.

[0306] In some embodiments, R 8 includes the formula (B): [ka] (In the formula, R 81 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl; R 87 are independently selected from -H, -C1-C2 alkyl, and a 4- to 6-membered heterocycle, preferably the heterocycle contains one heteroatom selected from O and N; p is 0, 1 or 2).

[0307] In some embodiments, R 8 comprises the formula (B), wherein: R 81 is independently, at each occurrence, selected from -H, and methyl; R 87 are independently selected from —H, methyl, and a 4- to 6-membered heterocycle; p is 0, 1 or 2, and preferably p is 0 or 2.

[0308] In some embodiments, R 8 comprises the formula (B), wherein: R 81 is independently, at each occurrence, selected from -H, and methyl; R 87 are independently selected from —H, methyl, oxetane, preferably 3-oxetane, and tetrahydropyran, preferably 4-tetrahydropyran; p is 0, 1 or 2, and preferably p is 0 or 2.

[0309] In some embodiments, R 8 comprises the formula (B), wherein: R 81 is independently, at each occurrence, selected from -H, and methyl; R 87 are independently selected from —H, methyl, oxetane, preferably 3-oxetane, and tetrahydropyran, preferably 4-tetrahydropyran; p is 0, 1 or 2, preferably p is 0 or 2; Preferably, two R 81 When present, they are attached to different carbon atoms.

[0310] In some embodiments, R 8 includes the formula (B-1): [ka] (In the formula, R 81 is independently, at each occurrence, selected from -H, and -C1-C2 alkyl; R 81A is independently, at each occurrence, selected from -H, and -C1-C2 alkyl; R 87 are independently selected from -H, -C1-C2 alkyl, and a 4- to 6-membered heterocycle, preferably the heterocycle contains one heteroatom selected from O and N).

[0311] In some embodiments, R 8 includes the formula (B-1), wherein R 81 is independently, at each occurrence, selected from -H, and methyl; R 81A is independently, at each occurrence, selected from -H, and methyl; R 87 are independently selected from -H, methyl, and a 4- to 6-membered heterocycle, preferably the heterocycle contains one heteroatom selected from O and N.

[0312] In some embodiments, R 8 includes the formula (B-1), wherein R 81 is independently, at each occurrence, selected from -H, and methyl; R 81A is independently, at each occurrence, selected from -H, and methyl; R 87 are independently selected from —H, methyl, oxetane, preferably 3-oxetane, and tetrahydropyran, preferably 4-tetrahydropyran.

[0313] In some embodiments, R 8 includes the formula (B-1), wherein R 81 and R 81A are jointly selected from -H, and methyl, respectively; R87 are independently selected from —H, methyl, oxetane, preferably 3-oxetane, and tetrahydropyran, preferably 4-tetrahydropyran.

[0314] In some embodiments, R 8 comprises the formula (C): [ka] (In the formula, Y 4 -CR 91 R 92 -, -NR 93 -, and O; R 91 and R 92 are each independently selected from —H, —C1-C6 alkyl, —OH, and —COOH; R 93 is selected from -H, and -C1-C6 alkyl.

[0315] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, -NR 93 -, and O; R 91 and R 92 are each independently selected from —H, —C1-C6 alkyl, and —OH; R 93 is selected from -H, and -C1-C6 alkyl.

[0316] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - is selected from.

[0317] In some embodiments, R 8 comprises the formula (C), wherein Y4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92 are each independently selected from —H, —C1-C4 alkyl, —OH, and —COOH; R 93 is selected from -H, and -C1-C4 alkyl.

[0318] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92 are each independently selected from —H, —C1-C4 alkyl, and —OH; R 93 is selected from -H, and -C1-C4 alkyl.

[0319] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92 are each independently selected from —H, —C1-C2 alkyl, —OH, and —COOH; R 93 is selected from -H, and -C1-C2 alkyl.

[0320] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92are each independently selected from —H, —C1-C2 alkyl, and —OH; R 93 is selected from -H, and -C1-C2 alkyl.

[0321] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92 are each independently selected from -H, -CH3, -OH, and -COOH; R 93 is selected from -H, and -CH3.

[0322] In some embodiments, R 8 comprises the formula (C), wherein Y 4 -CR 91 R 92 -, and -NR 93 - selected from R 91 and R 92 are each independently selected from -H, -CH3, and -OH; R 93 is selected from -H, and -CH3.

[0323] In some embodiments, R 8 comprises the formula (C), wherein Y 4 Ha-CR 91 R 92 - and R 91 and R 92 are each independently selected from —H, —CH 3 , —OH, and —COOH.

[0324] In some embodiments, R 8 comprises the formula (C), wherein Y 4 Ha-CR 91 R 92 - and R91 and R 92 are each independently selected from —H, —CH 3 , and —OH.

[0325] In some embodiments, R 8 comprises the formula (C), wherein Y 4 Ha-NR 93 - and R 93 is selected from -H, and -CH3.

[0326] In some embodiments, the compound of formula (I) is selected from: 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 1); 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 2); 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 3); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-2,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 4); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-2,9-diazaspiro[5.5]undecan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 5); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 6); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 7); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 8); 3-(2,4-dimethylbenzenesulfonyl)-8-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 9); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 10); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-1,6-diazaspiro[3.3]heptan-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 11); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 12); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 13); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 14); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 15); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 16); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 17); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 18); 3-(2,4-dimethylbenzenesulfonyl)-8-[(7R)-7-hydroxy-3,9-diazaspiro[5.5]undecan-3-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 19); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 20); 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 21); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 22); 3-(2,4-dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 23); 3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 24); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 25); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,5-dimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 26); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,4,5-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 27); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 28); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,3,4-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 29); 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrazino[2,1-c][1,4]oxazin-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 30); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 31); 8-[4-(dimethylamino)piperidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 32); 8-(4-aminopiperidin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 33); 3-(2,4-dimethylbenzenesulfonyl)-8-[3-(methylamino)pyrrolidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 34); 8-[(3R)-3-aminopyrrolidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 35); 3-(2,4-Dimethylbenzenesulfonyl)-8-{octahydropyrrolo[1,2-a]pyrazin-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 36); 8-[(8aS)-octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 37); 8-[(8aR)-octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 38); 3-(2,4-Dimethylbenzenesulfonyl)-8-{1-methyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 39); 8-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 40); 8-(4-tert-butylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 41); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methoxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 42); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 43); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 44); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 45); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 46); 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 47); 3-(2,4-dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 48); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methyl-1,4-diazepan-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 49); 8-{[(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl]amino}-3-(2,4-dimethylbenzenesulfonyl)-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 50); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 51); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropanoyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 52); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-1-methylpiperazin-2-one (compound 53); 3-(2,4-dimethylbenzenesulfonyl)-8-{5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 54); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetan-3-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 55); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxan-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 56); 8-[4-(2-aminoethyl)piperazin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 57); 8-{4-[3-(diethylamino)propanoyl]piperazin-1-yl}-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 58); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 59); 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 60); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methanesulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 61); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (compound 62); 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (compound 63); and 1-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (compound 64); or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound of formula (I) is selected from: 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 1); 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 2); 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 3); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 7); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 8); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 12); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 14); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 16); 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 21); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 22); 3-(2,4-dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 23); 3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 24); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 25); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 28); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 31); 3-(2,4-Dimethylbenzenesulfonyl)-8-{octahydropyrrolo[1,2-a]pyrazin-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 36); 3-(2,4-Dimethylbenzenesulfonyl)-8-{1-methyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 39); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 45); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 46); 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 47); 3-(2,4-dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 48); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropanoyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 52); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-1-methylpiperazin-2-one (compound 53); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetan-3-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 55); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxan-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 56); 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 60); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methanesulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 61); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (compound 62); 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (compound 63); and 1-[3-(2,4-Dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (Compound 64); or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 1) or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2) or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 3) or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-2,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 4) or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-2,9-diazaspiro[5.5]undecan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 5) or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 6) or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 7) or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 8) or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 9) or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 10) or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-1,6-diazaspiro[3.3]heptan-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 11) or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 12) or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 13) or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 14) or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 15) or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 16) or a pharmaceutically acceptable salt thereof.

[0344] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 17) or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 18) or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[(7R)-7-hydroxy-3,9-diazaspiro[5.5]undecan-3-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 19) or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 20) or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 21) or a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 22) or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 23) or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 24) or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the compound of Formula (I) is rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 25) or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(3,5-dimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 26) or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(3,4,5-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 27) or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the compound of Formula (I) is rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 28) or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(3,3,4-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 29) or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrazino[2,1-c][1,4]oxazin-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 30) or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 31) or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the compound of Formula (I) is 8-[4-(dimethylamino)piperidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 32) or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the compound of Formula (I) is 8-(4-aminopiperidin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 33) or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[3-(methylamino)pyrrolidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 34) or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the compound of Formula (I) is 8-[(3R)-3-aminopyrrolidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 35) or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrrolo[1,2-a]pyrazin-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 36) or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound of Formula (I) is 8-[(8aS)-octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 37) or a pharmaceutically acceptable salt thereof.

[0365] In some embodiments, the compound of Formula (I) is 8-[(8aR)-octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 38) or a pharmaceutically acceptable salt thereof.

[0366] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 39) or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound of Formula (I) is 8-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 40) or a pharmaceutically acceptable salt thereof.

[0368] In some embodiments, the compound of Formula (I) is 8-(4-tert-butylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 41) or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methoxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 42) or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 43) or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 44) or a pharmaceutically acceptable salt thereof.

[0372] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 45) or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 46) or a pharmaceutically acceptable salt thereof.

[0374] In some embodiments, the compound of Formula (I) is 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 47) or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 48) or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methyl-1,4-diazepan-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 49) or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, the compound of Formula (I) is 8-{[(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl]amino}-3-(2,4-dimethylbenzenesulfonyl)-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 50) or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 51) or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropanoyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 52) or a pharmaceutically acceptable salt thereof.

[0380] In some embodiments, the compound of Formula (I) is 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-1-methylpiperazin-2-one (Compound 53) or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 54) or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetan-3-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 55) or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxan-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 56) or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, the compound of Formula (I) is 8-[4-(2-aminoethyl)piperazin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 57) or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments, the compound of Formula (I) is 8-{4-[3-(diethylamino)propanoyl]piperazin-1-yl}-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 58) or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 59) or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, the compound of Formula (I) is 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 60) or a pharmaceutically acceptable salt thereof.

[0388] In some embodiments, the compound of Formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methanesulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 61) or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, the compound of Formula (I) is 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (Compound 62) or a pharmaceutically acceptable salt thereof.

[0390] In some embodiments, the compound of Formula (I) is 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (Compound 63) or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the compound of Formula (I) is 1-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (Compound 64) or a pharmaceutically acceptable salt thereof.

[0392] 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 a specifically defined N-linked heterocycle at the 8-position of the [1,2,3]triazolo[1,5a]quinazolin-5(4h)-one core. As shown in Example 3 and Table 2, 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 of the present invention were serially diluted in lysogeny broth (LB) with or without human serum (HS) or human serum albumin (HSA) 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).

[0393] Compounds of the present invention are potent inhibitors of lacZ expression, retaining activity in the presence of 40 mg / mL HSA, and exhibiting IC 50The values were as low as 3.7 μg / mL. Thus, the compounds of the present invention retained their activity in inhibiting the expression of AgrA-regulated genes, even when incubated with physiologically relevant concentrations of HSA. In contrast, as shown in Example 3, although compounds 45, 46, and 58 of WO 2020 / 109350 inhibited lacZ expression at concentrations of less than 1 μg / mL in the AgrA reporter assay in the absence of HSA or HS, when incubated with Staphylococcus aureus (S. aureus) in the presence of HSA (or HS), the compounds were inactive even at the highest concentration of the tested compound (i.e., 128 μg / mL; compound 45 of WO 2020 / 109350), or significantly lost activity (>200-fold) in the presence of HS (compounds 46 and 58 of WO 2020 / 109350).

[0394] Without wishing to be bound, a concentration of 40 mg / mL HSA was chosen because this is the same concentration of HSA found in human serum.

[0395] 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 systemically (e.g., to a subject such as a mammal, preferably a human, preferably orally and / or parenterally) 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.

[0396] Uses of the Compounds of the Invention 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 of 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.

[0397] 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, 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, the bacterium being 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 an inflammatory skin disease, preferably atopic dermatitis or Netherton syndrome. In a further highly preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis exacerbated by Staphylococcus aureus.The embodiments, preferred 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 whether their repetition is avoided for the sake of brevity.

[0398] 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.

[0399] 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.

[0400] 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).

[0401] 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.

[0402] In a further aspect, the present invention provides a method for preventing or treating a disease, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, in a subject in need thereof, preferably 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, 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.

[0403] Therefore, the compounds of the present invention of formula (I) described herein or compositions of the present invention comprising compounds of formula (I), preferably pharmaceutical compositions of the present 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 infection or disease states or disorders associated with bacterial infection. Examples of diseases and disorders associated with bacterial infection that are responsive to treatment with the compounds of the present invention and / or the compounds and / or compositions of the present invention may include, but are not limited to, skin and soft tissue infections, pulmonary infections, Netherton syndrome, or chronic inflammatory skin diseases such as atopic dermatitis.

[0404] 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), a pharmaceutical composition or a combination product, preferably a compound of formula (I).

[0405] 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 is topically administered to a subject, preferably the subject has a disease or disorder associated with bacterial infection, and the bacterial infection is caused or exacerbated by bacteria, preferably Staphylococcus aureus.In a further preferred embodiment, the bacterial infection is caused or exacerbated by SSTI, Netherton syndrome or atopic dermatitis.In a further preferred embodiment, the bacterial infection is SSTI or atopic dermatitis.

[0406] Therefore, the compounds of formula (I) of the present invention, or compositions of the present invention, or combination products of the present invention, preferably compounds of formula (I) of the present invention, or pharmaceutical compositions of the present invention containing 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 Staphylococcus aureus (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.

[0407] 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.

[0408] In a further aspect, the present invention provides a method for preventing or treating a bacterial infection in a subject in need thereof, comprising the step of administering to said subject in need thereof 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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.

[0427] The compounds of the present invention of formula (I), pharmaceutical compositions containing the same, or combination products can be administered to any subject who can experience the beneficial effects of the compounds, compositions, or products of the present invention described herein. Preferably, the subject is a human. The compounds of the present invention, compositions containing the same, or products described herein can be administered by any means that achieve their intended purpose. For example, administration can be parenteral, topical, local, subcutaneous, oral, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, buccal, oral mucosal, ocular, or by inhalation. Preferably, administration is oral or parenteral. In preferred embodiments, administration to a subject is systemic (e.g., oral or parenteral). In other embodiments, administration to a subject is local, such as in a topical solution, topical ointment, or topical cream.

[0428] 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.

[0429] 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 1]

[0430] Compound analysis: Unless otherwise specified, the purity and identity of intermediates or example compounds were assessed by state-of-the-art H(U)LPC-MS. The methods are described below:

[0431] Method A: HPLC-MS 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%): (i) at a flow rate of 2 mL / min for 3.25 minutes or less (a 5-minute run); or (ii) within 6.5 min (10 min run) at a flow rate of 2 mL / min.

[0432] Method B: UPLC-MS UPLC-MS analysis was performed using a Waters Acquity UPLC system coupled with an SQD mass spectrometer (scan 100-1500) and a photodiode array detector (210-350 nm). A BEH C18 column (particle size 1.71 μm, dimensions 50 × 2.1 mm) was used for UPLC analysis. The injection volume was 2 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 10 buffer solution.

[0433] The analysis time was 8 minutes (Method B1) or 12 minutes (Method B2) at a flow rate of 0.9 mL / min using a gradient starting from 97% aqueous buffer (10 mM aqueous ammonium formate for solutions at pH=10 (high), or 0.1% v / v aqueous formic acid for solutions at pH=3 (low)): 6.8 min, reaching 97% acetonitrile within 1.1 min (8 min run); 1.5 min, reaching 97% acetonitrile within 10 min (12 min run - high pH); or 9.5 min, reaching 97% acetonitrile within 0.5 min (12 min run - low pH) - in this case the flow rate was 0.5 mL / min.

[0434] Intermediate I-1: 8-Bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one [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).

[0435] 2-(2,4-Dimethylphenyl)-sulfanylacetonitrile was solubilized in DCM (250 ml) and cooled in an ice bath. mCPBA (<77%, 33 g, 147.2 mmol) was then added portionwise. 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 phases were 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).

[0436] To a cooled (4°C) solution of methyl 2-amino-4-bromobenzoate (7 g, 30.4 mmol) in anhydrous acetonitrile under an Ar atmosphere was added tert-butylnitrile (1.5 equiv.) dropwise. After stirring for 20 minutes, 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 minutes, then allowed to reach room temperature and stirred for an additional 2 hours. Concentrated aqueous NaHCO3 (500 ml) was added to the reaction mixture to give a suspension, which was extracted with EtOAc (3 x 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).

[0437] To an ice-cooled 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).

[0438] Intermediate I-2: 3-(2,4-dimethylphenyl)sulfonyl-8-fluoro-4H-triazolo[1,5-a]quinazolin-5-one [ka] Intermediate I-2 was synthesized following the method described for I-1 starting from 2,4-dimethylbenzenethiol and methyl 2-amino-4-fluoro-benzoate.

[0439] General reaction conditions for Buchwald coupling [ka] A round-bottom flask was charged with I-1 (1 equiv.), the corresponding amine (1–3 equiv.), Pd2dba3 (5 mol%), Cs2CO3 (1.5 equiv.), and RuPhos (10 mol%), and DMF (0.035 M) was added. The mixture was degassed with an Ar flush, then equipped with a reflux condenser and stirred at 120 °C in a preheated heating block until completion (TLC or LC-MS monitoring). After this time, the mixture was cooled to room temperature, diluted with MeOH, and filtered through Celite. The crude product was purified by flash chromatography using the appropriate eluent system and then triturated with diethyl ether to give the desired compound as a solid.

[0440] Nucleophilic aromatic substitution (S N General reaction conditions for the Ar reaction [ka] A round-bottom flask was charged with I-1 (1 equiv.), amine (1–5 equiv.), K2CO3, and NMP (0.1 M). The mixture was stirred at 130 °C until completion (TLC or LC-MS monitoring). Afterwards, NMP was removed under vacuum, and the crude product was diluted with EtOAc and washed with NH4Cl (sat. aq.). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. If necessary, the product was further purified by flash chromatography using an appropriate eluent system to give the corresponding compound as a solid.

[0441] General reaction conditions for Boc removal 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.

[0442] 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.

[0443] General reaction conditions for reductive amination Preparation of compound 25 starting from compound 24: To a suspension of compound 24 (1 equivalent) in DCM (0.12 M), formaldehyde (37% by weight aqueous solution, 4 equivalents) was added dropwise, and the resulting suspension was stirred at room temperature overnight (the suspension turned into a clear yellowish solution). NaBH(OAc)3 (2.5 equivalents) was then added portionwise, and the mixture was stirred until completion (monitored by TLC or LCMS). Water was added, and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, then dried over MgSO4, and concentrated to dryness. If necessary, the product was further purified by flash chromatography using an appropriate eluent system.

[0444] General reaction conditions for amide formation A reaction vial was charged with 3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one hydrochloride, compound 23 (20 mg, 0.042 mmol, 1 equiv.), and then acetone (1.5 mL), TEA (12 μL, 0.084 mmol, 2 equiv.), and 2-methylpropanoyl chloride (26.5 μL, 0.25 mmol, 6 equiv.) were added, and the mixture was stirred at 50° C. overnight. After this time, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using 100% DCM to DCM-MeOH (9-1) to afford 17 mg of a white solid (compound 52) (79% yield).

[0445] General reaction conditions for ester hydrolysis In a round-bottom flask, 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (compound 63) methyl ester or 1-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (compound 64) methyl ester (0.296 mmol) was solubilized with a solution of THF / HO (50 / 50, 10 ml), and then LiOH monohydrate (74 mg, 1.78 mmol, 6 equivalents) was added. The mixture was stirred at room temperature for 2 hours. After this time, the mixture was diluted with EtOAc and NaOH (1N), and the aqueous phase was washed twice with EtOAc to remove organic impurities, then acidified with HCl 1N to pH 2 and extracted twice with EtOAc. The combined organic layers were washed with NaCl brine, then dried over MgSO and concentrated to dryness to give the respective carboxylic acids as white solids in approximately 70% yield.

[0446] Example 1: Preparation of 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 1) [ka] To an ice-cooled solution of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate (500 mg, 2.3 mmol) and triethylamine (490 μL, 3.516 mmol) in anhydrous DCM (4.6 mL) was added dropwise a solution of tert-butyldimethylsilyl chloride (530 mg, 3.516 mmol) in anhydrous DCM (3.5 mL) under an Ar atmosphere. A white precipitate formed during the addition. The reaction mixture was stirred on ice for 30 min and then at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with concentrated aqueous NH4Cl (3 × 20 mL). The pooled aqueous phase was back-extracted with DCM (3 × 20 mL), and the pooled organic phase was concentrated in vacuo. The crude product was purified by flash chromatography (nHex to DCM:MeOH (10:0.5) to give, after evaporation, methyl-5-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-2-nitro-benzoate, which was used without further purification (62% yield, 84% purity by HPLC).

[0447] To a solution of methyl-5-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-2-nitrobenzoate (512.5 mg) in MeOH (27 ml) was added Pd / C (10%, 278 mg, 0.261 mmol) and the reaction mixture was stirred overnight under an atmosphere of H. The mixture was then filtered and the filtrate evaporated to give methyl 2-amino-5-[tert-butyl(dimethyl)silyl]oxy-4-fluorobenzoate (463 mg, 99% pure by HPLC).

[0448] To an ice-cooled solution of methyl 2-amino-5-[tert-butyl(dimethyl)silyl]oxy-4-fluorobenzoate (150 mg, 0.496 mmol) in anhydrous acetonitrile (0.73 mL) under an Ar atmosphere, tert-butylnitrile (90 μL, 0.757 mmol) was added dropwise, followed 10 min later by azidotrimethylsilane (80 μL, 0.603 mmol) (exothermic reaction). The resulting mixture was stirred on ice for an additional 20 min and then at room temperature for 2 h. HPLC monitoring indicated complete conversion, and concentrated aqueous NaHCO3 (10 mL) was added. The resulting suspension was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and evaporated. Further analysis indicated that the silyl protection had been removed during azide formation. Therefore, crude methyl 2-azido-4-fluoro-5-hydroxybenzoate (111 mg, 0.499 mmol) was suspended in anhydrous DMF (1.7 mL), and potassium carbonate (138 mg, 0.998 mmol) was added, followed by 1-(chloromethyl)-4-methoxy-benzene (PMB-Cl, 102 μL, 0.752 mmol). The resulting mixture was stirred overnight at room temperature. Water (40 mL) was then added, and the suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (cy-Hex / EtOAc). After evaporation of the desired fractions, methyl 2-azido-4-fluoro-5-[(4-methoxyphenyl)methoxy]benzoate was isolated as a colorless oil (80% yield, 99% purity).

[0449] To a cooled (ice bath) solution of 2-(2,4-dimethyl)sulfonylacetonitrile (84 mg, 0.393 mmol; see I-1 for experimental details) in anhydrous EtOH (0.6 mL) was added dropwise a solution of sodium ethoxide (15%) in EtOH. 15 min after the addition, a solution of the previous compound (128.9 mg, 0.385 mmol) in anhydrous EtOH was added dropwise. The resulting mixture was stirred on ice for 1 h and at room temperature for an additional 2.5 h. The reaction mixture was then concentrated, and the residue was dissolved in water (15 mL), and the pH was adjusted to 2 with 2 M HCl. The precipitate was collected by filtration, washed with water (4 × 10 mL), and finally dried in a desiccator with KOH. The crude product was purified by reverse phase chromatography to give 3-(2,4-dimethylphenyl)sulfonyl-8-fluoro-7-[(4-methoxyphenyl)methoxy]-4H-triazolo[1,5-a]quinazolin-5-one (115 mg, 97% purity) as a brownish solid.

[0450] S N N-Methyl-piperazine was introduced according to the general procedure of Ar to give the PMB protected title compound as a white solid (117 mg, 96% purity).

[0451] The PMB protecting group was removed by stirring the previous intermediate (102 mg) in TFA (1 mL) followed by concentration under a stream of nitrogen. The residue was diluted with MeOH, neutralized with ammonia, and after evaporation, the solid was triturated with several portions of water (20 mL), MeOH (10 mL), and EtO (5 mL). After drying, the title compound was obtained as a white solid (117 mg, 98.5% purity, Method B1-low).

[0452] Example 2: Preparation of 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2) [ka] Compound 2 was obtained following the same procedure as described for compound 1. The title product was isolated as a beige solid (94% purity by HPLC, Method B1-Low).

[0453] Compounds 3-59 of the present invention were prepared from the corresponding intermediates shown in Table 1 below, following the appropriate general protocol described above. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0454] 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: From an overnight culture plate, cells were resuspended in 0.9% (w / v) saline, and a bacterial inoculum of 5 × 10 5CFU / ml were prepared in LB medium. Compounds were serially diluted 2-fold in LB, and 50 μL of these 10-fold concentrated samples were 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 OD600 was measured using a TECAN Infinite F200 microplate reader to control for growth inhibition. An 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 with shaking at 37°C for 60 minutes. 20 μL of the substrate MUG (4-methylumbelliferyl β-D-galactopyranoside) was added at 0.25 mg / ml and incubated for 3 hours at 37°C with shaking. Fluorescence (excitation: 360 nm, emission: 450 nm) was then measured using a TECAN Infinite F200 microplate reader. After normalization to the DMSO control, IC values were calculated using GraphPad PRISM. 50 It was decided that:

[0455] 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 value was determined.

[0456] The activities of the compounds of the present invention and compound 45 of WO 2020 / 109350 in the absence of human serum albumin and in the presence of 40 mg / mL of human serum albumin are shown in Table 2 below. Compounds 46 and 58 of WO 2020 / 109350 were not determined in 40 mg / mL of HSA (nd), and their activity ratios were calculated based on their activities in the presence of 50% human serum. [Table 3]

[0457]

Table 4-1

Table 4-2

Table 4-3

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof: 【Chemical 1】 (In the formula, R １ -H, halogen, -C １ -C ６ Alkyl, and —C １ -C ６ and alkoxy, wherein said alkyl and alkoxy are independently selected from one or more R １１ and each may be replaced by R ３ But -H, -C １ -C ６ Alkyl, and —C １ -C ６ and alkoxy, wherein said alkyl and alkoxy are independently selected from one or more R １１ and each may be replaced by R ７ is independently selected from —H, and —OH; R ８ is a group of formula (A): 【Chemistry 2】 wherein n is independently an integer from 0 to 3; m is independently an integer from 0 to 3; Y １ independently, at each occurrence, CR ８１ R ８２ , C(O), and O; Y ２ independently, at each occurrence, CR ８１Ａ R ８２Ａ and O; Y ３ But, CR ８４ R ８５ ;CHR ８６ ;NR ８７ and O, Y ３ is CR ８４ R ８５ When Y is ３ is CHR ８６ , N.R. ８７ or O, the sum of m and n is at least 3; R ８１ , R ８２ , R ８１Ａ and R ８２Ａ independently, at each occurrence, —H, and —C １ -C ６ alkyl, or R ８１ and R ８１Ａ can be taken together with the carbon atoms to which they are attached to form a bridged ethylene, R ８４ and R ８５ together with the carbon atom to which they are attached, form -C ４ -C ７ cycloalkyl, or a 4- to 7-membered heterocycle, wherein the cycloalkyl and heterocycle are each independently selected from the group consisting of one or more halogens, —C １ -C ６ Alkyl, -C １ -C ６ each optionally substituted by haloalkyl, or —OH; R ８６ is —H, —COOH, and —NR ８８ R ８９ or R ８６ together with the carbon atom to which it is attached, R ８１ , R ８１Ａ , R ８２ Or R ８２Ａ and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle, said heterocycle containing one or more halogens, —C １ -C ６ Alkyl, —C １ -C ６ optionally substituted by haloalkyl, —OH, or —COOH; R ８８ and R ８９ independently, at each occurrence, —H, and —C １ -C ６ alkyl, or R ８８ Or R ８９ together with the nitrogen atom to which they are attached form R ８１ , R ８１Ａ , R ８２ Or R ８２Ａ and the carbon atom to which they are attached can combine to form a 5- or 6-membered heterocycle; R ８７ But -H, -C １ -C ６ Alkyl, —C(O)C １ -C ６ Alkyl, —S(O) ２ NH ２ , -S(O) ２ C １ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, and 4- to 6-membered heterocycle, each alkyl being independently selected from one or more halogens, —C １ -C ６ Alkoxy, —OH, —O(CH ２ ) ２ —OH, —NH ２ , -NHC １ -C ６ Alkyl, or N(C １ -C ６ alkyl) ２ wherein said cycloalkyl is optionally substituted by one or more halogens, —C １ -C ６ Alkyl, -C １ -C ６ The heterocycle may be substituted by one or more halogens, -C １ -C ６ Alkyl, -C １ -C ６ optionally substituted by haloalkyl or —OH; or R ８７ together with the nitrogen atom to which it is attached, R ８１ , R ８１Ａ , R ８２ Or R ８２Ａ and the carbon atom to which they are attached can combine to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of one or more halogens, —C １ -C ６ Alkyl, —C １ -C ６ each optionally substituted by haloalkyl or —OH; R １１ is independently at each occurrence a halogen, or —OH.

2. R １ Ga-CH ３ 2. The compound of claim 1, wherein:

3. R ３ Ga-CH ３ The compound according to any one of claims 1 to 2,

4. R ７ The compound of any one of claims 1 to 3, wherein is -H.

5. R ７ The compound according to any one of claims 1 to 4, wherein is -OH.

6. Y ３ is CR ８４ R ８５ The compound according to any one of claims 1 to 5,

7. Y ３ is CHR ８６ The compound according to any one of claims 1 to 5,

8. Y ３ NR ８７ The compound according to any one of claims 1 to 5,

9. R ８７ But -H, -C １ -C ６ Alkyl, —C(O)C １ -C ６ Alkyl, —S(O) ２ NH ２ , -S(O) ２ C １ -C ６ Alkyl, -C ３ -C ６ cycloalkyl, and 4- to 6-membered heterocycle, each alkyl being independently selected from one or more halogens, —C １ -C ６ Alkoxy, —OH, —O(CH ２ ) ２ —OH, —NH ２ , -NHC １ -C ６ Alkyl, or N(C １ -C ６ alkyl) ２ wherein said cycloalkyl is optionally substituted by one or more halogens, —C １ -C ６ Alkyl, -C １ -C ６ The heterocycle may be substituted by one or more halogens, -C １ -C ６ Alkyl, -C １ -C ６ The compound of claim 8, optionally substituted by haloalkyl or -OH.

10. R ８ The compound of claim 1 , wherein the compound comprises formula (B): 【Chemistry 3】 (In the formula, R ８１ independently, at each occurrence, —H, and —C １ -C ２ alkyl, R ８７ But -H, -C １ -C ２ alkyl, and a 4- to 6-membered heterocycle, preferably wherein said heterocycle contains one heteroatom selected from O and N; p is 0, 1 or 2).

11. R ８ The compound of claim 1 , wherein the compound comprises formula (C): 【Chemistry 4】 (In the formula, Y ４ But, -CR ９１ R ９２ -, -NR ９３ -, and O; R ９１ and R ９２ But -H, -C １ -C ６ alkyl, and —OH; R ９３ is -H, and -C １ -C ６ alkyl).

12. 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 1); 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 2); 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 3); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-2,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 4); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-2,9-diazaspiro[5.5]undecan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 5); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 6); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 7); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 8); 3-(2,4-dimethylbenzenesulfonyl)-8-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 9); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 10); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-1,6-diazaspiro[3.3]heptan-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 11); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 12); 3-(2,4-dimethylbenzenesulfonyl)-8-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 13); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 14); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 15); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 16); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 17); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 18); 3-(2,4-dimethylbenzenesulfonyl)-8-[(7R)-7-hydroxy-3,9-diazaspiro[5.5]undecan-3-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 19); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 20); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 21); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 22); 3-(2,4-dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 23); 3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 24); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 25); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,5-dimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 26); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,4,5-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 27); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 28); 3-(2,4-dimethylbenzenesulfonyl)-8-(3,3,4-trimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 29); 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrazino[2,1-c][1,4]oxazin-8-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 30); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 31); 8-[4-(dimethylamino)piperidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 32); 8-(4-aminopiperidin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 33); 3-(2,4-dimethylbenzenesulfonyl)-8-[3-(methylamino)pyrrolidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 34); 8-[(3R)-3-aminopyrrolidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 35); 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrrolo[1,2-a]pyrazin-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 36); 8-[(8aS)-Octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 37); 8-[(8aR)-Octahydropyrrolo[1,2-a]pyrazin-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 38); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 39); 8-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 40); 8-(4-tert-butylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 41); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methoxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 42); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 43); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 44); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 45); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 46); 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 47); 3-(2,4-dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 48); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methyl-1,4-diazepan-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 49); 8-{[(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl]amino}-3-(2,4-dimethylbenzenesulfonyl)-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 50); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 51); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropanoyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 52); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-1-methylpiperazin-2-one (compound 53); 3-(2,4-dimethylbenzenesulfonyl)-8-{5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 54); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetan-3-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 55); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxan-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 56); 8-[4-(2-aminoethyl)piperazin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 57); 8-{4-[3-(diethylamino)propanoyl]piperazin-1-yl}-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 58); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 59); 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 60); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methanesulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 61); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (Compound 62); and 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (compound 63); and 1-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (Compound 64); or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 selected from:

13. 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 1); 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 2); 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 3); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 7); 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 8); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptan-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 12); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 14); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 16); 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 21); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 22); 3-(2,4-dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 23); 3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 24); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 25); rac-3-(2,4-dimethylbenzenesulfonyl)-8-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 28); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 31); 3-(2,4-dimethylbenzenesulfonyl)-8-{octahydropyrrolo[1,2-a]pyrazin-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 36); 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 39); 3-(2,4-dimethylbenzenesulfonyl)-8-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 45); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 46); 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 47); 3-(2,4-dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 48); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropanoyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 52); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-1-methylpiperazin-2-one (compound 53); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetan-3-yl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 55); 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxan-4-yl)piperazin-1-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 56); 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 60); 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methanesulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (compound 61); 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (Compound 62); 2-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-aza-spiro[3.3]heptane-6-carboxylic acid (compound 63); and 1-[3-(2,4-dimethyl-benzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (Compound 64); or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 selected from:

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 medicament.

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