8-heterocycl-3-(benzenesulfonyl)-[1, 2, 3] triazolo [1, 5a] quinazoline-5 (4H)-one derivatives

Abstract

The invention relates to an 8-heterocycl-3-(benzenesulfonyl)-[1, 2, 3] triazolo [1, 5a] quinazoline-5 (4H)-ketone derivative and a pharmaceutical composition thereof. And their methods of reducing the virulence of a bacterium, preferably Staphylococcus aureus, expressing a subsidiary gene regulator A (AgrA) or ortholog of AgrA, methods of inhibiting quorum sensing of a bacterium, preferably Staphylococcus aureus, and preventing or treating a disease caused or aggravated by a bacterium, preferably Staphylococcus aureus, in a subject. The present invention relates to the use in a method for treating skin or pulmonary infections, atopic dermatitis, Neethton syndrome or psoriasis. The compound exhibits excellent ability to inhibit gene transcription under the control of a Staphylococcus aureus P3 promoter even in the presence of human serum or human serum albumin.

Description

Technical Field

[0001] 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 (accessory gene regulator A, AgrA) or a direct homologue of AgrA, in methods for inhibiting quorum sensing in bacteria (preferably Staphylococcus aureus), and in methods for preventing or treating a disease (e.g., skin or lung infection, atopic dermatitis, Netherton syndrome or psoriasis) caused or aggravated by bacteria (preferably Staphylococcus aureus) in a subject. Therefore, the present invention relates to anti-virulence compositions and methods for treating, alleviating and / or preventing diseases caused or aggravated by bacteria (preferably Staphylococcus aureus), and more particularly to compositions and methods for reducing the virulence of bacteria expressing AgrA or a direct homologue of AgrA (preferably AgrA). Background Art

[0002] Staphylococcus aureus is both a human commensal and a notorious opportunistic pathogen that causes severe community-acquired and hospital-acquired infections. Staphylococcus aureus can cause a wide range of infections, from mild superficial skin infections to serious life-threatening systemic conditions, such as endocarditis, pneumonia, or sepsis (Lee AS et al., (2018) Nat. Rev. Dis. Primers, Vol. 4, No. 18033, pp. 1-23). ​​In addition, Staphylococcus aureus is also associated with allergic skin conditions, such as atopic dermatitis (Geoghegan JA et al., (2018) Trends Microbiol. 26 (6): 484-497) or Netherton syndrome (Williams MR et al., (2020) Cell reports 30 (9): 2923-2933). The success of S. aureus in causing a variety of diseases is the result of a large repertoire of virulence factors combined with resistance to β-lactams and, for most clones, resistance to other antibiotic classes. Clinically relevant antibiotic resistance has evolved against almost every antibiotic used, while the discovery and development of new antibiotic classes has lagged behind, which has led to the antibiotic resistance crisis we face today. Therefore, there is a need for alternative strategies that are also effective against multidrug-resistant strains (e.g., methicillin-resistant S. aureus (MRSA)) for the treatment or prevention of S. aureus-mediated bacterial infections (Dickey SW et al., (2017) Nat. Rev. Drug Discov. 16(7): 457-471).

[0003] One of these strategies is the anti-virulence approach, which is only directed to traits related to virulence, not to survival / fitness. Compared with common antibiotic therapy, anti-virulence drugs themselves are not bacteriostatic (inhibiting bacterial growth) or bactericidal (killing bacteria). This method focuses on disarming pathogenic bacteria by blocking expression or neutralizing their virulence factors, ultimately interfering with the pathogenic mechanism of bacteria, thereby promoting the host immune system to remove pathogens. Because anti-virulence drugs do not interfere with the basic mechanisms of bacterial growth and survival, they should be able to reduce the pressure of pathogens to develop drug resistance. Another advantage is that specific anti-virulence drugs can protect healthy host microbiota, and eventually even help to combat microbial imbalance by reducing the invasiveness of pathogens (such as Staphylococcus aureus). Importantly, the anti-virulence approach provides an increased pharmacological target library, which is likely to produce alternative antimicrobial agents with novel modes of action (Mühlen, S. & Dersch, P., (2016) Curr. Top. Microbiol. Immunol. 398: 147-183).

[0004] How virulence factors are regulated in Staphylococcus aureus: The agr operon is a bacterial quorum sensing system that controls cell density-dependent expression of virulence factors in Staphylococcus aureus. It is driven by two different promoters, P 2 and P 3 Composition, among which, P 2 Responsible for the production of components of the quorum sensing system (AgrB, AgrD, AgrC, and AgrA; see Figure 1 The precursor peptide AgrD is processed by AgrB to form a mature autoinducing peptide (AIP) that is secreted across the bacterial membrane. AIP binds to the histidine kinase AgrC and activates the transcriptional regulator AgrA through phosphorylation, driving the secretion of P 2 and P 3 There are four allelic variants of agr (types I to IV), each encoding a different AIP that acts as a specific ligand for AgrC of its own cell but as an inhibitor of other AgrC variants. 3Produces agr effector molecule RNAIII, which together with AgrA is responsible for the transcriptional control of about 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 virulence factors regulated by AgrA are: cell surface-associated proteins, such as protein A (SpA) and fibronectin binding protein; secreted toxins, such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble regulatory protein (PSM), Panton-Valentine leukolysin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH); or, secreted proteases, such as SspA or Aureolysin. In summary, the multiple multifunctional virulence determinants make the pathogenesis of Staphylococcus aureus particularly complex and provide the pathogen with a series of mechanisms to damage the host or circumvent the host's immune defense. Notably, most AgrA-regulated virulence factors are responsible for the pathogenicity of Staphylococcus aureus in skin and soft tissue infections (SSTIs), lung infections, and have also been shown to cause 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] How virulence factor expression is prevented: Inhibition of expression of the central regulatory RNAIII, combined with inhibition of PSMα production, is thought to result in a significant overall reduction in virulence factor levels (see Figure 1 Current strategies for inhibiting RNAIII expression can be divided into different categories: (1) competitive inhibitors of the histidine kinase AgrC; (2) RNAIII transcription inhibitors (the exact mechanism has not yet been determined); (3) AgrA-P 2 / P 3 Inhibition of interactions. Targeting AgrA has the advantage of blocking the expression of AgrA-dependent virulence factors of all four agr groups (Gordon CP et al. (2013) J. Med. Chem. 56(4): 1389-404).

[0006] Sully and colleagues discovered an AgrA inhibitor called Savirin during a screen of 24,087 compounds selected for inhibition of agr induced by cyclic thiolactone pheromone (AIP) in studies related to acute bacterial skin and soft tissue infections caused by Staphylococcus aureus (Sully EK et al. (2014) PLoS Pathog. 10(6):e1004174). Savirin was shown to be a potent regulator of AgrA-regulated toxin gene transcription (e.g., hla, psmα, and pvl) in all four agr groups and did not affect the survival of S. aureus. Savirin inhibited exotoxin-induced red blood cell (RBC) lysis. No resistance was developed after multiple passages with Savirin. The molecule was shown to interfere with AgrA-DNA interactions and prevent virulence gene upregulation. When Savirin was applied multiple times, a significant reduction in abscess size and skin necrosis was observed in mice infected with MRSA USA300 strain.

[0007] Recently, WO 2020 / 109350 described 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives that are capable of reducing the virulence of bacteria (e.g., Staphylococcus aureus) by interacting with AgrA and inhibiting the expression of virulence factors regulated by AgrA, and their use for preventing or treating bacterial infections and / or diseases caused or aggravated by bacteria (preferably Staphylococcus aureus) (e.g., skin or lung infections, atopic dermatitis or psoriasis). Summary of the invention

[0008] The inventors unexpectedly discovered that the ability of the compounds of WO 2020 / 109350 to inhibit AgrA-related virulence factors may be affected and reduced when tested in the presence of human serum (HS) or human serum albumin (HSA; the main component of human serum). Without wishing to be bound, the reduced ability to inhibit the expression of AgrA-related virulence factors is believed to be due to the non-specific binding of the compound to serum proteins (e.g., HSA). This reduced efficacy in the presence of HS or HSA may limit the ability to inhibit AgrA-related virulence factors when administered systemically (e.g., in animals, preferably mammals, more preferably humans). The present invention now provides a class of new compounds that overcome the disadvantages, and thereby provides compounds that can reduce the virulence of bacteria (preferably bacteria expressing AgrA) and / or inhibit quorum sensing in bacteria (preferably Staphylococcus aureus) in biologically relevant systems comprising human serum or human serum albumin.

[0009] Thus, the present inventors unexpectedly identified a new class of compounds that can interact with AgrA and inhibit the expression of virulence factors regulated by AgrA even in the presence of human serum (HS) or human serum albumin (HSA). The present inventors transfected Staphylococcus aureus with a plasmid expressing the reporter gene lacZ under the control of the P3 promoter, wherein P 3 The promoter is regulated by AgrA. In the presence of the compounds of the invention, the inventors found that the production of the lacZ gene product (i.e., β-galactosidase) was inhibited. Unexpectedly, the compounds of the invention retained AgrA inhibitory activity even when assayed in the presence of HS or HSA.

[0010] Therefore, in the presence of HS or HSA, the compounds of the present invention can inhibit P 3 The transcription of a gene (preferably a virulence factor) under the control of a promoter (e.g., in bacteria, preferably in Staphylococcus aureus). This activity strongly suggests that the compounds of the present invention can be systemically administered (e.g., orally or parenterally) in biologically relevant systems (e.g., in animals, preferably mammals, more preferably humans) while still maintaining therapeutic efficacy. Those skilled in the art will understand the additional features and advantages of the present technology after reading the detailed description of the present invention below.

[0011] In a first aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0012]

[0013] in:

[0014] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0015] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0016] R 7 are independently selected from -H and -OH;

[0017] R 8A group of formula (A):

[0018]

[0019] wherein n is independently an integer from 0 to 3;

[0020] m is independently an integer from 0 to 3;

[0021] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0022] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0023] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0024] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0025] R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0026] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl halide, -OH or -COOH substitution;

[0027] R86 Independently selected from -H, -COOH and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0028] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0029] R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0030] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0031] R 11 is independently at each occurrence halogen or -OH.

[0032] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0033]

[0034] in:

[0035] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0036] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0037] R 7 are independently selected from -H and -OH;

[0038] R 8 A group of formula (A):

[0039]

[0040] wherein n is independently an integer from 0 to 3;

[0041] m is independently an integer from 0 to 3;

[0042] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0043] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0044] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0045] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0046] R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0047] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0048] R 86 Independently selected from -H and -NR 88 R 89or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0049] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0050] R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0051] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0052] R 11 is independently at each occurrence halogen or -OH.

[0053] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein for use in a method for reducing the virulence of bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0054] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein for use in a method of inhibiting quorum sensing of bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or an ortholog of AgrA; more preferably, the bacteria express AgrA.

[0055] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein, for use in a method for preventing or treating a disease caused or aggravated by bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0056] 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.

[0057] 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 DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 The quorum sensing signals that control the production of virulence factors in Staphylococci are shown. 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 on its own cells or other bacterial cells. AgrC then activates the response regulator AgrA by phosphorylation. Phosphorylated AgrA binds agr P 2 and P 3 The promoter of AgrA and the promoter of the psm operon are involved and activate transcription from these promoters (RNAIII-independent AgrA regulation). The classical targets of AgrA are under RNAIII-dependent control, including several upregulated toxins and proteases and several downregulated surface-bound proteins (e.g., protein A). Small molecule inhibitors that bind to the DNA binding domain of AgrA prevent binding to P 2 and P 3 promoter, thereby blocking AIP (P 2 Driver) and virulence factors (P 3 drive), but also blocked the expression of RNAIII-independent AgrA-regulated pathways, such as the production of PSM. DETAILED DESCRIPTION

[0059] The present invention relates to a method for inhibiting P even in the presence of HS or HSA. 3 A compound that controls the transcription of a gene under the control of a promoter (for example, in bacteria, preferably in Staphylococcus aureus) and a pharmaceutical composition comprising the compound.

[0060] definition

[0061] 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 the invention belongs. The embodiments, preferred embodiments and very preferred embodiments described and disclosed herein should be applicable to all aspects and other embodiments, preferred embodiments and very preferred embodiments, whether or not specifically mentioned again or repetition is avoided for the sake of brevity.

[0062] Unless the context clearly dictates otherwise, the articles "a" and "an" used in this disclosure are used to refer to more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means one or more than one element.

[0063] The term "and / or" used in this disclosure means "and" or "or" unless otherwise stated.

[0064] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) may (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any other functional groups.

[0065] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon. 1 -C 6 The alkyl group contains 1 to 6 carbon atoms. 1 -C 6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec- and tert-butyl, isopentyl, and neopentyl.

[0066] The term "cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0067] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic group of 5 to 6 ring atoms, containing one or more ring heteroatoms selected from N, S, P and O, the remaining ring atoms being C. Preferably, the heteroatoms are selected from N, S and O, more preferably, the heteroatoms are selected from N and O. Aromatic groups are optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl and pyrazinyl. Heteroaryl can be fused to a partially saturated heterocycle, for example, as shown in compound 54. Other exemplary ring systems of such heteroaryl or heteroheteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indolyl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl, and dihydrobenzooxanyl.

[0068] The term "heterocyclyl", "heterocycloalkyl" or "heterocycle" refers to a saturated or partially saturated 4- to 11-membered ring containing carbon and a monocyclic or bicyclic heteroatom selected from O, N and S (preferably O and N), and the ring does not contain delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. Heterocyclyl rings include, but are not limited to, oxetane, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, [1,4] diazepane and [1,2] diazepane. The heterocyclyl or heterocycloalkyl rings can be bridged, for example, as shown in compound 50.

[0069] As shown in compounds 3 to 21, when Y 3 CR 84 R 85 When R 8 With the ring of formula (A) forms a spirocyclic heterocycle. As used herein, a spirocyclic heterocycle or spiroheterocycle is understood to mean a bicyclic ring system in which the two rings are linked by a single atom and at least one ring is a heterocycle (e.g., at least one ring is azetidine, pyrrolidine, morpholine or piperidine).

[0070] As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0071] The term "oxo" refers to a carbonyl functional group consisting of a carbon atom double-bonded to an oxygen atom. It may be abbreviated herein as "oxo", C(O) or C═O.

[0072] The present invention also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" or "therapeutically acceptable" refers to a substance that does not interfere with the effectiveness or biological activity of the active ingredient and is non-toxic to the host. Representative "pharmaceutically acceptable salts" include, for example, water-soluble salts and water-insoluble salts, such as acetate, stilbenesulfonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, α-glycollylarsanilate, hexafluorophosphate, resorcinol hexanoate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate

[0013] The invention also includes but is not limited to the following: iodine, iodide, selenosulfate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-benzene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethyliodide, and valerate.

[0073] The term "tautomers" refers to a group of compounds that have the same number and type of atoms, but with different bond connections and are in equilibrium with each other. A "tautomer" is a single member of this group of compounds. Often a single tautomer is drawn, but it is understood that this single structure is intended to represent all possible tautomers that may exist. Examples include enol-keto tautomers. When a ketone is drawn, it is understood that both the enol and keto forms are part of the present disclosure.

[0074] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention 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. Solvates with water as the solvent molecule are commonly referred to as "hydrates." Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0075] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting an agent from one organ or part of the body of a subject to another organ or part of the body.

[0076] As used in this disclosure, the term "disorder" means a disease, condition, or illness, and are used interchangeably unless otherwise indicated.

[0077] As used in this disclosure, the terms "administering," "dosing," or "administering" refer to directly administering a disclosed compound or a pharmaceutically acceptable salt of a disclosed compound or composition to a subject, or administering a prodrug derivative or analog of a compound, or a pharmaceutically acceptable salt of a compound or composition to a subject, which can form an equivalent amount of the active compound in the subject's body.

[0078] As used herein, the term "ortholog" represents the well-known meaning of this term. In the art, orthologous genes are genes that evolved from common ancestral genes in different species. Since orthologs separate after the speciation event, they may diverge, but usually have similarities at the sequence and structural levels; in addition, orthologs usually have the same function. Orthologous homology is a kind of homology. In this application, the term "ortholog" is used to include orthologous genes (DNA or RNA) or peptides / protein products of orthologous genes. Sometimes, the peptide / protein products of orthologous genes are referred to as "orthologous products" or simply "orthologs". The meaning will be apparent from the context (e.g., an anti-virulence composition of the invention may include an anti-virulence agent that is capable of reducing the virulence of a bacterium expressing a peptide or protein that may be referred to as an ortholog of AgrA, i.e., a product of an orthologous gene of S. aureus AgrA from another bacterium, such as Streptococcus pyogenes). In certain aspects, an ortholog of AgrA produces a protein / peptide that has an amino acid sequence that is greater than about 70%, about 80%, or about 90% identity to the gene product of AgrA.

[0079] The terms "reduce" and "inhibit" have their commonly understood meanings, ie, to make less or to reduce.

[0080] As used herein, the expression "reducing the virulence of bacteria expressing AgrA" generally and preferably refers to inhibiting the synthesis of one or more virulence factors by the compound of formula (I) of the present invention or the composition of the present invention, preferably a pharmaceutical composition comprising the compound of formula (I) of the present invention. Examples of virulence factors regulated by AgrA are: cell surface-associated proteins, such as protein A (SpA) and fibronectin binding protein; secreted toxins, such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble regulatory protein (PSM), Panton-Valentin leukolysin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH); or secreted proteases, such as SspA or Aureolysin. In a preferred embodiment and embodiment of the present invention, the reduction of the virulence of bacteria expressing AgrA is the inhibition of the synthesis of one or more virulence factors selected from PSMα, RNAIII and downstream targets thereof. In a preferred embodiment and embodiment of the present invention, the reduction of the virulence of bacteria expressing AgrA is the inhibition of the synthesis of PSMα. In a preferred example and embodiment of the present invention, the reduction of the virulence of the bacteria expressing AgrA is to inhibit the synthesis of RNAIII and / or its downstream targets, preferably RNAIII.

[0081] As used herein, the term "inhibiting the synthesis of one or more virulence factors" shall mean: compared with the synthesis of one or more virulence factors by the bacteria in the absence of the compound of formula (I) of the present invention or the composition of the present invention, preferably the pharmaceutical composition, comprising the compound of formula (I) of the present invention, or compared with the method of the present invention in which the compound of formula (I) of the present invention or the composition of the present invention, preferably the pharmaceutical composition, comprising the compound of formula (I) of the present invention is not applied or used, the synthesis of one or more virulence factors is completely or partially inhibited (preferably more than 20%, further preferably more than 30%, further preferably more than 50%, further preferably more than 90%, more preferably more than 95%, or even more than 99%).

[0082] Virulence factors considered herein include any molecule expressed and secreted by bacteria that promotes colonization and / or adhesion in a host subject, inflammation in host tissues, evasion of the host's immune response, and nutrient acquisition from a host subject. Virulence factors may also include exotoxins and endotoxins. Non-limiting examples of virulence factors inhibited by the compounds of formula (I) of the present invention as described herein or the compositions of the present invention, preferably the pharmaceutical compositions of the present invention, include: one or more toxins (e.g., α, β, γ, γ-variants, and δ-hemolysins), PSMs (e.g., PSMα), Panton-Valentine leukolysin (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 protein, agglutination factors, pyrogenic toxin superantigens (e.g., TSST-1). In a preferred embodiment, the virulence factor inhibited is RNAIII and / or its downstream targets or PSMα.

[0083] Depending on the severity of the infection or if used in a prophylactic manner, anti-virulence drugs can be administered alone or in combination with therapeutic agents (e.g., antibiotics) that are commonly and preferably used to prevent and treat infections caused by bacteria (e.g., staphylococci, primarily S. aureus) (e.g., pneumonia, bloodstream infections, acute skin and skin structure infections).

[0084] Anti-virulence drugs may be administered alone or in combination with therapeutic agents typically and preferably used to prevent and treat chronic inflammatory skin diseases (eg, atopic dermatitis, Netherton's syndrome, psoriasis) exacerbated by bacteria (eg, Staphylococcus, primarily S. aureus).

[0085] As used herein, the term "antibiotic" refers to an antimicrobial or anti-infective agent that kills bacteria (bactericidal antibiotics) or inhibits bacterial growth and / or metabolism (bacteriostatic antibiotics). Antibiotics are well known to those skilled in the art, and specific and preferred examples include penicillins, cephalosporins, polymyxins, rifamycins, intercalary mycins, quinolones, sulfonamides, macrolides, oxazolidinones, lincosamides, and tetracyclines.

[0086] As used herein, the terms "treat," "treatment," or "therapy" refer to means of obtaining a desired physiological effect. The effect may be therapeutic, in the sense of partially or completely curing a disease or condition and / or symptoms attributable to a disease or condition. The terms mean: inhibiting a disease or condition, i.e., arresting its development; or relieving a disease or condition, i.e., causing regression of the disease or condition.

[0087] As used herein, the term "preventing" refers to means of preventing or delaying the onset of a disease or condition and / or symptoms attributable to a disease or condition.

[0088] As used herein, the term "subject" or "animal" or "patient" or "mammal" refers to any subject in need of diagnosis, prognosis, prevention or treatment, in particular a mammalian subject, such as a human or a domesticated mammal, such as a dog, cat or horse, or a food animal, such as a cow, sheep or pig; preferably a human. Therefore, in a preferred embodiment of the present invention, the subject is a human.

[0089] As used herein, the term "for use in..." used in "composition for use in treating or preventing a disease" shall also disclose the corresponding treatment or prevention method, as well as the corresponding use of the formulation for preparing a medicament for treating or preventing a disease.

[0090] "Therapeutically effective amount" or "effective amount" is the amount of a compound or pharmaceutical composition according to the present invention that will cause a biological or medical response in a subject (preferably a human subject) that a researcher, veterinarian, doctor or other clinician is looking for. As used herein, the term "therapeutic administration" shall refer to the administration of a therapeutically effective amount. In particular, as used herein, the terms "effective", "effective amount" and "therapeutically effective amount" generally and preferably refer to the amount of a compound of formula (I) of the present invention or a composition of the present invention comprising a compound of formula (I) of the present invention, preferably a pharmaceutical composition of the present invention, which reduces the virulence of bacteria or causes the alleviation of symptoms or prolonged survival of a subject suffering from a disease or condition associated with bacteria. The term "effective amount" is generally used herein to refer to the amount of a given compound, or in the case of a mixture, to refer to the combined amount of the mixture components that provide a measurable effect for the listed functions. It will be understood by those of ordinary skill in the art that for a given application, the effective amount can be determined by the application of routine experiments without excessive experimentation by methods described herein or known in the art. The term "therapeutically effective amount" is generally used herein to refer to an amount of a given compound, or in the case of a mixture, the combined amounts of the components of the mixture, which, when administered to a subject, including a human or non-human animal, provides a measurable therapeutic effect on the listed disease, disorder or condition to at least partially alleviate the symptoms of such disease, disorder or condition. The result of treatment can be partial or complete relief, inhibition, prevention, improvement and / or alleviation of the disease, condition or one or more symptoms thereof.

[0091] Compounds of the present invention

[0092] In a first aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0093]

[0094] in:

[0095] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0096] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0097] R 7 are independently selected from -H and -OH;

[0098] R 8 A group of formula (A):

[0099]

[0100] wherein n is independently an integer from 0 to 3;

[0101] m is independently an integer from 0 to 3;

[0102] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0103] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0104] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0105] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0106] R81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0107] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl halide, -OH or -COOH substitution;

[0108] R 86 Independently selected from -H, -COOH and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0109] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0110] R 87 Independently selected from -H, -C 1 -C 6 Alkyl, -C(O)C1 -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0111] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0112] R 11 is independently at each occurrence halogen or -OH.

[0113] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0114]

[0115] in:

[0116] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0117] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0118] R 7 are independently selected from -H and -OH;

[0119] R 8 A group of formula (A):

[0120]

[0121] wherein n is independently an integer from 0 to 3;

[0122] m is independently an integer from 0 to 3;

[0123] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0124] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0125] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0126] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0127] The condition is: when Y 1 CR 81 R 82, Y 2 CR 81A R 82A , Y 3 For 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;

[0128] R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0129] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl halide, -OH or -COOH substitution;

[0130] R 86 Independently selected from -H, -COOH and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0131] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0132] R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0133] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0134] R 11 is independently at each occurrence halogen or -OH.

[0135] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0136]

[0137] in:

[0138] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0139] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0140] R 7 are independently selected from -H and -OH;

[0141] R 8 A group of formula (A):

[0142]

[0143] wherein n is independently an integer from 0 to 3;

[0144] m is independently an integer from 0 to 3;

[0145] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0146] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0147] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0148] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0149] R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0150] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl halide, -OH or -COOH substitution;

[0151] R 86 -COOH or -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0152] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0153] R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0154] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0155] R 11 is independently at each occurrence halogen or -OH.

[0156] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof:

[0157]

[0158] in:

[0159] R 1 are independently selected from -H, halogen, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0160] R 3 Independently selected from -H, -C 1 -C 6 Alkyl and -C 1 -C 6 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace;

[0161] R 7 are independently selected from -H and -OH;

[0162] R 8 A group of formula (A):

[0163]

[0164] wherein n is independently an integer from 0 to 3;

[0165] m is independently an integer from 0 to 3;

[0166] Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O;

[0167] Y 2 Independently selected from CR at each occurrence 81A R 82A and O;

[0168] Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0169] Among them, when Y 3 CR 84R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0170] R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group;

[0171] R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 7 Cycloalkyl or 4- to 7-membered heterocyclic ring, wherein the cycloalkyl and heterocyclic ring are each optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0172] R 86 Independently selected from -H and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0173] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82AOne of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0174] R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0175] Or, R 87 Together with the nitrogen atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution; and

[0176] R 11 is independently at each occurrence halogen or -OH.

[0177] In some embodiments, R 1are independently selected from -H, halogen, -C 1 -C 4 Alkyl and -C 1 -C 4 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace.

[0178] In some embodiments, R 1 Independently selected from -H, -F, -Cl, -C 1 -C 4 Alkyl and -C 1 -C 4 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more F, Cl and -OH.

[0179] In some embodiments, R 1 Independently selected from -H, -F, -C 1 -C 2 Alkyl and -C 1 -C 2 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more -F and -OH.

[0180] In some embodiments, R 1 Independently selected from -H, -F and -C 1 -C 2 Alkyl, which is optionally substituted with one or more -F and -OH.

[0181] In some embodiments, R 1 Independently selected from -H, -F and -C 1 -C 2 alkyl.

[0182] In some embodiments, R 1 Independently selected from -H and -C 1 -C 2 alkyl.

[0183] In some embodiments, R 1 -CH 3 .

[0184] In some embodiments, R 3 Independently selected from -H, -C 1 -C 4 Alkyl and -C 1 -C 4 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more R 11 replace.

[0185] In some embodiments, R 3Independently selected from -H, -C 1 -C 4 Alkyl and -C 1 -C 4 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more -F, -Cl or -OH.

[0186] In some embodiments, R 3 Independently selected from -H and -C 1 -C 4 Alkyl, which is optionally substituted with one or more -F, -Cl or -OH.

[0187] In some embodiments, R 3 Independently selected from -H and -C 1 -C 4 alkyl.

[0188] In some embodiments, R 3 Independently selected from -H and -C 1 -C 2 alkyl.

[0189] In some embodiments, R 3 Independently for C 1 -C 2 alkyl.

[0190] In some embodiments, R 3 -CH 3 In some embodiments, R 1 and R 3 -CH 3 .

[0191] In some embodiments, R 7 In some embodiments, R 7 It is -OH.

[0192] In some embodiments, Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O;

[0193] Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3;

[0194] The condition is: when Y 1CR 81 R 82 , Y 2 CR 81A R 82A , Y 3 For 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.

[0195] In some embodiments, Y 1 Independently selected from CR at each occurrence 81 R 82 ; Y 2 Independently selected from CR at each occurrence 81A R 82A ; Y 3 Independently selected from CR 84 R 85 , CHR 86 and NR 87 .

[0196] In some embodiments, Y 3 CR 84 R 85 .

[0197] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl, -OH or -COOH.

[0198] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0199] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 -haloalkyl, -OH or -COOH.

[0200] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 -haloalkyl or -OH substituted.

[0201] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0202] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C1 -C 3 Alkyl or -OH substituted.

[0203] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or more heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0204] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or more heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0205] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0206] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C1 -C 3 Alkyl or -OH substituted.

[0207] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0208] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0209] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 and C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Alkyl, -OH or -COOH, preferably, each cycloalkyl, -C 4 Heterocyclic and -C 6The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0210] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 and C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Alkyl or -OH substituted, preferably, each cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0211] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C 1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3 or -OH substitution.

[0212] In some embodiments, Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C 1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3or -OH substitution.

[0213] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl, -OH or -COOH.

[0214] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82AEach occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0215] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 -haloalkyl, -OH or -COOH.

[0216] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 -haloalkyl or -OH substituted.

[0217] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1-C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0218] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0219] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring containing heteroatoms selected from O and N, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0220] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring containing heteroatoms selected from O and N, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0221] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0222] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0223] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0224] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0225] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 Heterocyclic and -C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Preferably, the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0226] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 Heterocyclic and -C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Alkyl or -OH substituted, preferably, the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0227] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3 or -OH substitution.

[0228] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A H; Y independently at each occurrence 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C 1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3 or -OH substitution.

[0229] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl, -OH or -COOH.

[0230] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0231] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 Substituted with haloalkyl, -OH or -COOH.

[0232] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 -haloalkyl or -OH substituted.

[0233] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0234] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0235] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring containing heteroatoms selected from O and N, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0236] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring containing heteroatoms selected from O and N, each of which is optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0237] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl, -OH or -COOH substituted.

[0238] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 3 Alkyl or -OH substituted.

[0239] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0240] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 -C 6 Cycloalkyl or 4- to 6-membered heterocyclic ring, the heterocyclic ring containing one or two heteroatoms selected from O and N, the cycloalkyl or heterocyclic ring each optionally substituted by one or more -C 1 -C 2 Preferably, the cycloalkyl or heterocyclic ring is each optionally substituted with one or two -CH 3 or -OH substitution.

[0241] In some embodiments, Y 1 CR independently at each occurrence 81 R 82or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 Heterocyclic and -C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Preferably, the cycloalkyl, -C 4 Heterocyclic, -C 6 The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0242] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form -C 4 Cycloalkyl, -C 4 Heterocyclic or -C 6 Heterocyclic ring, the C 4 Heterocyclic and -C 6 The heterocyclic rings each contain one or two heteroatoms selected from O and N, and the cycloalkyl, -C 4 Heterocyclic and -C 6 The heterocyclic rings are each optionally substituted with one or more -C 1 -C 2 Alkyl or -OH substituted, preferably, the cycloalkyl, -C 4 Heterocyclic, -C 6 The heterocyclic rings are each optionally substituted with one or two -CH 3 or -OH substitution.

[0243] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82Ais independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C 1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3 or -OH substitution.

[0244] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 or O, preferably, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A or O, preferably, Y 2 CR independently at each occurrence 81A R 82A ; R 81 and R 81A H independently at each occurrence; R 82 and R 82A Each occurrence is independently H or -C 1 -C 3 Alkyl, preferably, R 82 and R 82A is independently H at each occurrence; m and n are each independently 0, 1, 2 or 3, and the sum of m and n is 2, 3 or 4; Y 3 CR 84 R 85 ; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form cyclobutane, azetidine, oxetane, piperidine or morpholine; each of the cyclobutane, azetidine, oxetane, piperidine or morpholine may be optionally substituted by one or more -C 1 -C 2 Preferably, the cyclobutane, azetidine, oxetane, piperidine, or morpholine are each optionally substituted with one or two -CH 3 or -OH substitution.

[0245] In some embodiments, Y 3 For CHR 86 .

[0246] In some embodiments, Y 3 For CHR 86 ; R 86 Independently selected from -H, -COOH and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0247] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring;

[0248] The condition is: when Y 1 CR 81 R 82 , Y 2 CR 81A R 82A , Y 3 For 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.

[0249] In some embodiments, Y 3 For CHR 86 , R 86 It is -H or -COOH.

[0250] In some embodiments, Y 3 For CHR 86 , R 86 It's H.

[0251] In some embodiments, Y 3 For CHR 86 , R 86 It is -COOH.

[0252] In some embodiments, Y 3 For CHR 86 , R 86 is H, if: when Y 1 CR 81 R 82 , Y 2 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.

[0253] In some embodiments, Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 3 or 4.

[0254] In some embodiments, Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4, 5 or 6.

[0255] In some embodiments, Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4.

[0256] In some embodiments, Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 5.

[0257] In some embodiments, Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 6.

[0258] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 3 or 4.

[0259] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4, 5 or 6.

[0260] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4.

[0261] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 5.

[0262] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 6.

[0263] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81AR 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 3 or 4; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl, preferably, R 81 , R 82 , R 81A , R 82A and R 82A is H independently at each occurrence.

[0264] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4, 5 or 6; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl, preferably, R 81 , R 82 , R 81A , R 82A and R 82A is H independently at each occurrence.

[0265] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 4; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl, preferably, R 81 , R82 , R 81A , R 82A and R 82A is H independently at each occurrence.

[0266] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 5; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl, preferably, R 81 , R 82 , R 81A , R 82A and R 82A is H independently at each occurrence.

[0267] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 is H; the sum of m and n is 6; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl, preferably, R 81 , R 82 , R 81A , R 82A and R 82A is H independently at each occurrence.

[0268] In some embodiments, R 86 For-NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A, R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0269] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0270] In some embodiments, R 86 -COOH or -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substitution;

[0271] R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 88 or R 89 One of them, together with the nitrogen atom to which they are attached, can 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0272] In some embodiments, Y 3 For CHR 86 , R 86is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0273] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0274] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted by one or more -C 1 -C 6 Alkyl or -OH, preferably -C 1 -C 2 Alkyl or -OH substituted.

[0275] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted by one or more -C 1 -C 6Alkyl or -OH, preferably -C 1 -C 2 Alkyl or -OH substituted.

[0276] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0277] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0278] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more heteroatoms selected from O and N.

[0279] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more heteroatoms selected from O and N.

[0280] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A, R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N.

[0281] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N.

[0282] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0283] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0284] In some embodiments, Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0285] In some embodiments, Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached,81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0286] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0287] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted with one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0288] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted by one or more -C 1 -C 6 Alkyl or -OH, preferably -C 1 -C 2 Alkyl or -OH substituted.

[0289] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring, which may be optionally substituted by one or more -C 1 -C 6 Alkyl or -OH, preferably -C 1 -C 2 Alkyl or -OH substituted.

[0290] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81, R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0291] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0292] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more heteroatoms selected from O and N.

[0293] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R82 or R 82A One of the above and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more heteroatoms selected from O and N.

[0294] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N.

[0295] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N.

[0296] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0297] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0298] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86 is -COOH, or R 86 Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0299] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; The sum of m and n is 2, 3 or 4, preferably, the sum of m and n is 3; Y 3 For CHR 86 , R 86Together with the carbon atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0300] In some embodiments, Y 3 For CHR 86 , R 86 -COOH or NR 88 R 89 .

[0301] In some embodiments, Y 3 For CHR 86 , R 86 NR 88 R 89 .

[0302] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0303] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0304] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more atoms selected from O and N.

[0305] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more atoms selected from O and N.

[0306] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0307] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0308] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0309] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0310] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0311] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0312] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0313] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0314] In some embodiments, Y 3 For CHR 86 , R 86 -COOH or NR 88 R 89 , m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0315] In some embodiments, Y 3 For CHR 86 , R 86 NR 88 R 89 , m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0316] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0317] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0318] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0319] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0320] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0321] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0322] In some embodiments, Y 3 For CHR 86 ; R 86-COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0323] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0324] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0325] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0326] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0327] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0328] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 , R 86 -COOH or NR 88 R 89 , m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0329] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 , R 86 NR 88 R 89 , m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0330] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81, R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0331] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0332] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of them and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0333] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0334] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0335] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0336] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0337] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached are combined to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0338] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0339] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0340] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0341] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 88 and R 89 One of them, together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0342] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 alkyl.

[0343] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 alkyl.

[0344] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0345] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0346] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 .

[0347] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 .

[0348] In some embodiments, Y 3 For CHR 86 ; R 86 COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0349] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C1 -C 3 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0350] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0351] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0352] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 ; m and n are each independently 1 or 2, preferably, m is 2 and n is 1 or 2.

[0353] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 ; m and n are each independently 1 or 2, preferably, m is 2 and n is 1 or 2.

[0354] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0355] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 3 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0356] In some embodiments, Y 1 CR independently at each occurrence 81 R82 ; Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0357] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0358] In some embodiments, Y 1CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 ; m and n are each independently 1 or 2, preferably, m is 2 and n is 1 or 2.

[0359] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 81A , R 82 and R 82 Each is independently selected at each occurrence from C 1 -C 2 Alkyl and -H, preferably, R 81 , R 81A , R 82 and R 82 Each is independently H at each occurrence; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 and R 89 is independently selected at each occurrence from -H and -CH 3 ; m and n are each independently 1 or 2, preferably, m is 2 and n is 1 or 2.

[0360] In some embodiments, Y 3 For CHR86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0361] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the 2- and 2-carbon atoms to which they are attached combines to form a 5- to 6-membered heterocyclic ring.

[0362] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more atoms selected from O and N.

[0363] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or more atoms selected from O and N.

[0364] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0365] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring containing one or two atoms selected from O and N.

[0366] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82AOne of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0367] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine.

[0368] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0369] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the atoms and the carbon atom to which they are attached combine to form pyrrolidine.

[0370] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0371] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0372] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0373] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0374] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0375] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0376] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0377] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0378] In some embodiments, Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0379] In some embodiments, Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0380] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0381] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0382] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0383] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or more atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0384] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0385] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring comprising one or two atoms selected from O and N; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0386] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0387] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of them and the carbon atom to which they are connected combine to form a 5- to 6-membered heterocyclic ring selected from piperidine, morpholine, piperazine and pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0388] In some embodiments, Y 1 CR independently at each occurrence 81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 -COOH or NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0389] In some embodiments, Y 1 CR independently at each occurrence81 R 82 ; Y 2 CR independently at each occurrence 81A R 82A ; Y 3 For CHR 86 ; R 86 NR 88 R 89 ; R 88 independently -H or C 1 -C 2 Alkyl; R 89 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form pyrrolidine; m and n are each independently 1 or 2, preferably, m is 2, and n is 1 or 2.

[0390] In some embodiments, Y 3 NR 87 .

[0391] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6The 4- to 6-membered heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 haloalkyl or -OH; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein each of the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0392] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -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 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 6 Alkyl or -OH substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R82A and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more -C 1 -C 6 Alkyl, - or -OH substituted.

[0393] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 6 Alkyl or -OH substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group.

[0394] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 6 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group each contains one or more atoms selected from O and N.

[0395] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 4 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 4 Alkoxy, -OH, -NH 2 、-NHC 1 -C 4 Alkyl or N(C 1 -C 4 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 4 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A, R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group each contains one or two atoms selected from O and N.

[0396] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 2 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0397] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or more atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0398] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or two atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0399] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 A cycloalkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0400] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -C 1 -C 6 Alkoxy, -OH, -O(CH2 ) 2 -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The 4- to 6-membered heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein each of the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group is optionally substituted by one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0401] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C6 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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 6 Alkyl or -OH substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more -C 1 -C 6 Alkyl or -OH substituted.

[0402] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 6 Alkyl or -OH substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group.

[0403] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 6 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group.

[0404] In some embodiments, Y 3NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 4 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 4 Alkoxy, -OH, -NH 2 、-NHC 1 -C 4 Alkyl or N(C 1 -C 4 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 4 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 4 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group each contains one or more atoms selected from O and N.

[0405] In some embodiments, Y 3NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the cycloalkyl or 4- to 6-membered heterocyclic ring are each optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl group each contains one or two atoms selected from O and N.

[0406] In some embodiments, Y 3NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and a 4- to 6-membered heterocyclic ring containing one or more atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0407] In some embodiments, Y 3 NR 87 , R87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and a 4- to 6-membered heterocyclic ring containing one or two atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0408] In some embodiments, Y 3 NR 87 , R 87Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 A cycloalkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 The 4- to 6-membered heterocyclic ring may be substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; or, R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0409] In some embodiments, Y 3 NR 87 , R 87Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more halogens, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0410] In some embodiments, Y 3 NR 87 , R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atoms to which they are attached are combined to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one or more -C 1 -C 6 Alkyl or -OH, preferably C 1 -C 2 Alkyl or -OH substituted.

[0411] In some embodiments, Y 3 NR 87 , R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the above and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group.

[0412] In some embodiments, Y 3 NR 87 , R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the heterocyclic ring or heteroaryl group contains one or more atoms selected from O and N.

[0413] In some embodiments, Y 3 NR 87 , R 87 Together with the nitrogen atom to which it is attached, 81 , R81A , R 82 or R 82A One of the and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, wherein the heterocyclic ring or heteroaryl group contains one or two atoms selected from O and N.

[0414] In some embodiments, Y 3 NR 87 , R 87 Together with the nitrogen atom to which it is attached, 81 , R 81A , R 82 or R 82A One of the ions and the carbon atom to which they are attached combine to form piperidine, morpholine, piperazine, pyrrolidine or imidazole.

[0415] In some Y 3 NR 87 In the embodiment, R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Substituted with haloalkyl or -OH.

[0416] In some embodiments, Y 3 NR87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogens, -C 1 -C 6 Alkyl or -OH substituted.

[0417] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 6 Alkyl substitution.

[0418] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 4 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 4 Alkoxy, -OH, -NH 2 、-NHC 1 -C 4 Alkyl or N(C 1 -C 4 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 4 Alkyl substitution.

[0419] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 2 Alkyl substitution.

[0420] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or more atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substitution.

[0421] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or two atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substitution.

[0422] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 A cycloalkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substitution.

[0423] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 an alkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substitution.

[0424] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 2alkyl and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine and oxetane; the heterocyclic ring is optionally substituted by one or more -C 1 -C 2 Alkyl substitution.

[0425] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more halogen, -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 Substituted; the cycloalkyl group may be optionally substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 The heterocyclic ring may be substituted with one or more halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl or -OH substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 alkyl.

[0426] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl group may be optionally substituted with one or more -C 1 -C 6 The heterocyclic ring may be substituted with one or more -C 1 -C 6 Alkyl or -OH substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 alkyl.

[0427] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -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 heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 6 Alkoxy, -OH, -NH 2 、-NHC 1 -C 6 Alkyl or N(C 1 -C 6 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 6 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 6 alkyl.

[0428] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH2 、-S(O) 2 C 1 -C 4 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 4 Alkoxy, -OH, -NH 2 、-NHC 1 -C 4 Alkyl or N(C 1 -C 4 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 4 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 4 alkyl.

[0429] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic ring; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the cycloalkyl or heterocyclic ring are each optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0430] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or more atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0431] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 Cycloalkyl and 4- to 6-membered heterocyclic rings containing one or two atoms selected from O and N; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0432] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -S(O) 2 NH 2 、-S(O) 2 C 1 -C 2 Alkyl, -C 3 -C 6 A cycloalkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 Independently selected from CR at each occurrence 81 R 82 and C(O);Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R82A is independently selected at each occurrence from -H and -C 1 -C 2 alkyl.

[0433] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 4 an alkyl group and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine and oxetane; wherein each alkyl group is optionally substituted by one or more -C 1 -C 2 Alkoxy, -OH, -NH 2 、-NHC 1 -C 2 Alkyl or N(C 1 -C 2 alkyl) 2 Substituted; the heterocyclic ring may be optionally substituted with one or more -C 1 -C 2 Alkyl substituted; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 CR 81 R 82 ; Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m is 2, n is 2.

[0434] In some embodiments, Y 3 NR 87 , R 87 Independently selected from -H, -C 1 -C 2 alkyl and a 4- to 6-membered heterocyclic ring selected from piperidine, piperazine, morpholine, tetrahydropyran, pyrrolidine, tetrahydrofuran, azetidine and oxetane; the heterocyclic ring is optionally substituted by one or more -C 1 -C 2 Alkyl substituted; Y 1Independently selected from CR at each occurrence 81 R 82 , C(O) and O, preferably Y 1 CR 81 R 82 ; Y 2 Independently selected from CR at each occurrence 81A R 82A and O, preferably Y 2 CR independently at each occurrence 81A R 82A ; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C 1 -C 2 Alkyl; m is 2, n is 2.

[0435] In some embodiments, R 8 Including formula (B):

[0436]

[0437] in:

[0438] R 81 is independently selected at each occurrence from -H and -C 1 -C 2 alkyl;

[0439] R 87 Independently selected from -H, -C 1 -C 2 An alkyl group and a 4- to 6-membered heterocyclic ring, preferably, the heterocyclic ring contains one heteroatom selected from O and N; and

[0440] p is 0, 1 or 2.

[0441] In some embodiments, R 8 Comprising formula (B), wherein:

[0442] R 81 is independently selected at each occurrence from -H and methyl;

[0443] R 87 are independently selected from -H, methyl, and a 4- to 6-membered heterocyclic ring; and

[0444] p is 0, 1 or 2, preferably p is 0 or 2.

[0445] In some embodiments, R 8 Comprising formula (B), wherein:

[0446] R 81is independently selected at each occurrence from -H and methyl;

[0447] R 87 are independently selected from -H, methyl, oxetane (preferably 3-oxetane) and tetrahydropyran (preferably 4-tetrahydropyran); and

[0448] p is 0, 1 or 2, preferably p is 0 or 2.

[0449] In some embodiments, R 8 Comprising formula (B), wherein:

[0450] R 81 is independently selected at each occurrence from -H and methyl;

[0451] R 87 are independently selected from -H, methyl, oxetane (preferably 3-oxetane) and tetrahydropyran (preferably 4-tetrahydropyran); and

[0452] p is 0, 1 or 2, preferably p is 0 or 2;

[0453] Preferably, when there are 2 R 81 When they are attached to different carbon atoms.

[0454] In some embodiments, R 8 Including formula (B-1):

[0455]

[0456] in:

[0457] R 81 is independently selected at each occurrence from -H and -C 1 -C 2 alkyl;

[0458] R 81A is independently selected at each occurrence from -H and -C 1 -C 2 alkyl;

[0459] R 87 Independently selected from -H, -C 1 -C 2 Alkyl and 4- to 6-membered heterocyclic ring, preferably, the heterocyclic ring contains one heteroatom selected from O and N.

[0460] In some embodiments, R 8 Comprising formula (B-1), wherein:

[0461] R 81 is independently selected at each occurrence from -H and methyl;

[0462] R 81A is independently selected at each occurrence from -H and methyl;

[0463] R 87 Independently selected from -H, methyl and a 4- to 6-membered heterocyclic ring, preferably, the heterocyclic ring contains one heteroatom selected from O and N.

[0464] In some embodiments, R 8 Comprising formula (B-1), wherein:

[0465] R 81 is independently selected at each occurrence from -H and methyl;

[0466] R 81A is independently selected at each occurrence from -H and methyl;

[0467] R 87 Independently selected from -H, methyl, oxetane (preferably 3-oxetane) and tetrahydropyran (preferably 4-tetrahydropyran).

[0468] In some embodiments, R 8 Comprising formula (B-1), wherein:

[0469] R 81 and R 81A are each taken together selected from -H and methyl;

[0470] R 87 Independently selected from -H, methyl, oxetane (preferably 3-oxetane) and tetrahydropyran (preferably 4-tetrahydropyran).

[0471] In some embodiments, R 8 Including formula (C):

[0472]

[0473] in:

[0474] Y 4 Selected from -CR 91 R 92 -、-NR 93 - and O;

[0475] R 91 and R 92 Each independently selected from -H, -C 1 -C 6 Alkyl, -OH and -COOH; and

[0476] R 93 Selected from -H and -C 1 -C 6 alkyl.

[0477] In some embodiments, R 8 Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -、-NR 93 - and O;

[0478] R 91 and R 92 Each independently selected from -H, -C 1 -C 6 Alkyl and -OH; and

[0479] R 93 Selected from -H and -C 1 -C 6 alkyl.

[0480] In some embodiments, R 8 Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -.

[0481] In some embodiments, R 8 Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0482] R 91 and R 92 Each independently selected from -H, -C 1 -C 4 Alkyl, -OH and -COOH; and

[0483] R 93 Selected from -H and -C 1 -C 4 alkyl.

[0484] In some embodiments, R 8 Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0485] R 91 and R 92 Each independently selected from -H, -C 1 -C 4 Alkyl and -OH; and

[0486] R93 Selected from -H and -C 1 -C 4 alkyl.

[0487] In some embodiments, R 8 Including formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0488] R 91 and R 92 Each independently selected from -H, -C 1 -C 2 Alkyl, -OH and -COOH; and

[0489] R 93 Selected from -H and -C 1 -C 2 alkyl.

[0490] In some embodiments, R 8 Including formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0491] R 91 and R 92 Each independently selected from -H, -C 1 -C 2 Alkyl and -OH; and

[0492] R 93 Selected from -H and -C 1 -C 2 alkyl.

[0493] In some embodiments, R 8 Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0494] R 91 and R 92 Each independently selected from -H, -CH 3 , -OH and -COOH; and

[0495] R 93 Selected from -H and -CH 3 .

[0496] In some embodiments, R 8Comprising formula (C), wherein Y 4 Selected from -CR 91 R 92 -and-NR 93 -;

[0497] R 91 and R 92 Each independently selected from -H, -CH 3 and -OH; and

[0498] R 93 Selected from -H and -CH 3 .

[0499] In some embodiments, R 8 Comprising formula (C), wherein Y 4 For-CR 91 R 92 -;as well as

[0500] R 91 and R 92 Each independently selected from -H, -CH 3 , -OH and -COOH.

[0501] In some embodiments, R 8 Comprising formula (C), wherein Y 4 For-CR 91 R 92 -;as well as

[0502] R 91 and R 92 Each independently selected from -H, -CH 3 and -OH.

[0503] In some embodiments, R 8 Comprising formula (C), wherein Y 4 For-NR 93 -;as well as

[0504] R 93 Selected from -H and -CH 3 .

[0505] In some embodiments, the compound of formula (I) is selected from:

[0506] 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);

[0507] 3-(2,4-Dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2);

[0508] 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 3);

[0509] 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-2,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 4);

[0510] 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-2,9-diazaspiro[5.5]undec-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 5);

[0511] 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-3,9-diazaspiro[5.5]undec-3-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 6);

[0512] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 7);

[0513] 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);

[0514] 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);

[0515] 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);

[0516] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-methyl-1,6-diazaspiro[3.3]heptane-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 11);

[0517] 3-(2,4-Dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptane-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 12);

[0518] 3-(2,4-dimethylbenzenesulfonyl)-8-{2-oxa-6-azaspiro[3.3]heptane-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 13);

[0519] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 14);

[0520] 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 15);

[0521] 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 16);

[0522] 3-(2,4-Dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undec-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 17);

[0523] 3-(2,4-Dimethylbenzenesulfonyl)-8-{9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 18);

[0524] 3-(2,4-Dimethylbenzenesulfonyl)-8-[(7R)-7-hydroxy-3,9-diazaspiro[5.5]undec-3-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 19);

[0525] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-hydroxy-2-azaspiro[3.3]heptane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 20);

[0526] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 21);

[0527] 3-(2,4-Dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 22);

[0528] 3-(2,4-Dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 23);

[0529] 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);

[0530] 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);

[0531] 3-(2,4-Dimethylbenzenesulfonyl)-8-(3,5-dimethylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 26);

[0532] 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);

[0533] 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);

[0534] 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);

[0535] 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);

[0536] 3-(2,4-Dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 31);

[0537] 8-[4-(Dimethylamino)piperidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 32);

[0538] 8-(4-aminopiperidin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 33);

[0539] 3-(2,4-Dimethylbenzenesulfonyl)-8-[3-(methylamino)pyrrolidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 34);

[0540] 8-[(3R)-3-aminopyrrolidin-1-yl]-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 35);

[0541] 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);

[0542] 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);

[0543] 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);

[0544] 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);

[0545] 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);

[0546] 8-(4-tert-Butylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 41);

[0547] 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);

[0548] 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);

[0549] 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);

[0550] 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);

[0551] 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);

[0552] 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 47);

[0553] 3-(2,4-Dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 48);

[0554] 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);

[0555] 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);

[0556] 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);

[0557] 3-(2,4-Dimethylbenzenesulfonyl)-8-[4-(2-methylpropionyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 52);

[0558] 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);

[0559] 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);

[0560] 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);

[0561] 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);

[0562] 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);

[0563] 8-{4-[3-(Diethylamino)propionyl]piperazin-1-yl}-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 58);

[0564] 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);

[0565] 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 60);

[0566] 3-(2,4-Dimethylbenzenesulfonyl)-8-(4-methylsulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 61);

[0567] 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (Compound 62);

[0568] 2-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 63); and

[0569] 1-[3-(2,4-Dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-piperidine-4-carboxylic acid (Compound 64);

[0570] or a pharmaceutically acceptable salt thereof.

[0571] In some embodiments, the compound of formula (I) is selected from:

[0572] 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);

[0573] 3-(2,4-Dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2);

[0574] 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 3);

[0575] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 7);

[0576] 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);

[0577] 3-(2,4-Dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptane-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 12);

[0578] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 14);

[0579] 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 16);

[0580] 3-(2,4-Dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 21);

[0581] 3-(2,4-Dimethylbenzenesulfonyl)-8-(4-methylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 22);

[0582] 3-(2,4-Dimethylbenzenesulfonyl)-8-(piperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 23);

[0583] 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);

[0584] 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);

[0585] 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);

[0586] 3-(2,4-Dimethylbenzenesulfonyl)-8-[4-(methylamino)piperidin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 31);

[0587] 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);

[0588] 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);

[0589] 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);

[0590] 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);

[0591] 8-(1,4-diazepan-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 47);

[0592] 3-(2,4-Dimethylbenzenesulfonyl)-8-(1,4-oxazepan-4-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 48);

[0593] 3-(2,4-Dimethylbenzenesulfonyl)-8-[4-(2-methylpropionyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 52);

[0594] 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);

[0595] 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);

[0596] 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);

[0597] 8-(4-cyclopropylpiperazin-1-yl)-3-(2,4-dimethylbenzenesulfonyl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 60);

[0598] 3-(2,4-Dimethylbenzenesulfonyl)-8-(4-methylsulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 61);

[0599] 4-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]piperazine-1-sulfonamide (Compound 62);

[0600] 2-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 63); and

[0601] 1-[3-(2,4-Dimethylbenzenesulfonyl)-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.

[0602] 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.

[0603] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2), or a pharmaceutically acceptable salt thereof.

[0604] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{8-methyl-2,8-diazaspiro[4.5]decane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 3), or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{2-methyl-2,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 4), or a pharmaceutically acceptable salt thereof.

[0606] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-2,9-diazaspiro[5.5]undecane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 5), or a pharmaceutically acceptable salt thereof.

[0607] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-3,9-diazaspiro[5.5]undec-3-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 6), or a pharmaceutically acceptable salt thereof.

[0608] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-oxa-2,9-diazaspiro[4.5]decane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 7), or a pharmaceutically acceptable salt thereof.

[0609] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-6-oxa-2,9-diazaspiro[4.5]decane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 8), or a pharmaceutically acceptable salt thereof.

[0610] 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.

[0611] 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.

[0612] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-1,6-diazaspiro[3.3]heptane-1-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 11), or a pharmaceutically acceptable salt thereof.

[0613] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-methyl-1,6-diazaspiro[3.3]heptane-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 12), or a pharmaceutically acceptable salt thereof.

[0614] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{2-oxa-6-azaspiro[3.3]heptane-6-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 13), or a pharmaceutically acceptable salt thereof.

[0615] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 14), or a pharmaceutically acceptable salt thereof.

[0616] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 15), or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{4-methyl-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 16), or a pharmaceutically acceptable salt thereof.

[0618] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{1-oxa-4,9-diazaspiro[5.5]undec-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 17), or a pharmaceutically acceptable salt thereof.

[0619] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 18), or a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[(7R)-7-hydroxy-3,9-diazaspiro[5.5]undec-3-yl]-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 19), or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-2-azaspiro[3.3]heptane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 20), or a pharmaceutically acceptable salt thereof.

[0622] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl}-1H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 21), or a pharmaceutically acceptable salt thereof.

[0623] 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.

[0624] 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.

[0625] 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.

[0626] In some embodiments, the compound of formula (I) is racemic-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.

[0627] 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.

[0628] 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.

[0629] In some embodiments, the compound of formula (I) is racemic-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.

[0630] 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.

[0631] 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.

[0632] 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.

[0633] 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.

[0634] 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.

[0635] 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.

[0636] 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.

[0637] 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.

[0638] 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.

[0639] 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.

[0640] 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.

[0641] 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.

[0642] 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.

[0643] 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.

[0644] 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.

[0645] 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.

[0646] 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.

[0647] 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.

[0648] 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.

[0649] 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.

[0650] 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.

[0651] 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.

[0652] 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.

[0653] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(2-methylpropionyl)piperazin-1-yl]-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 52), or a pharmaceutically acceptable salt thereof.

[0654] 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.

[0655] 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.

[0656] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-[4-(oxetane-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.

[0657] 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.

[0658] 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.

[0659] In some embodiments, the compound of formula (I) is 8-{4-[3-(diethylamino)propionyl]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.

[0660] 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.

[0661] 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.

[0662] In some embodiments, the compound of formula (I) is 3-(2,4-dimethylbenzenesulfonyl)-8-(4-methylsulfonylpiperazin-1-yl)-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 61), or a pharmaceutically acceptable salt thereof.

[0663] 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.

[0664] In some embodiments, the compound of formula (I) is 2-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 63), or a pharmaceutically acceptable salt thereof.

[0665] In some embodiments, the compound of formula (I) is 1-[3-(2,4-dimethylbenzenesulfonyl)-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.

[0666] Antitoxic activity of the compounds of the present invention

[0667] The compounds of the present invention are 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives containing an N-bonded and specifically defined heterocyclic ring at the 8-position of the [1,2,3]triazolo[1,5a]quinazolin-5-(4H)-one nucleus. As shown in Example 3 and Table 2, the compounds of the present invention were tested in the AgrA reporter assay to evaluate their ability to inhibit P regulated by AgrA. 3 The ability of a gene to be expressed under the control of a promoter. Specifically, the reporter gene lacZ (which encodes a protein product β-galactosidase) is transfected into Staphylococcus aureus with a plasmid controlled by the P3 promoter. The compounds of the present invention are serially diluted in lysogenic broth (LB) with and without human serum (HS) or human serum albumin (HSA) and incubated with Staphylococcus aureus. After incubation, the Staphylococcus aureus cells are lysed and treated with 4-methylumbelliferyl-galactoside (MUG). The β-galactosidase produced by lacZ expression cleaves MUG into galactopyranose and 4-methylumbelliferyl, which are measured by fluorescence. Therefore, the fluorescence reading can be used as a measure of the inhibition of P by the compounds of the present invention. 3 An indicator of the competence of a gene under the control of a promoter (eg, in bacteria, preferably in Staphylococcus aureus).

[0668] The compounds of the present invention are potent inhibitors of lacZ expression and remain active in the presence of 40 mg / mL HSA, with IC 50The value is as low as 3.7 μg / mL. Therefore, even if incubated with HSA at physiologically relevant concentrations, the compounds of the present invention also maintain the activity of inhibiting the expression of genes regulated by AgrA. In contrast, as shown in Example 3, although compound 45, compound 46 and compound 58 of WO 2020 / 109350 inhibit the expression of lacZ at a concentration of less than 1 μg / mL in the AgrA reporter assay in the absence of HSA or HS, when incubated with Staphylococcus aureus in the presence of HSA (or HS), these compounds are not active even at the highest compound concentration tested (i.e., 128 μg / mL; compound 45 of WO 2020 / 109350), or the activity is severely lost (>200 times) in the presence of HS (compounds 46 and 58 of WO 2020 / 109350).

[0669] Without wishing to be bound, a concentration of 40 mg / mL HSA was chosen as this is the same concentration of HSA found in human serum.

[0670] Without wishing to be bound, the compounds of the present invention retain their activity even in the presence of HSA, which enables the compounds of the present invention to be administered systemically (e.g., to a subject, such as a mammal, preferably a human; preferably by oral and / or parenteral administration) while still maintaining therapeutic efficacy. Thus, the compounds of the present invention unexpectedly retain their activity even when incubated in biologically relevant concentrations of HSA.

[0671] Uses of the compounds of the present invention

[0672] 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 a bacterium, preferably a bacterium expressing AgrA or an ortholog of AgrA, preferably AgrA, further preferably a bacterium belonging to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium belonging to Staphylococcus, further more preferably Staphylococcus aureus. In a further very preferred embodiment, the bacterium expresses AgrA or an ortholog of AgrA. In a further very preferred embodiment, the bacterium expresses AgrA. In a further very preferred embodiment, the bacterium belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium. In a further very preferred embodiment, the bacterium belongs to the genus Staphylococcus. In a further very preferred embodiment, the bacterium is Staphylococcus aureus. The embodiments, preferred embodiments and very preferred embodiments of the compounds of formula (I) described and disclosed herein shall apply to the method according to the invention, regardless of whether they are specifically mentioned again or repetitions are avoided for the sake of brevity.

[0673] In yet another aspect, the present invention provides compounds according to formula (I) as disclosed herein and pharmaceutically acceptable salts, stereoisomers, enantiomers and tautomers of compounds of formula (I) for use in a method for preventing or treating a disease caused or aggravated by bacteria (preferably an infection or inflammatory disease, further preferably a bacterial infection or an inflammatory skin disease), preferably, the bacteria are selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, further preferably, the bacteria are Staphylococcus aureus. In yet another very preferred embodiment, the disease is an infection or an inflammatory disease. In yet another very preferred embodiment, the disease is an infection. In yet another very preferred embodiment, the disease is a bacterial infection or an inflammatory skin disease caused or aggravated by bacteria. In yet another very preferred embodiment, the disease is a bacterial infection, the bacteria are selected from Staphylococcus, Streptococcus or Clostridium. In yet another very preferred embodiment, the disease is aggravated by bacteria selected from Staphylococcus, preferably Staphylococcus aureus. In a further very preferred embodiment, the disease is an infection caused or aggravated by a bacterium selected from the genus Staphylococcus. In a further very preferred embodiment, the disease is an infection caused or aggravated by Staphylococcus aureus. In a further very preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis or Netherton's syndrome. In a further very preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis aggravated by Staphylococcus aureus. The embodiments, preferred embodiments and very preferred embodiments of the compounds of formula I described and disclosed herein shall apply to the method of the present invention, regardless of whether they are specifically mentioned again or repetition is avoided for the sake of brevity.

[0674] In yet another 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 bacteria, preferably selected from bacteria of the genus Staphylococcus, Streptococcus or Clostridium, more preferably selected from bacteria of the genus Staphylococcus, and even more preferably Staphylococcus aureus. The embodiments, preferred embodiments and very preferred embodiments of the compounds of formula I described and disclosed herein should apply to the method of the present invention, whether or not specifically mentioned again or repetition is avoided for the sake of brevity.

[0675] In another preferred embodiment, the bacterium is selected from Streptococcus pyogenes, Clostridium difficile or Staphylococcus aureus, preferably, the bacterium is Staphylococcus aureus. In a very preferred embodiment, the bacterium is Staphylococcus aureus.

[0676] Therefore, the compositions and compounds of the present invention represent anti-virulence therapies that can be used as stand-alone treatments to enhance the infected host's self-defense and self-healing abilities by reducing tissue damage, reducing inflammation, reducing disease transmission, maintaining immune responses, and reducing relapse rates. In cases where the host may not be able to adequately clear the disarmed pathogen, combined therapy with conventional antibiotics (for infections caused by S. aureus) or anti-inflammatory agents (for diseases exacerbated by S. aureus) may be considered, thereby ultimately optimizing the timeliness and / or dosage of treatment (Dickey SW et al., (2017) Nat Rev Drug Discov 16(7):457-471).

[0677] In a preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the synthesis of one or more virulence factors of bacteria, wherein the one or more virulence factors are selected from: toxins (e.g., α, β, γ, γ-variants and δ-hemolysin), PSM (e.g., PSMα), Panton-Valentin leukolysin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B), exfoliating toxins), proteases (e.g., serine proteases, metalloproteases and cysteine ​​proteases), nucleases, lipases, coagulase, hyaluronidase, agglutination factors, pyrogenic toxin superantigens (e.g., TSST-1), and combinations thereof. Therefore, in another preferred embodiment of the method of the present invention, the one toxin is selected from α, β, γ, γ-variants and δ-hemolysin. In another preferred embodiment of the method of the present invention, the PSM is PSMα. In another preferred embodiment of the method of the present invention, the enterotoxin is enterotoxin B or exfoliating toxin. In another preferred embodiment of the method of the present invention, the protease is selected from serine proteases, metalloproteases and cysteine ​​proteases. In another preferred embodiment of the method of the present invention, the pyrogenic toxin superantigen is TSST-1. In another preferred embodiment of the method of the present invention, the compound of formula (I) inhibits bacteria from synthesizing one or more virulence factors selected from α, β, γ, γ-variants and δ-hemolysins, PSMα, Panton-Valentine leukolysin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxin B, epidermal exfoliation toxin, serine proteases, metalloproteases, cysteine ​​proteases, nucleases, lipases, coagulases, hyaluronidases, coagulation factors, TSST-1, and any combination of any specific virulence factor or general virulence factor group thereof. In another very preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of PSMα, RNAIII and / or any downstream target thereof. In another very preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of PSMα. In another very preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of RNAIII. In another very preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of downstream targets of RNAIII. In another very preferred embodiment, the method further comprises administering an antibiotic or an anti-inflammatory agent to the subject, preferably the human. In another very preferred embodiment, the method further comprises administering an antibiotic to the subject, preferably the human. In another very preferred embodiment, the method further comprises administering an anti-inflammatory agent to the subject, preferably the human.

[0678] In another aspect, the present invention provides a method for preventing or treating a disease caused or aggravated by bacteria (preferably an infection or inflammatory disease, further preferably a bacterial infection or an inflammatory skin disease) in a subject in need thereof, preferably, the bacteria is selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further more preferably, the bacteria is Staphylococcus aureus; the method comprises administering to a subject in need of such prevention or treatment an effective amount of a compound of formula (I), a pharmaceutical composition or a combination product, preferably a compound of formula (I). In another very preferred embodiment, the disease is an infection or an inflammatory disease. In another very preferred embodiment, the disease is an infection. In another very preferred embodiment, the disease is a bacterial infection. In another very preferred embodiment, the disease is an inflammatory skin disease caused or aggravated by bacteria. Preferably, the infection, preferably the bacterial infection is caused by a bacterium selected from Staphylococcus, Streptococcus or Clostridium, more preferably caused by a bacterium of the genus Staphylococcus, and further more preferably caused by Staphylococcus aureus. In yet another very preferred embodiment, said infection, preferably said bacterial infection comprises an antibiotic resistant Staphylococcus infection, preferably said antibiotic resistant Staphylococcus infection comprises a methicillin resistant Staphylococcus aureus infection.

[0679] Therefore, the compounds of formula (I) of the present invention as described herein or the compositions of the present invention (preferably the pharmaceutical compositions of the present invention) comprising the compounds of formula (I) of the present invention can be administered to a subject to inhibit the activity of AgrA, thereby preventing the production of virulence factors that contribute to the development of bacterial infection or diseases, conditions or disorders associated with bacterial infection. Examples of diseases and disorders associated with bacterial infection that respond to treatment with the compounds and / or compositions of the present invention may include, but are not limited to, skin and soft tissue infections, lung infections, Netherton syndrome, or chronic inflammatory skin diseases, such as atopic dermatitis.

[0680] In another aspect, the present invention provides a method for inhibiting quorum sensing, preferably AgrA quorum sensing, in bacteria (preferably selected from bacteria of the genus Staphylococcus, Streptococcus or Clostridium, more preferably bacteria of the genus Staphylococcus, and even more preferably Staphylococcus aureus), the method comprising 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).

[0681] In another preferred embodiment of the present invention, the compound of formula (I) is provided in the form of an external composition together with a pharmaceutically acceptable carrier and applied externally to a subject, wherein the subject preferably suffers from a disease or condition associated with a bacterial infection, and the bacterial infection is an infection caused or aggravated by bacteria (preferably Staphylococcus aureus). In another preferred embodiment, the infection caused or aggravated by bacteria is SSTI, Netherton syndrome or atopic dermatitis. In another preferred embodiment, the bacterial infection is SSTI or atopic dermatitis.

[0682] Therefore, the compound of formula (I) of the present invention as described herein or the composition of the present invention or the combination product of the present invention, preferably the compound of formula (I) of the present invention, the pharmaceutical composition of the present invention comprising the compound of formula (I) of the present invention, can be used to prevent or treat any bacterial species that utilizes AgrA response regulators for quorum sensing and produces virulence factors to infect a subject. The compounds and compositions of the present invention are usually and preferably applied to subjects suffering from infection or at risk of infection (preferably bacterial infection, such as staphylococcal and / or streptococcal infection). For example, a subject that can benefit from the treatment of the compounds or compositions of the present invention as described herein can be an inpatient at risk of developing a nosocomial infection, or a subject known to be infected or exposed to antibiotic-resistant bacteria (e.g., methicillin-resistant Staphylococcus aureus, vancomycin-moderately sensitive Staphylococcus aureus, and vancomycin-resistant Staphylococcus aureus). Methods for detecting Staphylococcus bacterial infection are well known, for example, methods for culturing from a sample of a subject, such as blood culture, can be used.

[0683] In another aspect, the present invention provides a method for treating a subject suffering from an infection or inflammatory disease (preferably a bacterial infection or an inflammatory skin disease) caused by a bacterium selected from the genus Staphylococcus, Streptococcus or Clostridium (more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus), the method comprising administering to the subject a compound of formula (I) according to the present invention and at least one antibiotic having antibacterial (preferably anti-bacterial selected from the genus Staphylococcus, Streptococcus or Clostridium, more preferably anti-bacterial of the genus Staphylococcus, and further preferably anti-Staphylococcus aureus) activity.

[0684] In yet another 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 an effective amount of a compound of formula (I) of the present invention to the subject in need of such prevention or treatment. Preferably, the bacterial infection is caused by a bacterium selected from the genus Staphylococcus, Streptococcus or Clostridium, more preferably caused by a bacterium of the genus Staphylococcus, and even more preferably caused by Staphylococcus aureus.

[0685] In yet another aspect, the present invention provides a method for preventing or treating a disease caused or aggravated by Gram-positive quorum sensing bacteria, comprising administering an effective amount of a compound of formula (I) of the present invention to a subject in need of such prevention or treatment.

[0686] 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.

[0687] 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.

[0688] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein for use in a method for reducing the virulence of bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0689] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein for use in a method of inhibiting quorum sensing of bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or an ortholog of AgrA; more preferably, the bacteria express AgrA.

[0690] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein, for use in a method for preventing or treating a disease caused or aggravated by bacteria; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0691] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in a method for reducing the virulence of bacteria, preferably in a method for reducing the virulence of bacteria in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0692] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in a method for inhibiting quorum sensing of bacteria, preferably in a method for inhibiting quorum sensing of bacteria in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0693] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in a method for preventing or treating a disease caused or aggravated by bacteria, preferably in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0694] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in the preparation of a medicament for reducing the virulence of bacteria, preferably in a medicament for reducing the virulence of bacteria in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0695] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in the preparation of a medicament for inhibiting quorum sensing of bacteria, preferably in a medicament for inhibiting quorum sensing of bacteria in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0696] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein in the preparation of a medicament for preventing or treating a disease caused or aggravated by bacteria, preferably in a medicament for preventing or treating a disease caused or aggravated by bacteria in a subject in need thereof; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0697] In some embodiments, the present invention provides a method for treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a compound of the present invention as described herein or a pharmaceutical composition comprising a composition of the present invention as described herein, preferably, the virulence of the bacteria is reduced; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0698] In some embodiments, the present invention provides a method for treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a compound of the present invention as described herein or a pharmaceutical composition comprising a composition of the present invention as described herein, preferably, quorum sensing of the bacteria is inhibited; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0699] In some embodiments, the present invention provides a method for treating a disease caused or aggravated by a bacterial infection in a subject in need thereof, the method comprising administering to the subject a compound of the present invention as described herein or a pharmaceutical composition comprising a composition of the present invention as described herein; preferably, the bacterium belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0700] In some embodiments, the present invention provides a method for reducing the virulence of bacteria, the method comprising exposing the bacteria to a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0701] In some embodiments, the present invention provides a method for inhibiting bacterial quorum sensing, the method comprising exposing the bacteria to a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the bacteria express AgrA or a direct homolog of AgrA; more preferably, the bacteria express AgrA.

[0702] In some embodiments, the present invention provides a method for preventing or treating a disease caused or aggravated by bacteria, the method comprising exposing the bacteria to a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention as described herein; preferably, the bacteria belongs to a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably belongs to Staphylococcus, and even more preferably is Staphylococcus aureus; preferably, the disease is a skin disease or a lung disease, more preferably, the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0703] As described herein, the compound of formula (I) of the present invention, the pharmaceutical composition comprising it or the combination product can be applied to any subject who can experience the beneficial effects of the compound, composition or product of the present invention. Preferably, the subject is human. The compound of the present invention as described herein, the composition comprising it or the product can be applied by any means to achieve its intended purpose. For example, application can be by parenteral, topical, local, subcutaneous, oral, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, oral, oral mucosa, eye or via inhalation. Preferably, application is oral administration or parenteral administration. In a preferred embodiment, it is systemic (for example, by oral administration or parenteral administration) to the subject. In other embodiments, it is local to the subject, for example, in the form of a topical solution, topical ointment or topical cream.

[0704] Example

[0705] The present invention will now be described by way of the following non-limiting examples. Although specific embodiments of the present invention are described below, it will be appreciated by those skilled in the art that various changes and modifications may be made. The mentioning of the preparations prepared in a similar manner to other preparations or by the general methods of other preparations may encompass the variation of conventional parameters (such as time, temperature, post-processing conditions, the slight variation of reagent amount, etc.).

[0706] abbreviation

[0707] The following list provides definitions of certain abbreviations and symbols used herein. It should be understood that this list is not exhaustive, but those skilled in the art will readily understand the meaning of abbreviations and symbols not defined below. In describing the present invention, chemical elements are identified according to the periodic table of elements.

[0708] Ar Argon DCM Dichloromethane DMF dimethylformamide eq. equivalent EtOAc Ethyl acetate EtOH Ethanol <![CDATA[Et 2 The]]> Diethyl ether h Hour HPLC High performance liquid chromatography HS human serum HSA Human serum albumin LC Liquid chromatography M Moore mCPBA m-Chloroperbenzoic acid MS Mass spectrometry min minute NMR NMR spectroscopy rt Room temperature R Retention time sat. saturation UPLC Ultra-high performance liquid chromatography

[0709] Analysis of compounds: Unless otherwise stated, the purity and identity of intermediates or example compounds were assessed by H(U)LPC-MS, a state-of-the-art technique. The method is as follows:

[0710] Method A: HPLC-MS

[0711] HPLC-MS analysis was performed on a LC-MS Waters Alliance Micromass ZQ 2000 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). An XBridge C18 column (particle size 3.5 μm, 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. HCOOH and NH 4 The pH of the mobile phase was adjusted with 100% aqueous buffer (pH 3.8 ± 0.3 (NH 4 OH 0.01%, HCOOH 0.02%) and reached 100% acetonitrile buffer (NH 4 OH 0.01%, HCOOH 0.02%) gradient:

[0712] (i) 3.25 minutes at a flow rate of 2 mL / min (5-minute run); or

[0713] (ii) 6.5 min at a flow rate of 2 mL / min (10 min run).

[0714] Method B: UPLC-MS

[0715] UPLC-MS analysis was performed on a Waters Acquity UPLC system coupled to a 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. HCOOH and NH 4 OH adjusts the pH of the mobile phase to form a buffer solution of pH 10.

[0716] 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 ammonium formate in water for solutions at pH = 10 (high) or 0.1% v / v formic acid in water for solutions at pH = 3 (low)):

[0717] 6.8 min duration, 97% acetonitrile in 1.1 min (8 min run);

[0718] 1.5 minutes duration, 97% ACN in 10 minutes (12 minutes run - High pH); or

[0719] 9.5 min duration, reaching 97% acetonitrile in 0.5 min (12 min run - low pH) - flow rate in this case was 0.5 mL / min.

[0720] Intermediate I-1: 8-bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one

[0721]

[0722] 2-Bromoacetonitrile (76.09 mmol) was added 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). The reaction mixture was stirred for 1.5 hours (on ice). Water (350 ml) was then added and the mixture was stirred with Et 2 O (3 × 100 ml) to extract the product. The organic layers were combined, washed with brine (3 × 80 ml), and MgSO 4 Drying, filtration and evaporation gave the intermediate 2-(2,4-dimethylphenyl)-sulfonylacetonitrile as a colorless oil (99.8% yield, purity >99% by HPLC).

[0723] 2-(2,4-Dimethylphenyl)-sulfonylacetonitrile was dissolved in DCM (250 ml) and cooled in an ice bath. Then mCPBA (<77%, 33 g, 147.2 mmol) was added in portions. The reaction mixture was stirred on ice for 40 minutes and left at room temperature overnight. The reaction mixture was then diluted with DCM (250 ml) and washed with 5% Na 2 S 2 O 3 Aqueous solution (2×100 ml) and concentrated NaHCO 3 The combined aqueous phases were extracted with DCM (2 x 100 ml). The organic phases were combined and washed with MgSO 4 Drying, filtration and evaporation gave 2-(2,4-dimethylphenyl)-sulfonylacetonitrile as a white powder (92.1% yield, 98% purity by HPLC).

[0724] To a cooled (4°C) solution of methyl 2-amino-4-bromobenzoate (7 g, 30.4 mmol) in anhydrous acetonitrile was added tert-butyl nitrite (1.5 eq) dropwise under Ar. After stirring for 20 min, trimethylsilyl azide (1.2 eq) was added dropwise (exothermic reaction - reaction temperature was maintained below 15°C). After the addition was complete, the reaction mixture was stirred in an ice bath for 40 min, then allowed to reach room temperature and stirred for an additional 2 h. Concentrated NaHCO 3 Aqueous solution (500 ml) was added to the reaction mixture to give a suspension, which was extracted with EtOAc (3×200 ml). The combined organic layers were washed with brine (200 ml) and MgSO 4 Drying, filtration and evaporation gave 2-azido-4-bromo-benzoic acid methyl ester as an orange oil (97% yield, 99% purity by HPLC).

[0725] To an ice-cooled solution of 2-(2,4-dimethylphenyl)-sulfonylacetonitrile (11.67 g, 54.65 mmol) in anhydrous ethanol (560 ml) was added dropwise a freshly prepared solution of sodium ethoxide in ethanol (15%, 117 mmol). After 30 minutes, a solution of 2-azido-4-bromo-benzoic acid methyl ester (54.13 mmol) in anhydrous ethanol (225 ml) was added dropwise. The resulting mixture was stirred on ice for 1 hour, then at room temperature for 1.5 hours, 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 washed with cold EtOAc and Et 2 O for several times and dried overnight to afford the title intermediate I-1 as a beige solid (yield 86.6%, purity 99.1% by HPLC).

[0726] Intermediate I-2: 3-(2,4-dimethylphenyl)sulfonyl-8-fluoro-4H-triazolo[1,5-a]quinazolin-5-one

[0727]

[0728] Intermediate 1-2 was synthesized starting from 2,4-dimethylbenzenethiol and methyl 2-amino-4-fluorobenzoate according to the method described for 1-1.

[0729] General reaction conditions for Buchwald coupling

[0730]

[0731] A round-bottom flask was charged with I-1 (1 equivalent), the corresponding amine (1-3 equivalents), Pd 2 dba 3 (5 mol%), Cs 2 CO 3(1.5 equiv.) and RuPhos (10 mol%), DMF (0.035 M) was added. The mixture was degassed by Ar flushing and 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 on celite. The crude product was purified by flash chromatography with an appropriate eluent system and then triturated in ether to give the desired compound as a solid.

[0732] Nucleophilic aromatic substitution (S N General reaction conditions for the reaction of

[0733]

[0734] A round-bottom flask was charged with I-1 (1 equivalent), amine (1-5 equivalents), K 2 CO 3 and NMP (0.1 M). The mixture was stirred at 130°C until completion (TLC or LC-MS monitoring). NMP was then removed under vacuum, the crude product was diluted with EtOAc, and NH 4 Cl (saturated aqueous solution) and washed with Na 2 SO 4 The organic layer was dried 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.

[0735] General reaction conditions for removal of Boc protecting group

[0736] A 50 ml flask was charged with the Boc protected derivative (1 eq.) in anhydrous dioxane (0.35 M), and then 4N HCl (15 eq.) in dioxane was added dropwise and the mixture was stirred at 80° C. When the reaction was judged complete by LC-MS, heating was stopped and the precipitate was filtered and concentrated into Et 2 O to give the desired product.

[0737] Alternatively, using TFA: a 50 ml flask was charged with the Boc protected derivative (1 eq) in anhydrous DCM (1.7 M), then TFA (15 eq) was added dropwise and the mixture was stirred at 40° C. When the reaction was judged complete by LC-MS, heating was stopped and the mixture was concentrated under reduced pressure and heated to 40° C. 2 O to give the desired product.

[0738] General reaction conditions for reductive amination

[0739] Compound 25 was prepared from compound 24: To a suspension of compound 24 (1 eq) in DCM (0.12 m) was added formaldehyde (37 wt% aqueous solution, 4 eq) dropwise, and the resulting suspension was stirred at room temperature overnight (the suspension became a clear light yellow solution). NaBH(OAc) was then added portionwise. 3 (2.5 eq.), 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 and then with MgSO 4 Dry and concentrate to dryness. If necessary, further purify the product by flash chromatography using an appropriate eluent system.

[0740] General reaction conditions for amide formation

[0741] 3-(2,4-dimethylphenyl)sulfonyl-8-piperazine-1-yl-4H-triazolo[1,5-a]quinazoline-5-one hydrochloride (compound 23) (20 mg, 0.042 mmol, 1 equivalent) was loaded into a reaction bottle, followed by the addition of acetone (1.5 mL), TEA (12 μL, 0.084 mmol, 2 equivalents) and 2-methylpropanoyl chloride (26.5 μL, 0.25 mmol, 6 equivalents), 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 give 17 mg of a white solid (compound 52) in 79% yield.

[0742] General reaction conditions for ester hydrolysis

[0743] In a round-bottom flask, use THF / H 2 O solution (50 / 50, 10 ml) was dissolved with 2-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl-2-azaspiro[3.3]heptane-6-carboxylic acid methyl ester (Compound 63) or 1-[3-(2,4-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2-3]triazolo[1,5-a]quinazolin-8-yl-piperidine-4-carboxylic acid methyl ester (Compound 64) (0.296 mmol), 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 (1 N), the aqueous phase was washed twice with EtOAc to remove organic impurities, then acidified with 1 N HCl at pH 2 and extracted twice with EtOAc. The combined organic layers were washed with NaCl brine and then MgSO 4Drying and concentration to dryness gave the corresponding carboxylic acid as a white solid in about 70% yield.

[0744] 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)

[0745]

[0746] Under Ar atmosphere, to a solution of 4-fluoro-5-hydroxy-2-nitro-benzoic acid methyl ester (500 mg, 2.3 mmol) and triethylamine (490 μL, 3.516 mmol) in anhydrous DCM (4.6 mL) was added dropwise tert-butyldimethylsilyl chloride (530 mg, 3.516 mmol) in anhydrous DCM (3.5 mL). A white precipitate appeared during the addition. The reaction mixture was stirred on ice for 30 minutes and then stirred at room temperature overnight. The mixture was then diluted with DCM (50 ml) and NH 4 Cl concentrated aqueous solution (3 × 20mL) washing. The combined aqueous phase was back extracted with DCM (3 × 20mL), and the combined organic phase was concentrated under vacuum. The crude product was purified by flash chromatography (nHex to DCM: MeOH (10: 0.5)), and 5- [tert-butyl (dimethyl) silyl] oxy-4-fluoro-2-nitro-benzoic acid methyl ester was obtained after evaporation, which can be used without further purification (62% yield, HPLC measured purity 84%).

[0747] To a solution of 5-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-2-nitro-benzoic acid methyl ester (512.5 mg) in MeOH (27 ml) was added Pd / C (10%, 278 mg, 0.261 mmol) and stirred in H 2 The reaction mixture was stirred overnight under atmospheric pressure. The mixture was then filtered and the filtrate was evaporated to give 2-amino-5-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-benzoic acid methyl ester (463 mg, 99% purity by HPLC).

[0748] Under Ar atmosphere, tert-butyl nitrite (90 μL, 0.757 mmol) was added dropwise to a solution of 2-amino-5-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-benzoic acid methyl ester (150 mg, 0.496 mmol) in anhydrous acetonitrile (0.73 ml) cooled with ice, and trimethylsilyl azide (80 μL, 0.603 mmol) was added dropwise 10 minutes later (exothermic reaction). The resulting mixture was stirred on ice for another 20 minutes and then at room temperature for 2 hours. HPLC monitoring showed complete conversion, and NaHCO was added. 3The aqueous solution was concentrated (10 mL). The resulting suspension was extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine (15 mL) and washed with Na 2 SO 4 Dry, filter and evaporate. Further analysis showed that the silyl protection was removed during the azide formation. Therefore, the crude product methyl 2-azido-4-fluoro-5-hydroxybenzoate (111 mg, 0.499 mmol) was suspended in anhydrous DMF (1.7 mL), potassium carbonate (138 mg, 0.998 mmol) was added, and then 1-(chloromethyl)-4-methoxy-benzene (PMB-Cl, 102 μL, 0.752 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water (40 mL) was then added and the suspension was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine and washed with Na 2 SO 4 Dry, filter and evaporate under vacuum. The crude product is purified by flash chromatography (cy-Hex / EtOAc). After evaporation of the desired fractions, methyl 2-azido-4-fluoro-5-(4-methoxyphenyl)methoxybenzoate is isolated as a colorless oil (80% yield, 99% purity).

[0749] 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 ethanol (0.6 mL) was added a solution of sodium ethoxide (15%) in EtOH. After 15 minutes of addition, a solution of the aforementioned compound (128.9 mg, 0.385 mmol) in anhydrous EtOH was added dropwise. The resulting mixture was stirred on ice for 1 hour and stirred at room temperature for another 2.5 hours. The reaction mixture was then concentrated, the residue was dissolved in water (15 mL), and the pH was adjusted to 2 with 2M HCl. The precipitate was collected by filtration, washed with water (4×10 mL), and finally dried with KOH in a desiccator. 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 as a brown solid (115 mg, 97% purity).

[0750] According to S N The general procedure for Ar introduced N-methyl-piperazine to afford the PMB protected title compound as a white solid (117 mg, 96% purity).

[0751] The PMB protecting group was removed by stirring the previous intermediate (102 mg) in TFA (1 mL) and then concentrating under a stream of nitrogen. The residue was diluted in MeOH, neutralized with ammonia and, after evaporation, washed with several portions of water (20 mL), MeOH (10 mL) and Et 2 The solid was triturated with 4% paraformaldehyde (5 mL). After drying, the title compound was obtained as a white solid (117 mg, 98.5% purity, Method B1-low).

[0752] Example 2: Preparation of 3-(2,4-dimethylbenzenesulfonyl)-7-hydroxy-8-{6-methyl-2,6-diazaspiro[3.3] Heptane-2-yl}-4H,5H-[1,2,3]triazolo[1,5-a]quinazolin-5-one (Compound 2)

[0753]

[0754] 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).

[0755] Compounds 3 to 59 of the present invention were prepared from the corresponding intermediates shown in Table 1 below according to the appropriate general schemes as described above.

[0756] Table 1: Exemplary compounds of the invention

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765] Example 3: AgrA reporter assay

[0766] Staphylococcus aureus USA300 strain UAMS-1625 was transformed with a plasmid expressing the reporter gene lacZ under the control of the AgrA-regulated P3 promoter. The resulting reporter strain was used to measure AgrA repression activity as follows: From overnight culture plates, cells were resuspended in 0.9% (w / v) saline and bacterial inocula were prepared in LB medium at a concentration of 5 × 10 5CFU / ml. Compounds were serially diluted two-fold in LB and 50 μL of 10X concentrated samples were added to a 96-deep well plate. Finally, 500 μL of bacterial suspension was 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 the OD600 was measured using a TECAN Infinite F200 microplate reader to control for growth inhibition. Another 100 μL was transferred to a 96-well plate containing 30 μL of lysis buffer (20 mM Tris / HCl, 3 mM MgCl 2 , 0.5% Tween 20 (v / v), 0.5% NP-40 (v / v)) in a new black 96-well plate, and the plate was shaken and incubated at 37°C for 60 minutes. 20 μL of substrate MUG (4-methylumbelliferyl β-D-pyranogalactoside) at 0.25 mg / ml was added, and after shaking and incubation at 37°C for 3 hours, fluorescence was measured using a TECAN Infinite F200 microplate reader (excitation: 360 nm, emission: 450 nm). After normalization to DMSO control, IC was determined using GraphPad PRISM 50 .

[0767] IC in the presence of human serum albumin (HSA, 40 mg / mL) was determined by supplementing the LB medium used to prepare the inoculum. 50 value.

[0768] 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 human serum albumin are shown in Table 2 below. Compounds 46 and 58 of WO 2020 / 109350 were not tested in 40 mg / mL HSA (nd), and their activity ratios were calculated based on their activities in the presence of 50% human serum.

[0769]

[0770] Table 2: Reporter assay data

[0771] IC 50 (without HSA):+++:IC 50 ≤1μg / mL,++:1μg / mL <IC 50 ≤5 μg / mL

[0772] IC 50 (with HSA):+++:IC 50 ≤10μg / mL,++:10μg / mL <IC 50 ≤50μg / mL,+:IC 50 >50 μg / mL

[0773] Ratio IC 50 (HSA exists) / IC 50 (HSA not present):+++Ratio≤25,++Ratio≤125,+:Ratio>125

[0774]

[0775]

[0776]

[0777] (*) The ratio of compounds 46 and 58 of WO 2020 / 109350 was calculated based on the activity in the presence of 50% human serum.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof: in: R 1 independently selected from -H, halogen, -C1-C6 alkyl and -C1-C6 alkoxy, wherein the alkyl and alkoxy are each optionally substituted by one or more R 11 replace; R 3 independently selected from -H, -C1-C6 alkyl and -C1-C6 alkoxy, wherein the alkyl and alkoxy are each optionally substituted by one or more R 11 replace; R 7 are independently selected from -H and -OH; R 8 A group of formula (A): wherein n is independently an integer from 0 to 3; m is independently an integer from 0 to 3; Y 1 Independently selected from CR at each occurrence 81 R 82 , C(O) and O; Y 2 Independently selected from CR at each occurrence 81A R 82A and O; Y 3 Independently selected from CR 84 R 85 , CHR 86 NR 87 and O; Among them, when Y 3 CR 84 R 85 When the sum of m and n is at least 2, when Y 3 For CHR 86 NR 87 or O, the sum of m and n is at least 3; R 81 , R 82 , R 81A and R 82A is independently selected at each occurrence from -H and -C1-C6 alkyl; or, R 81 and R 81A One of them, together with the carbon atoms to which they are attached, may combine to form a bridging ethylene group; R 84 and R 85 Together with the carbon atoms to which they are attached, they combine to form a -C4-C7 cycloalkyl group or a 4- to 7-membered heterocyclic ring, wherein the cycloalkyl group and the heterocyclic ring are each optionally substituted with one or more halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups or -OH; R 86 Independently selected from -H, -COOH and -NR 88 R 89 or, R 86 Together with the carbon atom to which it is attached, it can 81 , R 81A , R 82 or R 82A One of and the carbon atom to which they are attached combine to form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -OH or -COOH; R 88 and R 89 is independently selected at each occurrence 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, can 81 , R 81A , R 82 or R 82A One of the and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring; R 87 Independently selected from -H, -C1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2NH2, -S(O)2C1-C6 alkyl, -C3-C6 cycloalkyl and 4-6 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; the cycloalkyl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl or -OH; 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, it can 81 , R 81A , R 82 or R 82A One of and the carbon atoms to which they are attached combine to form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl group, each of which is optionally substituted with one or more halogens, -C1-C6 alkyl groups, -C1-C6 haloalkyl groups or -OH; and R 11 is independently at each occurrence halogen or -OH.

2. The compound according to claim 1, wherein R 1 It is -CH3.

3. A compound according to any one of the preceding claims, wherein R 3 It is -CH3.

4. A compound according to any one of the preceding claims, wherein R 7 is -H.

5. A compound according to any one of the preceding claims, wherein R 7 It is -OH.

6. A compound according to any one of the preceding claims, wherein Y 3 is CR 84 R 85 .

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

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

9. The compound according to claim 8, wherein R 87 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 halogen, -C1-C6 alkoxy, -OH, -O(CH2)2-OH, -NH2, -NHC1-C6 alkyl or N(C1-C6 alkyl)2; the cycloalkyl is optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl or -OH; the heterocycle is optionally substituted by one or more halogen, -C1-C6 alkyl, -C1-C6 haloalkyl or -OH.

10. The compound according to claim 1, wherein R 8 Including formula (B): in: R 81 is independently selected at each occurrence from -H and -C1-C2 alkyl; R 87 independently selected from -H, -C1-C2 alkyl and 4- to 6-membered heterocyclic ring, preferably, the heterocyclic ring contains one heteroatom selected from O and N; and p is 0, 1 or 2.

11. The compound according to claim 1, wherein R 8 Including formula (C): in: Y 4 Selected from -CR 91 R 92 -、-NR 93 - and O; R 91 and R 92 are each independently selected from -H, -C1-C6 alkyl and -OH; and R 93 Selected from -H and -C1-C6 alkyl.

12. The compound according to claim 1, wherein The compound 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]heptane-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]decane-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]undec-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]undec-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]undec-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]decane-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]heptane-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]heptane-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]heptane-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]heptane-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]undec-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]undec-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]undec-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]undec-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]undec-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]heptane-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]heptane-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-methylpropionyl)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)propionyl]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-methylsulfonylpiperazin-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-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 63); and 1-[3-(2,4-Dimethylbenzenesulfonyl)-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.

13. The compound according to claim 1, wherein The compound 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]heptane-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]decane-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]decane-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]heptane-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]heptane-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]undec-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]heptane-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-methylpropionyl)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-methylsulfonylpiperazin-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-dimethylbenzenesulfonyl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazolin-8-yl]-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 63); and 1-[3-(2,4-Dimethylbenzenesulfonyl)-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.

14. A pharmaceutical composition, wherein The pharmaceutical composition comprises at least one compound according to any one of the preceding claims or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

15. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or the pharmaceutical composition according to claim 14, for use as a medicament.

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