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

Abstract

The present invention relates to 3-(benzenesulfonyl)-[1, 2, 3] triazolo [1, 5a] quinazoline-5 (4H)-one derivatives and pharmaceutical compositions thereof, and their use in methods of reducing the virulence of a bacterium expressing a helper gene regulator A (AgrA) or ortholog of AgrA, preferably Staphylococcus aureus; a method of inhibiting quorum sensing of bacteria, preferably Staphylococcus aureus; and methods of preventing or treating a disease caused or aggravated by bacteria, preferably Staphylococcus aureus, such as a skin infection or a pulmonary infection, for example wherein the skin infection is atopic dermatitis, internal sephton syndrome or psoriasis in a subject. The compound exhibits an excellent ability to inhibit transcription of a gene controlled by a P3 promoter of Staphylococcus aureus even in the presence of human serum or human serum albumin.

Description

Technical Field

[0001] The present invention relates to 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, as well as their use in methods for reducing the virulence of bacteria (preferably Staphylococcus aureus) expressing auxiliary gene regulator A (AgrA) or a direct homologue of AgrA; in methods for inhibiting quorum sensing of bacteria (preferably Staphylococcus aureus), and in methods for preventing or treating diseases caused or aggravated by bacteria (preferably Staphylococcus aureus), diseases caused or aggravated by bacteria include but are not limited to skin infection or lung infection, atopic dermatitis, Netherton syndrome and / or psoriasis of a subject. Therefore, the present invention relates to anti-virulence compositions and methods for treating, ameliorating 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 can cause severe community-acquired and hospital-acquired infections. Staphylococcus aureus can cause a variety of infections, from mild epidermal infections to severe systemic life-threatening diseases, such as endocarditis, pneumonia, or sepsis (Lee AS et al. (2018) Nat. Rev. Dis. Primers, Vol. 4, Chapter 18033, pp. 1-23). ​​In addition, Staphylococcus aureus is also believed to cause allergic skin diseases, such as atopic dermatitis (Geoghegan JA et al. (2018) Trends Microbiol. 26 (6): 484-497) and Netherton syndrome (Williams MR et al. (2020) Cell reports 30 (9): 2923-2933). The ability of S. aureus to successfully cause such a wide range of diseases is the result of the large number of virulence factors it produces combined with β-lactam resistance, and most clones are also resistant to other antibiotic classes. Clinically relevant antibiotic resistance has evolved against almost all antibiotics in use, while the discovery and development of new antibiotic classes has lagged behind, leading to the antibiotic resistance crisis we face today. Therefore, alternative strategies are needed to treat or prevent bacterial infections mediated by S. aureus, which are also effective against multidrug-resistant strains such as methicillin-resistant S. aureus (MRSA) (Dickey SW et al. (2017) Nat. Rev. Drug Discov. 16(7): 457-471).

[0003] One of these strategies is the anti-virulence approach, which targets only features associated with virulence, not features associated with survival / fitness. Unlike common antibiotic therapies, anti-virulence drugs themselves do not have bacteriostatic effects (inhibiting bacterial growth) or bactericidal effects (killing bacteria). This approach focuses on destroying the armament of pathogenic bacteria by blocking the expression of virulence factors of pathogenic bacteria or neutralizing them, ultimately interfering with the pathogenic mechanism of bacteria, thereby promoting the host immune system to clear pathogens. Since anti-virulence drugs do not interfere with the basic mechanisms of bacterial growth and survival, they are thought to reduce the pressure on pathogens to develop resistance. Another advantage is that specific anti-virulence drugs can retain healthy host microbiota, and ultimately even help to offset microbial imbalance by reducing the aggressiveness of pathogens such as Staphylococcus aureus. Importantly, the anti-virulence approach provides increased pharmacological targets, so it is possible to produce alternative antibacterial agents with new modes of action (Mühlen, S. & Dersch, P. (2016) Curr. Top. Microbiol. Immunol. 398: 147-183).

[0004] Regulation of virulence factors in Staphylococcus aureus: The agr operon is a bacterial quorum sensing system that controls the cell density-dependent expression of virulence factors in Staphylococcus aureus. It consists of two different promoters, P2 and P3, of which P2 is 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), which is secreted across the bacterial membrane. AIP binds to the histidine-kinase AgrC and activates the transcription regulator AgrA through phosphorylation, thereby driving the expression of P2 and P3. There are four allelic variants of agr (types I-IV), each of which encodes a different AIP that functions as a specific ligand for the AgrC of its own cell, but is also an inhibitor of other AgrC variants. P3 produces the agr effector molecule RNAIII, which, together with AgrA, is responsible for the transcriptional control of approximately 200 genes, including a variety of virulence factors and metabolic pathways associated with stationary phase growth (Khan, BA et al. (2015) Expert Opin. Investig. Drugs 24(5): 689-704). Examples of virulence factors regulated by AgrA include 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 leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), or secreted proteases such as SspA or chlortetracycline. In summary, the numerous multifunctional virulence determinants make the pathogenesis of S. aureus particularly complex and provide the pathogen with a range of mechanisms to damage the host or circumvent and escape the host's immune defenses. Notably, most AgrA-regulated virulence factors are responsible for the pathogenicity of S. 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 to prevent the expression of virulence factors: Inhibition of central regulatory RNAIII expression and inhibition of PSMα production are 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 precise mechanism has not yet been determined); and (3) inhibition of the AgrA-P2 / P3 interaction. The advantage of targeting AgrA is that the expression of AgrA-dependent virulence factors in all four agr groups can be blocked (Gordon CP et al. (2013) J. Med. Chem. 56(4): 1389-404).

[0006] Recently, Sully and colleagues screened 24,087 compounds for inhibitors of agr induced by cyclic thiolactone pheromone (AIP) in a study related to acute bacterial skin and soft tissue infections caused by Staphylococcus aureus and discovered an inhibitor of AgrA named Savirin (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 without affecting the viability 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, thereby preventing the upregulation of virulence genes. After multiple applications of Savirin, abscess size and skin necrosis were significantly reduced in mice infected with MRSA USA300 strain.

[0007] Recently, WO2020 / 109350 described 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4h)-one derivatives, which can reduce the virulence of bacteria (e.g., Staphylococcus aureus) by interacting with AgrA and inhibiting the expression of virulence factors regulated by AgrA, as well as their use in preventing or treating bacterial infections and / or diseases caused or exacerbated by bacteria (preferably Staphylococcus aureus), including skin infections or lung infections, atopic dermatitis or psoriasis. Summary of the invention

[0008] The inventors unexpectedly discovered that the ability of the compounds of WO2020 / 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 limits the ability to inhibit AgrA-related virulence factors when administered (e.g., in animals, preferably mammals, more preferably humans). The present invention now provides a new class of compounds that overcome the above-mentioned shortcomings, thereby providing compounds that can reduce the virulence of bacteria (preferably bacteria expressing AgrA) and / or inhibit quorum sensing in bacteria (preferably Staphylococcus aureus) in biologically related systems including human serum or human serum albumin.

[0009] Thus, the 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 inventors transfected Staphylococcus aureus with a plasmid expressing the reporter gene lacZ, which is controlled by the P3 promoter, which 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. Surprisingly, the compounds of the invention retained AgrA inhibitory activity even when assayed in the presence of HSA.

[0010] Therefore, the compounds of the present invention can inhibit the transcription of genes (preferably virulence factors) controlled by the P3 promoter in the presence of HS or HSA (e.g., in bacteria, preferably in Staphylococcus aureus). This activity strongly indicates that the compounds of the present invention can be administered in biologically relevant systems (e.g., in animals, preferably in mammals, more preferably in humans) while still maintaining efficacy. Those skilled in the art will understand other features and advantages of the present technology after reading the following specific embodiments of the present invention.

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

[0012]

[0013] Where:

[0014] 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;

[0015] R 3 independently selected from -H, halogen, -C1-C6 alkyl, -C1-C6 alkoxy and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally substituted by one or more R 11 replace;

[0016] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0017] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 wherein the alkyl group is optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl); wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 85 replace;

[0018] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl;

[0019] Each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, -C6-C 10 Aryl and oxo;

[0020] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 replace;

[0021] Each occurrence of R 86independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkylene-OH, -N(R 83 )(R 84 )、-C1-C6 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl and oxo;

[0022] Each occurrence of R 11 are independently halogen or -OH;

[0023] m is independently 1 or 2; and

[0024] n is independently 0 or 1.

[0025] 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 bacterial virulence, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0026] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention for use in a method for inhibiting quorum sensing of bacteria, preferably wherein the bacteria is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacteria express AgrA or a direct homolog of AgrA, more preferably wherein the bacteria express AgrA.

[0027] On the one hand, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention, for use in a method for preventing or treating a disease caused or aggravated by bacteria, wherein the bacteria are preferably selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0028] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0029] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising the compound of formula (I), for use as a medicament. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Quorum sensing signals controlling virulence factor production 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 and activates transcription of the agr P2 and P3 promoters and the promoter of the psm operon (RNAIII-independent AgrA regulation). Classical targets of AgrA are subject to RNAIII-dependent control, including several toxins and proteases that are upregulated and several surface-bound proteins, such as protein A, that are downregulated. Small molecule inhibitors that bind to the DNA binding domain of AgrA block AgrA binding to the P2 and P3 promoters, thereby preventing the continued production of AIP (P2-driven) and virulence factors (P3-driven), and also preventing the expression of RNAIII-independent AgrA regulation, such as the production of PSM. DETAILED DESCRIPTION

[0031] The present invention relates to compounds that can inhibit the transcription of genes controlled by the P3 promoter (for example in bacteria, preferably in Staphylococcus aureus) and pharmaceutical compositions comprising said compounds.

[0032] definition

[0033] 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 cited again or repetition is avoided for brevity.

[0034] Unless the context clearly dictates otherwise, the articles "a" and "an" as used herein are used to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0035] The term "and / or" used in this disclosure means "and" or "or" unless otherwise stated.

[0036] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) can (but does not have to) be combined with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point in 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.

[0037] The term "alkyl" refers to a straight or branched saturated hydrocarbon. A C1-C6 alkyl group contains 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

[0038] As used herein, the term "alkylene" or "alkene" refers to a straight or branched hydrocarbon chain diradical derived from an alkyl group as defined herein, wherein one hydrogen of the alkyl group is removed to produce a second radical of the alkylene group. For example, alkylene groups are exemplified by -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-.

[0039] 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.

[0040] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 2 aromatic rings, including monocyclic or bicyclic groups, such as phenyl and naphthyl. 10 The aryl group contains 6 to 10 carbon atoms; preferably 6 or 10 carbon atoms. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be fused (e.g., naphthyl). The aryl group can optionally be substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-C1-C6 alkyl, -C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), and -N(C1-C6 alkyl). The substituent (e.g., alkyl) itself can be optionally substituted.

[0041] Unless otherwise expressly defined, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, which contains one or more heteroatoms selected from N, S, P and O, and the remaining ring atoms are C. The heteroatoms are preferably selected from N, S and O, more preferably N and O. The aromatic group is optionally substituted independently 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.

[0042] The term "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refers to a monocyclic or bicyclic saturated or partially saturated 4 to 11-membered ring containing carbon and heteroatoms from O, N and S (preferably O and N), and wherein at least one ring does not contain delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, [1,4] diazepane and [1,2] diazepane. In some embodiments, the heterocyclyl ring is a fused bicyclic heterocycle, such as, but not limited to, compounds 129, 130 and 153, such as R of compounds 129, 130 and 153 81 and R 82 .

[0043] In some embodiments, the heterocyclyl or heterocycloalkyl is a spirocyclic heterocycle. Spirocyclic heterocycle or spiral heterocycle (spiroheterocycle) used herein is understood to refer to a bicyclic system, wherein the two rings are connected by a single atom, and wherein at least one ring is a heterocycle (e.g., at least one ring is azetidine, pyrrolidine, morpholine or piperidine). Exemplary spirocyclic heterocycles include, but are not limited to, compounds 124, 125, 126, 127, 128, 149, 150, 151 and 152, such as compounds 124, 125, 126, 127, 128, 149, 150, 151 and 152 R 81 and R 82 .

[0044] As used herein, the term "halogen" or "halogen element" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0045] 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.

[0046] The present invention also includes pharmaceutical compositions comprising an effective amount of the 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, (4,4-diaminostilbene-2,2-disulfonate) stilbenesulfonate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediaminetetraacetate (calcium edetate), camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisulphonate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium salt, malate, maleic acid salt, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, acetalate, naphthylsulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-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, triethyl iodide and valerate.

[0047] 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 the group. Typically 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 tautomerism. When a ketone is drawn, it is understood that both the enol and keto forms are part of the present disclosure.

[0048] The term "solvate" refers to a complex with a variable stoichiometry of 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.

[0049] The term "carrier" as used in the present disclosure includes vehicles, excipients and diluents, and refers to a material, composition or vehicle used to carry or transport an agent from one organ or part of the body of a subject to another organ or part of the body, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.

[0050] As used in this disclosure, the term "disease" refers to, and is used interchangeably with, a disease, condition, or illness, unless otherwise indicated.

[0051] The terms "administering" or "administration" as used in the present disclosure refer to directly administering a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound to a subject, or administering to a subject a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound that can form an equivalent amount of an active compound in the subject.

[0052] The term "ortholog" as used herein represents the well-known meaning of the term. In the art, orthologs are genes that evolved from a common ancestral gene in different species. Due to their separation after the speciation event, orthologs may diverge, but usually have similarities at the sequence and structural levels; in addition, orthologs usually have the same function. Orthologs are a kind of homologs. In this application, the term ortholog is used to include orthologous genes (DNA or RNA) or peptide / protein products of orthologs. Sometimes, the peptide / protein products of orthologs are referred to as "ortholog products" or simply "orthologs". Its meaning is obvious from the context (for example, the anti-toxic composition of the present invention can include an anti-toxic agent that can reduce bacterial toxicity, and the bacterial expression can be called a peptide or protein of an ortholog of AgrA, i.e., a product of an orthologous gene of Staphylococcus aureus AgrA from another bacterium (e.g., Streptococcus pyogenes)). In certain aspects, an ortholog of AgrA produces a protein / peptide that has greater than about 70%, about 80%, or about 90% identity to the amino acid sequence of the gene product of AgrA.

[0053] The terms "reduce" and "inhibit" have the commonly understood meaning of lessening or decreasing.

[0054] As used herein, the term "reducing the virulence of bacteria expressing AgrA" generally and preferably refers to inhibiting the synthesis of one or more virulence factors of the bacteria by a compound of formula (I) of the present invention or a composition (preferably a pharmaceutical composition) comprising a 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 (e.g., α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble regulatory protein (PSM), Panton-Valentine leukocytoxin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH)) or secreted proteases (e.g., SspA or chlortetracycline). In preferred embodiments and embodiments of the present invention, the virulence of bacteria expressing AgrA is reduced by inhibiting the synthesis of one or more virulence factors selected from PSMα, RNAIII and its downstream targets. In preferred embodiments and embodiments of the present invention, the virulence of bacteria expressing AgrA is reduced by inhibiting 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).

[0055] The term "inhibiting the synthesis of one or more virulence factors" as used herein refers to complete or partial inhibition (preferably more than 20%, further preferably more than 30%, further preferably more than 50%, further preferably more than 90%, still more preferably more than 95% or even more than 99%) of the synthesis of one or more virulence factors of the bacteria compared to the synthesis of one or more virulence factors of the bacteria in the absence of the compound of formula (I) of the present invention or a composition (preferably a pharmaceutical composition) comprising the compound of formula (I) of the present invention, or compared to a method in which the compound of formula (I) of the present invention or a composition (preferably a pharmaceutical composition) comprising the compound of formula (I) of the present invention is not applied or used.

[0056] Virulence factors as used herein include any molecule expressed and secreted by bacteria that promotes colonization and / or adhesion in a host, inflammation in host tissues, evasion of host immune responses, and nutrient acquisition from a host. 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 or compositions (preferably pharmaceutical compositions) comprising the compounds of formula (I) include one or more toxins (e.g., α, β, γ, γ-variants and α-hemolysin, PSM (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B, exfoliative toxins), proteases (e.g., serine proteases, metalloproteases and cysteine ​​proteases), nucleases, lipases, coagulase, hyaluronidase, fibronectin binding protein, coagulation 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.

[0057] Depending on the severity of the infection or when 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 (e.g., pneumonia, bloodstream infections, acute skin and skin structure infections) caused by bacteria (e.g., staphylococci), primarily Staphylococcus aureus.

[0058] Antivirulence drugs can be administered alone or in combination with therapeutic agents generally and preferably used for the prevention and treatment of chronic inflammatory skin diseases (eg, atopic dermatitis, Netherton syndrome, psoriasis) exacerbated by bacteria (eg, staphylococci), primarily by Staphylococcus aureus.

[0059] The term "antibiotic" as used herein 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 thereof include penicillins, cephalosporins, polymyxins, rifamycins, rapamycins (lipiarmycin), quinolones, sulfonamides, macrolides, oxazolidinones, lincosamides and tetracycline antibiotics.

[0060] As used herein, the terms "treat," "treatment," or "therapy" refer to a method of obtaining a desired physiological effect. The effect may be therapeutic, i.e., partially or completely curing a disease, condition, and / or symptoms attributable to the disease or condition. The term refers to inhibiting the disease or condition, i.e., preventing its development; or ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0061] As used herein, the term "preventing" or "prophylaxis" refers to a method of preventing or delaying the onset of a disease or condition and / or symptoms attributable to the disease or condition.

[0062] The terms "subject", "animal", "patient" or "mammal" as used herein refer to any subject (particularly a mammalian subject) for whom diagnosis, prognosis, prevention or treatment is desired, such as a human, a domesticated mammal (e.g., a dog, a cat or a horse) or a food animal (e.g., a cow, a sheep or a pig), preferably a human. Therefore, in a preferred embodiment of the present invention, the subject is a human.

[0063] The term "for" in the "composition for treating or preventing a disease" used herein also discloses the corresponding treatment or prevention method and the use of the corresponding preparation in the preparation of a medicament for treating or preventing a disease.

[0064] "Therapeutically effective amount" or "effective amount" is the amount of a compound or pharmaceutical composition of the present invention that will cause a biological or medical response in a subject, preferably a human subject sought by a researcher, veterinarian, doctor or other clinician. The term "therapeutic administration" as used herein refers to the administration of a therapeutically effective amount. Specifically, the terms "effective", "effective amount" and "therapeutically effective amount" as used herein generally and preferably refer to the amount of a compound of the present invention of formula (I) or a composition (preferably a pharmaceutical composition) comprising a compound of formula (I) that reduces the virulence of bacteria or causes an improvement in symptoms or a prolonged survival of a subject suffering from a bacterial-related disease or condition. In this article, the term "effective amount" generally refers to the amount of a given compound that provides a measurable effect on the listed function, or in the case of a mixture, refers to the total amount of the mixture components. Those of ordinary skill in the art understand 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. As used herein, the term "therapeutically effective amount" generally refers to the amount of a given compound that provides a measurable therapeutic effect on a listed disease, disorder, or condition when administered to an individual (including a human or non-human animal), or in the case of a mixture, the total amount of the components of the mixture, to at least partially ameliorate the symptoms of such disease, disorder, or condition. The result of treatment can be partial or complete relief, inhibition, prevention, amelioration, and / or alleviation of a disorder, condition, or one or more symptoms thereof.

[0065] Compounds of the present invention

[0066] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0067]

[0068] Where:

[0069] 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;

[0070] R 3 independently selected from -H, halogen, -C1-C6 alkyl, -C1-C6 alkoxy and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally substituted by one or more R 11 replace;

[0071] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0072] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 wherein the alkyl group is optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl); wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 85 replace;

[0073] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl;

[0074] Each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, -C6-C 10 Aryl and oxo;

[0075] Or, R 81 and R 82Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 replace;

[0076] Each occurrence of R 86 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkylene-OH, -N(R 83 )(R 84 )、-C1-C6 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl and oxo;

[0077] Each occurrence of R 11 are independently halogen or -OH;

[0078] m is independently 1 or 2; and

[0079] n is independently 0 or 1.

[0080] In some embodiments, the compound is a compound of formula (IA) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0081]

[0082] Among them, R 8A , R 8B , R 81 , R 82 , m and n are as defined in formula (I).

[0083] In some embodiments, the compound is a compound of formula (I-A1) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0084]

[0085] Among them, R 81 , R 82 and m are as defined in formula (I).

[0086] In some embodiments, the compound is a compound of formula (I-A2) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0087]

[0088] Among them, R 81 , R 82 and m are as defined in formula (I).

[0089] In some embodiments, the compound is a compound of formula (I-A3) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0090]

[0091] Among them, R 81 , R 82 and m are as defined in formula (I).

[0092] In some embodiments, the compound is a compound of formula (I-A4) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0093]

[0094] Among them, R 81 , R 82 and m are as defined in formula (I).

[0095] In some embodiments, the compound is a compound of formula (IB) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0096]

[0097] Among them, R 3 , R 8A , R 8B , R 81 , R 82 , m and n are as defined in formula (I).

[0098] In some embodiments, the compound is a compound of formula (I-B1) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0099]

[0100] Among them, R 3 , R 81 , R 82 and m are as defined in formula (I).

[0101] In some embodiments, the compound is a compound of formula (I-B2) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0102]

[0103] Among them, R 3 , R 81 , R 82 and m are as defined in formula (I).

[0104] In some embodiments, the compound is a compound of formula (I-B3) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0105]

[0106] Among them, R 3 , R 81 , R 82 and m are as defined in formula (I).

[0107] In some embodiments, the compound is a compound of formula (I-B4) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0108]

[0109] Among them, R 3 , R 81 , R 82 and m are as defined in formula (I).

[0110] In some embodiments, the compound is a compound of formula (IC) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0111]

[0112] Among them, R 8A , R 8B , R 81 , R 82 and n are as defined in formula (I).

[0113] In some embodiments, the compound is a compound of formula (I-C1) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0114]

[0115] Among them, R 81 and R 82 As defined in formula (I).

[0116] In some embodiments, the compound is a compound of formula (I-C2) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0117]

[0118] Among them, R 81 and R 82 As defined in formula (I).

[0119] In some embodiments, the compound is a compound of formula (I-C3) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0120]

[0121] Among them, R 81 and R 82 As defined in formula (I).

[0122] In some embodiments, the compound is a compound of formula (I-C4) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0123]

[0124] Among them, R 81 and R 82 As defined in formula (I).

[0125] In some embodiments, the compound is a compound of formula (ID) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0126]

[0127] Among them, R 8A , R 8B , R 81 , R 82 and n are as defined in formula (I).

[0128] In some embodiments, the compound is a compound of formula (I-D1) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0129]

[0130] Among them, R 81 and R 82 As defined in formula (I).

[0131] In some embodiments, the compound is a compound of formula (I-D2) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0132]

[0133] Among them, R 81 and R 82 As defined in formula (I).

[0134] In some embodiments, the compound is a compound of formula (I-D3) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0135]

[0136] Among them, R 81and R 82 As defined in formula (I).

[0137] In some embodiments, the compound is a compound of formula (I-D4) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0138]

[0139] Among them, R 81 and R 82 As defined in formula (I).

[0140] In some embodiments, R 1 independently selected from -H, halogen, -C1-C4 alkyl and -C1-C4 alkoxy, wherein the alkyl and alkoxy are each optionally substituted by one or more R 11 replace.

[0141] In some embodiments, R 1 Independently selected from -H, -F, -Cl, -C1-C4 alkyl and -C1-C4 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more F, Cl or -OH.

[0142] In some embodiments, R 1 Independently selected from -H, -F, -C1-C2 alkyl and -C1-C2 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more -F or -OH.

[0143] In some embodiments, R 1 Independently selected from -H, -F and -C1-C2 alkyl, wherein the alkyl is optionally substituted with one or more -F or -OH.

[0144] In some embodiments, R 1 Independently selected from -H, -F and -C1-C2 alkyl.

[0145] In some embodiments, R 1 Independently selected from -H and -C1-C2 alkyl.

[0146] In a preferred embodiment, R 1 It is -CH3.

[0147] In some embodiments, R 3 independently selected from -H, halogen, -C1-C4 alkyl, -C1-C4 alkoxy and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally substituted by one or more R 11 replace.

[0148] In some embodiments, R3 independently selected from -H, halogen, -C1-C3 alkyl, -C1-C3 alkoxy and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally substituted by one or more R 11 replace.

[0149] In some embodiments, R 3 independently selected from -H, halogen, -C1-C3 alkyl, -C1-C2 alkoxy and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are each optionally substituted by one or more R 11 replace.

[0150] In some embodiments, R 3 Independently selected from -H, -Cl, -C1-C3 alkyl, -C1-C2 alkoxy and cyclopropyl, wherein the alkyl is optionally substituted with one or more -F, -Cl or -OH.

[0151] In some embodiments, R 3 Independently selected from -H, -Cl, -C1-C3 alkyl, -C1-C2 alkoxy and cyclopropyl, wherein the alkyl is optionally substituted with one or more -F, preferably wherein the alkyl is unsubstituted or substituted with three -F.

[0152] In some embodiments, R 3 Independently selected from -Cl, -C1-C3 alkyl, -C1-C2 alkoxy and cyclopropyl, wherein the alkyl is optionally substituted with one or more -F, preferably wherein the alkyl is unsubstituted or substituted with three -F.

[0153] In some embodiments, R 3 Independently selected from -CH3, -CF3, -Cl, -CH(CH3)2, -OCH3 and cyclopropyl.

[0154] In some embodiments, R 3 It is -CF3.

[0155] In some embodiments, R 3 It is -Cl.

[0156] In some embodiments, R 3 It is -CH(CH3)2.

[0157] In some embodiments, R 3 It is -OCH3.

[0158] In some embodiments, R 3 It is cyclopropyl.

[0159] In a preferred embodiment, R 3In a preferred embodiment, R 1 and R 3 All are -CH3.

[0160] In a preferred embodiment, R 8A and R 8B All are -H.

[0161] In some embodiments, R 8A and R 8B All are -H or all are -CH3.

[0162] In some embodiments, R 8A and R 8B All are -CH3.

[0163] In some embodiments, R 8A -H and R 8B It is -CH3.

[0164] In a preferred embodiment, n is 0 and m is 1.

[0165] In some embodiments, n is 0.

[0166] In some embodiments, n is 1.

[0167] In some embodiments, m is 1.

[0168] In some embodiments, m is 2.

[0169] In some embodiments, n is 0 and m is 2.

[0170] In some embodiments, n is 1 and m is 1

[0171] In some embodiments, n is 1 and m is 2.

[0172] In a preferred embodiment, each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl).

[0173] In some embodiments, R 81 and R 82 All are -H.

[0174] In some embodiments, each occurrence of R 81 and R82 Each is independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C4 alkyl).

[0175] In some embodiments, each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -S(C1-C4 alkyl)substituted.

[0176] In some embodiments, each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0177] In some embodiments, each occurrence of R 81 and R 82 Each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three halogens; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0178] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F, -Cl or -Br; and wherein the alkyl is further optionally substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2-OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0179] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0180] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It is substituted with -OH, -C1-C2 alkoxy, -NH2 or -S(C1-C2 alkyl).

[0181] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -OCH3, -NH2 or SCH3 substituted.

[0182] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -OCH3 or -NH2 substituted.

[0183] In some embodiments, each occurrence of R 81 and R 82Each is independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -OCH3 or -NH2.

[0184] In some embodiments, each occurrence of R 81 and R 82 Each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three halogens; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0185] In some embodiments, each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F, -Cl or -Br; or wherein the alkyl is optionally substituted with one or two, preferably exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0186] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 or -S(C1-C2 alkyl).

[0187] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 It is substituted with -OH, -C1-C2 alkoxy, -NH2 or -S(C1-C2 alkyl).

[0188] In some embodiments, each occurrence of R 81 and R 82 each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -OCH3, -NH2 or -SCH3 substitution.

[0189] In some embodiments, each occurrence of R 81 and R 82 Each independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -OH, -(OCH2-CH2) 1-2 -OH, -OCH3 or -NH2 substituted.

[0190] In some embodiments, each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably exactly one -OH, -OCH3 or -NH2.

[0191] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl); and R 82 is -H.

[0192] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C4 alkyl); and R 82 is -H.

[0193] In some embodiments, R 81independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2-C4 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or -S(C1-C4 alkyl); and R 82 is -H.

[0194] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more -C2 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0195] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three halogens; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0196] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F, -Cl or -Br; and wherein the alkyl is further optionally substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0197] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2-OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0198] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2 or -S(C1-C2 alkyl); and R 82 is -H.

[0199] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -OCH3, -NH2 or -SCH3; and R 82 is -H.

[0200] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably with exactly one -OH, -(OCH2-CH2) 1-2 -OH, -OCH3 or -NH2; and R 82 is -H.

[0201] In some embodiments, R 81 is independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; and wherein the alkyl is further optionally substituted with one or two, preferably exactly one -OH, -OCH3 or -NH2; and R 82 is -H.

[0202] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three halogens; or wherein the alkyl is optionally substituted with one or two, preferably exactly one, -C2 alkynyl, -OH, -(OCH2-CH2) 1-2-OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0203] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F, -Cl or -Br; or wherein the alkyl is optionally substituted with one or two, preferably exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0204] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, or -S(C1-C2 alkyl); and R 82 is -H.

[0205] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -NH2 or -S(C1-C2 alkyl); and R 82 is -H.

[0206] In some embodiments, R 81 independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably with exactly one -C2 alkynyl, -OH, -(OCH2-CH2) 1-2 -OH, -OCH3, -NH2 or -SCH3; and R 82 is -H.

[0207] In some embodiments, R 81independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably exactly one -OH, -(OCH2-CH2) 1-2 -OH, -OCH3 or -NH2; and R 82 is -H.

[0208] In some embodiments, R 81 is independently selected from -H and -C1-C6 alkyl; wherein the alkyl is optionally substituted with one to three -F; or wherein the alkyl is optionally substituted with one or two, preferably exactly one -OH, -OH, -OCH3 or -NH2; and R 82 is -H.

[0209] In some embodiments, R 81 and R 82 Each is a -C1-C6 alkyl group.

[0210] In some embodiments, R 81 and R 82 Each is a -C1-C4 alkyl group.

[0211] In some embodiments, R 81 and R 82 Each is -C1-C2 alkyl, preferably wherein R 81 is -CH3 and R 82 It is -C1-C2 alkyl.

[0212] In a preferred embodiment, R 81 Selected from -C3-C8 cycloalkyl and -C1-C6 alkylene-(C3-C8 cycloalkyl).

[0213] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C6 alkylene-(C3-C8 cycloalkyl); and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0214] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C6 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ),-C6-C 10aryl and oxo; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0215] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C4 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0216] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C4 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C6-C 10 aryl; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0217] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 is independently selected from -C1-C3 alkyl, halogen, -OH, -C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0218] In some embodiments, R 81 -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl groups are each independently substituted by one or more R85 Replace, and where each occurrence of R 85 R is independently selected from -C1-C3 alkyl, halogen, -OH, -C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0219] In some embodiments, R 81 -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 is independently selected from -C1-C3 alkyl, -OH, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0220] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(-C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is each independently substituted by one or two, preferably by exactly one R 85 Replace, and where each occurrence of R 85 are independently selected from -OH, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0221] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is each independently substituted by one or two, preferably by exactly one R 85 Replace, and where each occurrence of R 85 are independently selected from -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 and phenyl; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0222] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is each independently substituted by one or two, preferably by exactly one R 85 Replace, and where each occurrence of R 85 are independently selected from -OH, -N(C1-C2 alkyl)2 and phenyl; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0223] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C6 alkylene-(C3-C8 cycloalkyl), wherein when R 81 When it is -C3-C8 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C6 alkylene-(C3-C8 cycloalkyl), R 81 Not replaced; each occurrence of R 85 independently selected from C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ),-C6-C 10 aryl and oxo; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0224] In some embodiments, R 81 is selected from C3-C8 cycloalkyl and -C1-C4 alkylene-(C3-C8 cycloalkyl), wherein when R 81 When it is -C3-C8 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C4 alkylene-(C3-C8 cycloalkyl), R 81 Not replaced; each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0225] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C4 alkylene-(C3-C8 cycloalkyl), wherein when R 81 When it is -C3-C8 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C4 alkylene-(C3-C8 cycloalkyl), R 81 Not replaced; each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C6-C 10 aryl; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0226] In some embodiments, R 81 is selected from -C3-C8 cycloalkyl and -C1-C3 alkylene-(C3-C8 cycloalkyl), wherein when R 81 When it is -C3-C8 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C8 cycloalkyl), R 81 Not replaced; each occurrence of R 85 R is independently selected from -C1-C3 alkyl, halogen, -OH, -C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0227] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein when R 81 When it is -C3-C7 cycloalkyl or C3-C6 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C7 cycloalkyl) or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 Not replaced; each occurrence of R 85is independently selected from -C1-C3 alkyl, halogen, -OH, -C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0228] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein when R 81 When it is -C3-C7 cycloalkyl or C3-C6 cycloalkyl, R 81 Independently by more than one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C7 cycloalkyl) or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 Not replaced; each occurrence of R 85 is independently selected from -C1-C3 alkyl, -OH, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0229] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein when R 81 When it is -C3-C7 cycloalkyl or C3-C6 cycloalkyl, R 81 independently by one or two, preferably by exactly one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C7 cycloalkyl) or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 Not replaced; each occurrence of R 85 are independently selected from -OH, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and phenyl; and R 82 is -H or -C1-C3 alkyl, R 82 Preferred is -H.

[0230] In some embodiments, R 81is selected from -C3-C7 cycloalkyl and -C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein when R 81 When it is -C3-C7 cycloalkyl or C3-C6 cycloalkyl, R 81 independently by one or two, preferably by exactly one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C7 cycloalkyl) or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 Not replaced; each occurrence of R 85 are independently selected from -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2 and phenyl; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0231] In some embodiments, R 81 is selected from -C3-C7 cycloalkyl and C1-C3 alkylene-(C3-C7 cycloalkyl), preferably -C3-C6 cycloalkyl and -C1-C3 alkylene-(C3-C6 cycloalkyl), wherein when R 81 When it is -C3-C7 cycloalkyl or C3-C6 cycloalkyl, R 81 independently by one or two, preferably by exactly one R 85 Replace, and where, when R 81 When it is -C1-C3 alkylene-(C3-C7 cycloalkyl) or -C1-C3 alkylene-(C3-C6 cycloalkyl), R 81 Not replaced; each occurrence of R 85 are independently selected from -OH, -N(C1-C2 alkyl)2 and phenyl; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0232] In a preferred embodiment, R 81 Selected from 4- to 8-membered heterocycloalkyl and -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl).

[0233] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl); and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0234] In some embodiments, R 81is selected from 4 to 8 membered heterocycloalkyl and -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ),-C6-C 10 aryl and oxo; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0235] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C4 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0236] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C4 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0237] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C4 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0238] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C4 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen, -OH and oxo; and R 82 is -H or -C1-C4 alkyl, preferably R 82 is -H.

[0239] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl); wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C2 alkyl, halogen, -OH and oxo; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0240] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl); wherein each of the heterocycloalkyl groups independently contains one or more heteroatoms selected from N and O, preferably one or two heteroatoms selected from N and O, and wherein each of the heterocycloalkyl groups is independently substituted by one or more R 85 Replace; where each occurrence of R 85 are independently selected from -C1-C2 alkyl, halogen, -OH and oxo; and R 82 is -H or -C1-C2 alkyl, preferably R 82 Preferred is -H.

[0241] In some embodiments, R 81 is selected from 4 to 8 membered heterocycloalkyl and -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl); wherein each of the heterocycloalkyl groups independently contains one or more heteroatoms selected from N and O, preferably one or two heteroatoms selected from N and O, and wherein each of the heterocycloalkyl groups is independently substituted by one or more R 85 Replace; where each occurrence of R 85 are independently selected from -C1-C2 alkyl and oxo; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0242] In some embodiments, R 81is selected from 4 to 6 membered heterocycloalkyl and -C1-C3 alkylene-(4 to 6 membered heterocycloalkyl); wherein the heterocycloalkyl is selected from azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran and morpholine; wherein the heterocycloalkyl is each independently substituted by one or more R 85 Replace; where each occurrence of R 85 are independently selected from -C1-C2 alkyl and oxo; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0243] In some embodiments, R 81 is selected from 4 to 6 membered heterocycloalkyl and -C1-C3 alkylene-(4 to 6 membered heterocycloalkyl); wherein the heterocycloalkyl is selected from azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran and morpholine; wherein, when R 81 When R is a 4- to 6-membered heterocycloalkyl, the heterocycloalkyl may be optionally substituted by one or more, preferably one or two -C1-C2 alkyl groups; 81 When it is -C1-C3 alkylene-(4 to 6 membered heterocycloalkyl), the heterocycloalkyl may be optionally substituted by one or more, preferably one or two, -C1-C2 alkyl or oxo; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0244] In a preferred embodiment, R 81 Selected from -C6-C 10 Aryl and -C1-C6 alkylene-(C6-C 10 aryl).

[0245] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C6 alkylene-(C6-C 10 aryl); and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0246] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C6 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ),-C6-C10 aryl and oxo; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0247] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C6 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) and -C6-C 10 aryl; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0248] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C4 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C6-C 10 aryl; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0249] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C4 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0250] In some embodiments, R 81 Selected from -C6-C 10Aryl and -C1-C2 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted with one or more RR 85 Replace, and where each occurrence of R 85 independently selected from -C1-C2 alkyl, halogen, -OH, -C1-C2 alkoxy, -NH2, -NH(C1-C2 alkyl) and -N(C1-C2 alkyl)2; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0251] In some embodiments, R 81 Selected from -C6-C 10 Aryl and -C1-C2 alkylene-(C6-C 10 wherein the aryl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C2 alkyl, halogen, -OH and -C1-C2 alkoxy; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0252] In some embodiments, R 81 is selected from phenyl and -C1-C2 alkylene-(phenyl); wherein the phenyl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C2 alkyl, halogen, -OH and -C1-C2 alkoxy; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0253] In some embodiments, R 81 is selected from phenyl and -C1-C2 alkylene-(phenyl); wherein the phenyl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C2 alkyl, -F, -Cl, -OH and -C1-C2 alkoxy; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0254] In some embodiments, R 81 is selected from phenyl and -C1-C2 alkylene-(phenyl); wherein the phenyl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85are independently selected from -C1-C2 alkyl, -Cl, -OH and -C1-C2 alkoxy; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0255] In some embodiments, R 81 is selected from phenyl and -C1-C2 alkylene-(phenyl); wherein the phenyl groups are each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -Cl, -OH and -C1-C2 alkoxy; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0256] In a preferred embodiment, R 81 is selected from 5- to 10-membered heteroaryl and -C1-C6 alkylene-(5- to 10-membered heteroaryl).

[0257] In some embodiments, R 81 is selected from 5- to 10-membered heteroaryl and -C1-C6 alkylene-(5- to 10-membered heteroaryl); and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0258] In some embodiments, R 81 is selected from 5- to 10-membered heteroaryl and -C1-C6 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ), -C6-C10 aryl and oxo; and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0259] In some embodiments, R 81 is selected from 5- to 10-membered heteroaryl and -C1-C4 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -C6-C 10 aryl and oxo; and R 82is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0260] In some embodiments, R 81 is selected from 5- to 10-membered heteroaryl and -C1-C4 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0261] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is each independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0262] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein each of the heteroaryl groups independently contains one or more heteroatoms selected from N, O and S, preferably one or two heteroatoms selected from N, O and S, and wherein each of the heteroaryl groups is independently substituted by one or more R 85 Replace, and each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0263] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is each independently selected from pyrrole, furan, thiophene, oxazole, imidazole, pyridine, pyrazole, isoxazole, triazole and pyrimidine; and wherein the heteroaryl is each independently replaced by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0264] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is each independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; and wherein the heteroaryl is each independently replaced by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0265] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl groups are each independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0266] In some embodiments, R 81 is selected from 5- to 6-membered heteroaryl and -C1-C2 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl groups are each independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; and R 82 -H or -C 1- C2 alkyl, R 82 Preferred is -H.

[0267] In some embodiments, R 81 It is -C1-C6 alkylene-(5- to 10-membered heteroaryl).

[0268] In some embodiments, R 81 is -C1-C6 alkylene-(5- to 10-membered heteroaryl); and R 82 is -H or -C1-C6 alkyl, R 82 Preferred is -H.

[0269] In some embodiments, R 81 is -C1-C6 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ),-C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82Preferred is -H.

[0270] In some embodiments, R 81 is -C1-C4 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -C6-C 10 aryl and oxo; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0271] In some embodiments, R 81 is -C1-C4 alkylene-(5- to 10-membered heteroaryl); wherein the heteroaryl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0272] In some embodiments, R 81 is -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0273] In some embodiments, R 81 -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl independently contains one or more heteroatoms selected from N, O and S, preferably one or two heteroatoms selected from N, O and S, and wherein the heteroaryl is independently substituted by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0274] In some embodiments, R 81is -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole, pyridine, pyrazole, isoxazole, triazole and pyrimidine; and wherein the heteroaryl is independently replaced by one or more R 85 Replace, and where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0275] In some embodiments, R 81 is -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; wherein the heteroaryl is independently replaced by one or more R 85 Replace, where each occurrence of R 85 are independently selected from -C1-C4 alkyl, halogen and -OH; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0276] In some embodiments, R 81 is -C1-C4 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; and R 82 is -H or -C1-C4 alkyl, R 82 Preferred is -H.

[0277] In some embodiments, R 81 is -C1-C2 alkylene-(5- to 6-membered heteroaryl); wherein the heteroaryl is independently selected from pyrrole, furan, thiophene, oxazole, imidazole and pyridine; and R 82 is -H or -C1-C2 alkyl, R 82 Preferred is -H.

[0278] In a preferred embodiment, R 82 is -H or C1-C6 alkyl, R 82 Preferably -H or C1-C2 alkyl, more preferably R 82 For H.

[0279] In some embodiments, R 82 It is -H or -C1-C2 alkyl.

[0280] In some embodiments, R 82 Yes -H.

[0281] In a preferred embodiment, R 81 and R82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 replace.

[0282] In some embodiments, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C4 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C4 alkylene-NH2, -C1-C4 alkylene-NH(C1-C4 alkyl), -C1-C4 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl and oxo.

[0283] In some embodiments, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl and oxo.

[0284] In some embodiments, R 81 and R 82 Together with the nitrogen atom to which they are attached, to form a 4- to 11-membered heterocycloalkyl group, wherein the heterocycloalkyl group contains one or more heteroatoms selected from O and N, and wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl and oxo.

[0285] In some embodiments, R 81 and R 82 are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl group, wherein the heterocycloalkyl group contains one or two heteroatoms selected from O and N, and wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, halogen, -OH, -C1-C2 alkylene-OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C2 alkylene-NH2, -C1-C2 alkylene-NH(C1-C4 alkyl), -C1-C2 alkylene-N(C1-C4 alkyl)2, -C3-C6 cycloalkyl and oxo.

[0286] In some embodiments, R 81 and R 82 are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl group, wherein the heterocycloalkyl group contains one or two heteroatoms selected from O and N, and wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, -F, -Cl, -OH, -C1-C2 alkylene-OH, -NH2, -N(C1-C2 alkyl)2, -C1-C2 alkylene-NH2, -C3-C6 cycloalkyl and oxo.

[0287] In some embodiments, R 81 and R 82 are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl group, wherein the heterocycloalkyl group contains one or two heteroatoms selected from O and N, and wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, -F, -OH, -C1-C2 alkylene-OH, -NH2, -N(C1-C2 alkyl)2, -C1-C2 alkylene-NH2, -C3-C6 cycloalkyl (preferably cyclopropyl) and oxo.

[0288] In some embodiments, R 81 and R 82The heterocycloalkyl radicals are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl radical, wherein the heterocycloalkyl radical is selected from azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azepane, oxazepane (preferably [1,4]oxazepane), diazepane (preferably [1,4]diazepane), 7- to 11-membered spirocyclic heterocycloalkyl radicals and 8- to 10-membered fused bicyclic heterocycloalkyl radicals; and wherein the 4- to 11-membered heterocycloalkyl radicals are optionally substituted by one or two R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, -F, -OH, -C1-C2 alkylene-OH, -NH2, -N(C1-C2 alkyl)2, -C1-C2 alkylene-NH2, -C3-C6 cycloalkyl (preferably cyclopropyl) and oxo.

[0289] In some embodiments, R 81 and R 82 The heterocycloalkyl radicals are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl radical, wherein the heterocycloalkyl radical is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, oxazepane (preferably [1,4]oxazepane), diazepane (preferably [1,4]diazepane), 7- to 11-membered spirocyclic heterocycloalkyl radicals and 8- to 10-membered fused bicyclic heterocycloalkyl radicals; wherein the 4- to 11-membered heterocycloalkyl radicals are optionally substituted by one or two R 86 Replace, where each occurrence of R 86 Independently selected from -C1-C4 alkyl, -F, -OH, -C1-C2 alkylene-OH, -NH2, -N(C1-C2 alkyl)2, -C1-C2 alkylene-NH2, -C3-C6 cycloalkyl (preferably cyclopropyl) and oxo.

[0290] In some embodiments, R 81 and R 82 Combined with the nitrogen atom to which they are attached to form pyrrolidine, piperidine or morpholine, wherein the pyrrolidine, piperidine or morpholine is optionally replaced by one or two R 86 replace.

[0291] In some embodiments, R 81 and R 82 Combined with the nitrogen atom to which they are attached to form pyrrolidine or morpholine, wherein the pyrrolidine or morpholine is optionally replaced by one or two R 86 replace.

[0292] In some embodiments, R 81 and R 82are combined with the nitrogen atom to which they are attached to form pyrrolidine, wherein the pyrrolidine is optionally replaced by one or two R 86 replace.

[0293] In some embodiments, R 81 and R 82 Together with the nitrogen atom to which they are attached, to form a pyrrolidine, wherein the pyrrolidine is unsubstituted.

[0294] In some embodiments, R 81 and R 82 are combined with the nitrogen atom to which they are attached to form an N-bound pyrrolidine, wherein the N-bound pyrrolidine is optionally substituted by one or two R 86 replace.

[0295] In some embodiments, R 81 and R 82 Together with the nitrogen atom to which they are attached, to form an N-bound pyrrolidine, wherein the N-bound pyrrolidine is unsubstituted.

[0296] In some embodiments, R 81 and R 82 are combined with the nitrogen atom to which they are attached to form morpholine, wherein the morpholine is optionally substituted by one or two R 86 replace.

[0297] In some embodiments, R 81 and R 82 Combined with the nitrogen atom to which they are attached to form morpholine, wherein the morpholine is unsubstituted.

[0298] In some embodiments, R 81 and R 82 and the nitrogen atom to which they are attached to form an N-bound morpholine, wherein the N-bound morpholine is optionally substituted by one or two R 86 replace.

[0299] In some embodiments, R 81 and R 82 Combined with the nitrogen atom to which they are attached to form an N-bound morpholine, wherein the N-bound morpholine is unsubstituted.

[0300] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0301]

[0302] Where:

[0303] R1 is -CH3;

[0304] R 3 is -CH3;

[0305] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0306] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0307] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0308] Wherein, the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0309] wherein the 4 to 8 membered heterocycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0310] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ) or -C1-C6 alkoxy substituted;

[0311] wherein the 5- to 10-membered heteroaryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0312] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted;

[0313] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl;

[0314] m is independently 1 or 2; and

[0315] n is independently 0 or 1.

[0316] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0317]

[0318] Where:

[0319] R 1 is -CH3;

[0320] R 3 is -CH3;

[0321] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0322] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0323] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2-OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0324] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0325] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C6 alkyl groups or oxo groups;

[0326] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C6 alkoxy;

[0327] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted;

[0328] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl;

[0329] m is independently 1 or 2; and

[0330] n is independently 0 or 1.

[0331] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0332]

[0333] Where:

[0334] R 1 is -CH3;

[0335] R 3 is -CH3;

[0336] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0337] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene, -C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl);

[0338] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0339] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0340] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0341] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C2 alkoxy;

[0342] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C 1- C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0343] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3;

[0344] m is independently 1 or 2; and

[0345] n is independently 0 or 1.

[0346] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0347]

[0348] Where:

[0349] R 1 is -CH3;

[0350] R 3 is -CH3;

[0351] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0352] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0353] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0354] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0355] wherein the 4 to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0356] wherein the -C6 aryl groups are each independently optionally substituted by one or more halogens, -OH or -C1-C2 alkoxy groups;

[0357] Or, R 81 and R 82Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0358] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3;

[0359] m is independently 1 or 2; and

[0360] n is independently 0 or 1.

[0361] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0362]

[0363] Where:

[0364] R 1 is -CH3;

[0365] R 3 is -CH3;

[0366] Each occurrence of R 8A and R 8B Each is independently -H or -CH3;

[0367] Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0368] wherein the -C1-C6 alkyl group is optionally substituted by one or two, preferably by exactly one -C2 alkynyl group, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0369] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -OH, -N(R 83 )(R 84 ) or phenyl;

[0370] wherein the 4- to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -C1-C2 alkyl or oxo;

[0371] wherein the -C6 aryl groups are each independently optionally substituted by one or two, preferably by exactly one, halogen, -OH or -C1-C2 alkoxy;

[0372] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two -C1-C2 alkyl groups, halogen groups, -OH groups, -C1-C3 alkylene groups, -OH groups, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0373] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3;

[0374] m is independently 1 or 2; and

[0375] n is independently 0 or 1.

[0376] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0377] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0378] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0379] wherein the 4 to 8 membered heterocycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0380] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ) or -C1-C6 alkoxy substituted;

[0381] wherein the 5- to 10-membered heteroaryl groups are independently and optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0382] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted; and

[0383] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0384] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0385] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0386] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0387] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more C1-C6 alkyl groups or oxo groups;

[0388] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C6 alkoxy;

[0389] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted; and

[0390] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0391] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene, -C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl);

[0392] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0393] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0394] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0395] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C2 alkoxy;

[0396] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84)、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted; and

[0397] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0398] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0399] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0400] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0401] wherein the 4 to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0402] wherein the -C6 aryl groups are each independently optionally substituted by one or more halogens, -OH or -C1-C2 alkoxy groups;

[0403] Or, R 81 and R 82Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0404] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0405] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0406] wherein the -C1-C6 alkyl group is optionally substituted by one or two, preferably by exactly one -C2 alkynyl group, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0407] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -OH, -N(R 83 )(R 84 ) or phenyl;

[0408] wherein the 4- to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -C1-C2 alkyl or oxo;

[0409] wherein the -C6 aryl groups are each independently optionally substituted by one or two, preferably by exactly one, halogen, -OH or -C1-C2 alkoxy;

[0410] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two -C1-C2 alkyl groups, halogen groups, -OH groups, -C1-C3 alkylene groups, -OH groups, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0411] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0412] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0413] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0414] Wherein, the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0415] wherein the 4 to 8 membered heterocycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0416] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ) or -C1-C6 alkoxy substituted;

[0417] wherein the 5- to 10-membered heteroaryl groups are independently and optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0418] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted; and

[0419] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0420] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-Bl), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0421] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0422] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0423] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C6 alkyl groups or oxo groups;

[0424] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C6 alkoxy;

[0425] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted; and

[0426] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0427] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene, -C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl);

[0428] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0429] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0430] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0431] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C2 alkoxy;

[0432] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted; and

[0433] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0434] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0435] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0436] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0437] wherein the 4 to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0438] wherein the -C6 aryl groups are each independently optionally substituted by one or more halogens, -OH or -C1-C2 alkoxy groups;

[0439] Or, R 81 and R 82Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0440] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0441] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0442] wherein the -C1-C6 alkyl group is optionally substituted by one or two, preferably by exactly one -C2 alkynyl group, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0443] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -OH, -N(R 83 )(R 84 ) or phenyl;

[0444] wherein the 4- to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -C1-C2 alkyl or oxo;

[0445] wherein the -C6 aryl groups are each independently optionally substituted by one or two, preferably by exactly one, halogen, -OH or -C1-C2 alkoxy;

[0446] Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or two -C1-C2 alkyl groups, halogen groups, -OH groups, -C1-C3 alkylene groups, -OH groups, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted;

[0447] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0448] In some embodiments of any one of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0449] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0450] Wherein, the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0451] wherein the 4 to 8 membered heterocycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0452] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ) or -C1-C6 alkoxy substituted;

[0453] wherein the 5- to 10-membered heteroaryl groups are independently and optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted; and

[0454] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0455] In some embodiments of any one of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0456] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0457] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0458] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C6 alkyl groups or oxo groups;

[0459] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C6 alkoxy; and

[0460] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0461] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene, -C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl);

[0462] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0463] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0464] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0465] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C2 alkoxy; and

[0466] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0467] In some embodiments of any one of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0468] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0469] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0470] wherein the 4 to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0471] wherein the -C6 aryl groups are each independently optionally substituted by one or more halogens, -OH or -C1-C2 alkoxy groups; and

[0472] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0473] In some embodiments of any of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0474] wherein the -C1-C6 alkyl group is optionally substituted by one or two, preferably by exactly one -C2 alkynyl group, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0475] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -OH, -N(R 83 )(R 84 ) or phenyl;

[0476] wherein the 4- to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -C1-C2 alkyl or oxo;

[0477] wherein the -C6 aryl groups are each independently optionally substituted by one or two, preferably by exactly one, halogen, -OH or -C1-C2 alkoxy; and

[0478] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0479] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4) or (I-D4), R82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0480] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0481] Wherein, the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0482] wherein the 4 to 8 membered heterocycloalkyl groups are each independently optionally substituted with one or more -C1-C6 alkyl groups, halogen groups, -OH groups, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted;

[0483] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ) or -C1-C6 alkoxy substituted;

[0484] The 5- to 10-membered heteroaryl groups may be independently substituted with one or more -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, phenyl or oxo-substituted; and

[0485] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0486] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0487] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2-C6 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl);

[0488] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0489] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C6 alkyl groups or oxo groups;

[0490] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C6 alkoxy; and

[0491] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0492] In some embodiments of any one of Formulas (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-Bl), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C3 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene, -C6-C 10 Aryl, 5- to 10-membered heteroaryl, or -C1-C3 alkylene-(5- to 10-membered heteroaryl);

[0493] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0494] wherein the -C3-C8 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0495] wherein the 4 to 8-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0496] Wherein, the -C6-C 10 The aryl groups are each independently optionally substituted with one or more halogen, -OH or -C1-C2 alkoxy; and

[0497] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0498] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0499] Wherein, the -C1-C6 alkyl group may be optionally substituted with one or more -C2 alkynyl groups, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0500] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted with one or more -OH, -N(R 83 )(R 84 ) or phenyl;

[0501] wherein the 4 to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or more -C1-C2 alkyl groups or oxo groups;

[0502] wherein the -C6 aryl groups are each independently optionally substituted by one or more halogens, -OH or -C1-C2 alkoxy groups; and

[0503] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0504] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D4) or (I-D4), R82 is -H or C1-C2 alkyl, R 82 Preferably H; each occurrence of R 81 independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocycloalkyl, -C1-C3 alkylene-(4- to 6-membered heterocycloalkyl), -C6 aryl, -C1-C3 alkylene-C6 aryl, 5- to 6-membered heteroaryl, or -C1-C3 alkylene-(5- to 6-membered heteroaryl);

[0505] wherein the -C1-C6 alkyl group is optionally substituted by one or two, preferably by exactly one -C2 alkynyl group, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C2 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C2 alkyl);

[0506] wherein the -C3-C6 cycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -OH, -N(R 83 )(R 84 ) or phenyl;

[0507] wherein the 4- to 6-membered heterocycloalkyl groups are each independently optionally substituted by one or two, preferably by exactly one -C1-C2 alkyl or oxo;

[0508] wherein the -C6 aryl groups are each independently optionally substituted by one or two, preferably by exactly one, halogen, -OH or -C1-C2 alkoxy; and

[0509] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0510] In some embodiments of any of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4), R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 groups, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl or oxo-substituted; and

[0511] Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl.

[0512] In some embodiments of any one of Formula (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-Bl), (I-B2), (I-B3), (I-B4), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3) or (I-D4),

[0513] R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more -C1-C2 alkyl, halogen, -OH, -C1-C3 alkylene-OH, -N(R 83 )(R 84 )、-C1-C3 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl (preferably cyclopropyl) or oxo-substituted; and

[0514] Each occurrence of R 83 and R 84 Independently selected from -H and C1-C2 alkyl, preferably -H and -CH3.

[0515] In a preferred embodiment, the compound is selected from:

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530] as well as

[0531] In some embodiments, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 1).

[0532] In some embodiments, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-morpholino-2-oxo-ethyl)piperazin-1-yl]-4H-triazolo[1,5-a]quinazolin-5-one (Compound 2).

[0533] Antitoxic activity of the compounds of the present invention

[0534] The compounds of the present invention are 3-(benzenesulfonyl)-[1,2,3]triazolo[1,5a]quinazoline-5(4h)-one derivatives, which contain an N-linked piperazine or homopiperazine at the 8th position of the [1,2,3]triazolo[1,5a]quinazoline-5(4h)-one nucleus, and are further substituted (on the second nitrogen atom) with an (optionally substituted) acetyl or propionamide group. As shown in Table 3, the compounds of the present invention were tested in an AgrA reporter assay to evaluate their ability to inhibit gene expression controlled by the P3 promoter regulated by AgrA. Specifically, the reporter gene lacZ (which encodes the protein product β-galactosidase) was transfected into Staphylococcus aureus via a plasmid controlled by the P3 promoter. The compounds were serially diluted in lysogenic medium (LB) and incubated with Staphylococcus aureus. After incubation, Staphylococcus aureus cells were lysed and treated with 4-methylumbelliferyl-galactoside (MUG). The B-galactosidase produced by lacZ expression cleaves MUG into galactopyranose and 4-methylumbelliferone, which is measured by fluorescence. Therefore, the fluorescence reading can be used as an indicator of the ability of the compounds of the invention to inhibit genes controlled by the P3 promoter (e.g., in bacteria, preferably in Staphylococcus aureus).

[0535] The compound of the present invention remains active in the presence of 40mg / mL HSA, with an IC50 value as low as 8pg / mL. Therefore, even if incubated with HSA at physiologically relevant concentrations, the compound of the present invention remains active in inhibiting gene expression regulated by AgrA. On the contrary, as shown in Example 3, even if compound 45 of WO 2020 / 109350 inhibits lacZ expression at a concentration of less than 1pg / mL in an AgrA reporter assay in the absence of HSA, when incubated with Staphylococcus aureus in the presence of HSA, the compound is inactive even at the highest concentration (i.e., 128pg / mL) of the tested compound. It is not desirable to be constrained, and the concentration of 40mg / mL HSA is selected because this is the same concentration of HSA found in human serum.

[0536] Without wishing to be bound, the compounds of the present invention can maintain their activity even in the presence of HSA, which allows the compounds of the present invention to be administered (e.g., administered to a subject, such as a mammal, preferably a human being; and preferably administered topically) while still maintaining efficacy. Therefore, the compounds of the present invention surprisingly maintain their activity even when incubated in biologically relevant concentrations of HSA.

[0537] Application of the compounds of the present invention

[0538] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0539] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising the compound of formula (I), for use as a medicament.

[0540] In another aspect, the present invention provides compounds of formula (I) disclosed herein and pharmaceutically acceptable salts, stereoisomers, enantiomers, tautomers thereof, for use in a method of reducing bacterial virulence, preferably bacteria expressing AgrA or an AgrA ortholog (preferably AgrA), and further preferably bacteria selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably bacteria of the genus Staphylococcus, and further preferably Staphylococcus aureus. In another very preferred embodiment, the bacteria express AgrA or an AgrA ortholog. In another very preferred embodiment, the bacteria express AgrA. In another very preferred embodiment, the bacteria is a bacteria selected from the following genera: Staphylococcus, Streptococcus or Clostridium. In another very preferred embodiment, the bacteria is a bacteria of the genus Staphylococcus. In another very preferred embodiment, the bacteria is Staphylococcus. In another very preferred embodiment, the bacteria is Staphylococcus. In another very preferred embodiment, the bacteria is Staphylococcus. 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 they are specifically mentioned again or repetition is avoided for brevity.

[0541] On the other hand, the present invention provides a compound of formula (I) disclosed herein and a pharmaceutically acceptable salt, stereoisomer, enantiomer, tautomer thereof, for use in a method for preventing or treating a disease in a subject, wherein the disease is preferably an infection or an inflammatory disease, further preferably a bacterial infection or an inflammatory skin disease caused or aggravated by bacteria, wherein preferably, the bacteria is selected from bacteria of the genus Staphylococcus, Streptococcus or Clostridium, more preferably a bacteria of the genus Staphylococcus, and further preferably wherein the bacteria is Staphylococcus aureus. 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 or an inflammatory skin disease caused or aggravated by bacteria. In another very preferred embodiment, the disease is a bacterial infection, wherein the bacteria is selected from bacteria of the genus Staphylococcus, Streptococcus or Clostridium. In another very preferred embodiment, the disease is aggravated by bacteria selected from the genus Staphylococcus, preferably by Staphylococcus aureus. In another very preferred embodiment, the disease is an infection caused or aggravated by a bacterium selected from the genus Staphylococcus. In another very preferred embodiment, the disease is an infection caused or aggravated by Staphylococcus aureus. In another very preferred embodiment, the disease is Netherton syndrome or an inflammatory skin disease, preferably atopic dermatitis. In another very preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis aggravated by Staphylococcus aureus. In a preferred embodiment, the disease is Netherton syndrome. 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, whether or not specifically mentioned again or repetition is avoided for the sake of brevity.

[0542] In another aspect, the present invention provides a compound of formula (I) for use in a method of inhibiting quorum sensing (preferably AgrA quorum sensing) in bacteria, preferably bacteria selected from the genus Staphylococcus, Streptococcus or Clostridium, more preferably bacteria of the genus Staphylococcus, and further preferably 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, whether or not specifically mentioned again or repetition thereof is avoided for the sake of brevity.

[0543] In another preferred embodiment, the bacterium is selected from Streptococcus pyogenes, Clostridium difficile or Staphylococcus aureus, preferably Staphylococcus aureus. In a very preferred embodiment, the bacterium is Staphylococcus aureus.

[0544] Therefore, the compositions and compounds of the present invention represent anti-virulence therapies that can be used as stand-alone therapies to enhance the self-defense and healing capabilities of the infected host by reducing tissue damage, reducing inflammation, reducing disease transmission, complete immune response, and reducing relapse rates. In cases where the disarmed pathogen may not be adequately cleared by the host, combined therapy with traditional 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).

[0545] In a preferred embodiment of the method of the present invention, the compound of formula (I) inhibits one or more virulence factors synthesized by bacteria, wherein the one or more virulence factors are selected from one or more of the following: toxins (e.g., α, β, γ, γ-variants and δ-hemolysin, PSM (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B, exfoliative toxins), proteases (e.g., serine proteases, metalloproteases and cysteine ​​proteases), nucleases, lipases, coagulase, hyaluronidase, 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 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 In another preferred embodiment of the method of the present invention, the enterotoxin is enterotoxin B or exfoliative 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 more than one virulence factor, wherein the more than one virulence factor is selected from: α, β, γ, γ-variant and δ-hemolysin, PSMα, Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxin B, exfoliative toxin, serine proteases, metalloproteases, cysteine ​​proteases, nucleases, lipases, coagulase, hyaluronidase, agglutination factor, TSST-1, and any one or more specific virulence factors or generic categories of virulence factors (generic group). 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 to the human being). In another very preferred embodiment, the method further comprises administering an antibiotic to the subject (preferably to the human being). In another very preferred embodiment, the method further comprises administering an anti-inflammatory agent preferably to the human being.

[0546] On the other hand, the present invention provides a method for preventing or treating a disease in a subject, the disease is preferably an infection or an inflammatory disease, further preferably a bacterial infection or an inflammatory skin disease caused or aggravated by bacteria, wherein preferably, the bacteria is selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably wherein the bacteria is Staphylococcus aureus, the method comprising administering to an individual 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 a bacterial infection) is caused by a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably caused by a bacterium of the genus Staphylococcus, and further preferably caused by Staphylococcus aureus. In another very preferred embodiment, the infection (preferably a bacterial infection) comprises an antibiotic resistant Staphylococcus infection, preferably, the antibiotic resistant Staphylococcus infection comprises a methicillin resistant Staphylococcus aureus infection.

[0547] Thus, the compounds of the present invention of formula (I) as described herein or the compositions of the present invention comprising the compounds of formula (I) (preferably the pharmaceutical compositions of the present invention) can be administered to a subject to inhibit AgrA activity, thereby preventing the production of virulence factors that contribute to the development of bacterial infection or disease conditions or disorders associated with bacterial infection. Examples of diseases and disorders associated with bacterial infection that are responsive 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, or chronic inflammatory skin diseases, such as atopic dermatitis or Netherton syndrome.

[0548] On the other hand, the present invention provides a method for inhibiting bacterial quorum sensing (preferably AgrA quorum sensing), wherein the bacteria are preferably selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, wherein the method comprises administering to a subject an effective amount of a compound of formula (I), a pharmaceutical composition or a combination product, preferably a compound of formula (I).

[0549] In another preferred embodiment of the present invention, the compound of formula (I) is provided in a topical composition together with a pharmaceutically acceptable carrier and topically applied to a subject, wherein preferably the subject suffers from a disease or condition associated with a bacterial infection, wherein the bacterial infection is an infection caused or aggravated by bacteria, preferably an infection caused or aggravated by 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, Netherton syndrome or atopic dermatitis.

[0550] Thus, the compounds of the invention of formula (I) as described herein, or the compositions of the invention comprising the compounds of the invention of formula (I), or the combination products of the invention (preferably the compounds of the invention of formula (I) or the pharmaceutical compositions of the invention) can be used to prevent or treat infection in a subject by any bacterial species that utilizes the AgrA response regulator for quorum sensing and produces virulence factors. The compounds and compositions of the invention are typically and preferably administered to a subject suffering from an infection or at risk of infection, preferably a bacterial infection, such as a Staphylococcus and / or Streptococcus infection. For example, a subject who may benefit from treatment with the compounds or compositions of the invention as described herein may be a hospitalized patient 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-sensitive Staphylococcus aureus, and vancomycin-resistant Staphylococcus aureus). Methods for detecting the presence of Staphylococcus bacterial infection are well known, for example, and can be detected by culturing a sample (e.g., blood culture) of a subject.

[0551] On the other hand, 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), wherein the infection or inflammatory disease is caused by bacteria selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably caused by bacteria of the genus Staphylococcus, and further preferably caused by Staphylococcus aureus, the method comprising administering to the subject a compound of formula (I) of the present invention and at least one antibacterial antibiotic, the antibiotic preferably being resistant to bacteria selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably resistant to bacteria of the genus Staphylococcus, and further preferably resistant to Staphylococcus aureus.

[0552] On the other hand, the present invention provides a method for preventing or treating a bacterial infection in a subject, the method 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 further preferably caused by Staphylococcus aureus.

[0553] In another aspect, the present invention provides a method for preventing or treating a disease caused or exacerbated 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.

[0554] In one aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0555] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I), for use as a medicament.

[0556] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention for use in a method for reducing bacterial virulence, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0557] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention for use in a method of inhibiting quorum sensing of bacteria, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0558] In one aspect, the present invention provides a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention, for use in a method for preventing or treating a disease caused or exacerbated by bacteria in a subject, wherein the bacteria are preferably bacteria selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably bacteria of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0559] 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 in a method for reducing bacterial virulence, preferably in a subject in need thereof, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0560] 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 in a method for inhibiting quorum sensing of bacteria, preferably in a subject in need thereof, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0561] 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 in a method for preventing or treating a disease caused or aggravated by bacteria, preferably in a subject in need thereof, preferably wherein the bacteria is selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0562] 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 in the preparation of a medicament for reducing bacterial virulence, preferably in a subject in need thereof, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0563] In some embodiments, the present invention provides a use of a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention in the preparation of a medicament for inhibiting bacterial quorum sensing, preferably in a subject in need thereof, preferably wherein the bacterium is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacterium expresses AgrA or a direct homolog of AgrA, more preferably wherein the bacterium expresses AgrA.

[0564] In some embodiments, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutical composition comprising the compound of the present invention in the preparation of a medicament for preventing or treating a disease caused or aggravated by bacteria, preferably in a subject in need thereof, preferably wherein the bacteria is selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0565] 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, preferably wherein the virulence of the bacteria is reduced; preferably wherein the bacteria is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacteria express AgrA or a direct homolog of AgrA, more preferably wherein the bacteria express AgrA.

[0566] In some embodiments, the present invention provides a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject a compound of the present invention as described herein or a pharmaceutical composition comprising a composition of the present invention, preferably wherein quorum sensing of the bacteria is inhibited, preferably wherein the bacteria is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacteria express AgrA or an ortholog of AgrA, more preferably wherein the bacteria express AgrA.

[0567] In some embodiments, the present invention provides a method for treating a disease caused or exacerbated 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, preferably wherein the bacterium is selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis.

[0568] In some embodiments, the present invention provides a method for reducing the virulence of bacteria, preferably wherein the bacteria is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacteria express AgrA or a direct homolog of AgrA, more preferably wherein the bacteria express AgrA, 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.

[0569] In some embodiments, the present invention provides a method for inhibiting quorum sensing of bacteria, preferably wherein the bacteria is a bacterium selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably a bacterium of the genus Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the bacteria express AgrA or a direct homolog of AgrA, more preferably wherein the bacteria express AgrA, and the method comprises exposing the bacteria to a compound of the present invention as described herein or a pharmaceutical composition comprising a compound of the present invention.

[0570] In some embodiments, the present invention provides a method for preventing or treating a disease caused or exacerbated by bacteria, preferably wherein the bacteria is selected from the following genera: Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and further preferably Staphylococcus aureus, preferably wherein the disease is a skin disease or a lung disease, more preferably wherein the skin disease is atopic dermatitis, Netherton syndrome or psoriasis, 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.

[0571] The compounds of the present invention of formula (I), pharmaceutical compositions comprising the compounds, or combination products can be administered to any subject who can experience the beneficial effects of the compounds of the present invention, compositions, or products described herein. Preferably, the subject is a human being. The compounds of the present invention, compositions, or products comprising the compounds described herein can be administered in any manner that can achieve their intended purpose. For example, administration can be topical or systemic, for example, administration can be parenteral, topical, topical, subcutaneous, oral, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, oral, oral mucosal, or ocular, or administered by inhalation.

[0572] Equivalent method

[0573] Although the present technology has been described in conjunction with the above specific embodiments, many substitutions, modifications and other variations of the present technology will be apparent to those skilled in the art. All these substitutions, modifications and variations are intended to fall within the spirit and scope of the present invention.

[0574] Example

[0575] The present invention will now be described by 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 multiple changes and modifications may be made. The preparations mentioned in a similar manner to other preparations or by the general method of other preparations may include variations in conventional parameters, such as time, temperature, processing conditions, small changes in reagent volume, etc.

[0576] abbreviation

[0577] The following list provides the definition of certain abbreviations and symbols used in this article. It should be understood that the list is not exhaustive, and the meaning of those abbreviations and symbols that are not defined below will be apparent to those skilled in the art. In describing the present invention, the identification of chemical elements follows the provisions of the periodic table of elements.

[0578]

[0579]

[0580] HPLC-MS

[0581] Unless otherwise stated, the purity and identity of the intermediate or exemplified compound are evaluated by the most advanced HLPC-MS as described below.HPLC-MS analysis is carried out on the LC-MS Waters Alliance Micromass ZQ 2000 system equipped with Waters 2747 sample manager, Waters 2695 separation module, Waters 2996 photodiode array detector (200-800nm) and Waters Micromass ZQ2000 detector (scan 100-800).HPLC analysis uses XBridge C18 column (3.5μm particle size, size 50x 4.6mm).Injection volume is 20μL.A mixture of water and acetonitrile is used as mobile phase in gradient elution.The pH of mobile phase is adjusted with HCOOH and NH4OH to form a buffer solution with a pH of 3.8. The analysis time was 5 min (method A1) or 10 min (method A2) using a gradient starting from 100% aqueous buffer pH = 3.8 ± 0.3 (NH4OH 0.01%, HCOOH 0.02%) to 100% acetonitrile buffer (NH4OH 0.01%, HCOOH 0.02%).

[0582] - 3.25 min at a flow rate of 2 mL / min (5 min run; Method A1),

[0583] - 6.5 min at a flow rate of 2 mL / min (10 min run; Method A2).

[0584] Preparation Example 1: 8-Bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one (Intermediate I-1)

[0585]

[0586] In ice-cold anhydrous DMF (200ml) 2,4-dimethylbenzenethiol (9.8ml, 72.46mmol) and potassium carbonate (20g, 144.7mmol) suspension, add 2-bromoacetonitrile (76.09mmol). The reaction mixture (on ice) is stirred for 1.5 hours. Then water (350ml) is added and the product is extracted with Et2O (3x100 ml). The organic layers are combined, washed with brine (3x80 ml), dried with MgSO4, filtered and evaporated to obtain intermediate 2-(2,4-dimethylphenyl)-sulfanylacetonitrile, which is a colorless oil (yield is 99.8%, HPLC purity>99%).

[0587] The previous intermediate was dissolved in DCM (250ml) and cooled on an ice bath. Then mCPBA (<77%, 33g, 147.2mmol) was added in batches. The reaction mixture was stirred on ice for 40 minutes and then left overnight at room temperature. The reaction mixture was then diluted with DCM (250ml), washed with 5% Na2S2O3 aqueous solution (2x100 ml) and concentrated NaHCO3 aqueous solution (8x200ml). The combined aqueous solution was extracted with DCM (2x100 ml). The organic phases were combined, dried with MgSO4, filtered and evaporated to obtain 2- (2,4- dimethylphenyl) -sulfonylacetonitrile, which was a white powder (yield of 92.1%, HPLC purity of 98%).

[0588] Under Ar atmosphere, in the methyl 2-amino-4-bromo-benzoate (7g, 30.4mmol) solution in the anhydrous acetonitrile of cooling (4 ℃), tert-butyl nitrite (1.5 equivalents) is added dropwise. After stirring for 20 minutes, azidotrimethylsilane (1.2 equivalents) is added dropwise (exothermic reaction-reaction temperature remains below 15 ℃). After the addition is completed, the reaction mixture is stirred in an ice bath for 40 minutes, then it is brought to room temperature and stirred for another 2 hours. Concentrated NaHCO3 aqueous solution (500ml) is added to the reaction mixture, a suspension is formed, extracted with EtOAc (3x200 ml). The organic layer merged is washed with brine (200ml), dried with MgSO4, filtered and evaporated to obtain methyl 2-azido-4-bromo-benzoic acid methyl ester, which is an orange oil (yield is 97%, HPLC purity is 99%).

[0589] In an ice-cold anhydrous EtOH (560ml) solution of 2-(2,4-dimethylphenyl)-sulfonylacetonitrile (11.67g, 54.65mmol), a freshly prepared sodium ethoxide solution (15%, 117mmol) in EtOH was added dropwise. After 30 minutes, a solution (225ml) of 2-azido-4-bromo-benzoic acid methyl ester (54.13mmol) in anhydrous EtOH was added dropwise. The resulting mixture was stirred on ice for 1 hour, stirred at room temperature for 1.5 hours, and then concentrated under vacuum. The pH was adjusted to 3.1 with aqueous hydrochloric acid solution (2M). The precipitate was filtered out. The solid was washed with water (3x400 ml) and dried under vacuum. The crude product was ground several times with cold EtOAC and Et2O and dried overnight to give the intermediate I-1 of the title, which was a beige solid (yield of 86.6% and HPLC purity of 99.1%).

[0590] Preparation Example 2: 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinoline [oxazoline-8-yl]piperazine-1-yl]acetic acid (Intermediate II-1)

[0591]

[0592] Intermediate II-1 is prepared from Intermediate I-1 in at least two ways according to the following general scheme:

[0593]

[0594] Path A:

[0595] Intermediate I-1 (600 mg, 1.38 mmol), tert-butyl piperazine-1-carboxylate (516 mg, 2.77 mmol, 2 eq.), Pd2dba3 (39.8 mg, 5 mol%), Cs2CO3 (677 mg, 2.08 mmol, 1.5 eq.), RuPhos (64.6 mg, 0.138 mmol, 10 mol%) and DMF (40 ml) were added to a 100 ml round bottom flask. The mixture was degassed with Ar purge and then equipped with a reflux condenser and stirred in a preheated heating block at 120 ° C for 3 hours. Afterwards, the mixture was cooled to room temperature, diluted with MeOH, filtered on celite and evaporated to dryness. The crude product was purified by flash chromatography with EtOAc-MeOH (100-0 to 95-5) to give 750 mg of a brown solid which was triturated in Et2O to give 514 mg of tert-butyl 4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazine-1-carboxylate as a beige solid (yield 68%, HPLC purity 99%, Method A1). MS (ES+) m / z 539.

[0596] To a solution of tert-butyl 4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazine-1-carboxylate (500 mg, 0.928 mmol) in 20 ml of dioxane was added 4M HCl in dioxane (3.45 ml, 15 eq.) and the mixture was stirred overnight at 80°C. The precipitate was filtered and triturated with Et2O to give 410 mg of 3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one as a beige solid (yield 93%, HPLC purity 100%, method A1). MS (ES+) m / z 439.

[0597] Intermediate II-1 was then prepared in two additional steps starting from the previous compound (3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one) and methyl bromoacetate in the presence of sodium bicarbonate in acetone, followed by saponification of the ester in the presence of lithium hydroxide as described below in Pathway B.

[0598] Alternatively, intermediate II-1 was prepared in two additional steps starting from (3-(2,4-dimethylphenyl)sulfonyl-8-piperazin-1-yl-4H-triazolo[1,5-a]quinazolin-5-one and methyl bromoacetate (3.0 equiv.) in the presence of potassium carbonate in DMSO. The mixture was stirred at 120 °C overnight and then cooled to room temperature. The DMSO was removed by freeze drying and the crude product was purified by flash chromatography using ethyl acetate / MeOH (100 to 80-20) to give a beige solid. The ester was then saponified in the presence of lithium hydroxide as described in Pathway B below.

[0599] Path B:

[0600] In a sealed vial, methyl 2-piperazine-1-yl acetate dihydrochloride (80 mg, 0.35 mmol, 1 eq.), Cs2CO3 (395 mg, 1.21 mmol, 3.5 eq.) were dissolved in anhydrous DMF (9 ml) and stirred for 2 h. Then tris(dibenzylideneacetone)dipalladium(0) (9.95 mg, 5 mol%), 2-dicyclohexylphosphine-2',6'-di-isopropoxy-1,1'-biphenyl (16.2 mg, 10 mol%), I-1 (150 mg, 0.35 mmol) were added to the vial flushed with argon. The vial was then sealed and stirred in a preheated heating block. After 4 h, the mixture was cooled to room temperature and filtered on celite. The celite pad was rinsed with MeOH. The solution was then concentrated to dryness and the residue was purified by flash chromatography using ethyl acetate / MeOH (100 to 80-20) to give a beige solid (137 mg, yield 73.9%, HPLC purity: 95.3%, LC tR = 2.01 min, MS (ESI + ): m / z = 511 [M + H] + , MS (ESI - ): m / z = 509 [M + H] - ).

[0601] In a round-bottom flask, 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[l,5-a]quinazolin-8-yl]piperazine-1-yl]acetic acid methyl ester (159mg, 0.311mmol) was dissolved in THF-H2O (50:50, 50ml) solution, and then LiOH monohydrate (52.3mg, 1.25mmol, 4 equivalents) was added. The mixture was stirred at 0°C for 2 hours and then stirred at room temperature overnight. After that, THF was removed under reduced pressure, and then the mixture was brought to 0°C and HCl1N was added dropwise until precipitation. The crude solid was filtered, washed with cold EtOH, and then dried under vacuum overnight. 140mg of a white solid was obtained with a yield of 90%.

[0602] Alternatively, the crude solid was filtered and triturated with CHCl3 and then dried under vacuum overnight. 148 mg of a white solid was obtained with a yield of 95%, HPLC purity: 100%, LC T R = 1.60 min, MS (ESI + ): m / z = 497.2 [M + H] + , MS (ESI - ): m / z = 495.2 [M + H] - .

[0603] Intermediates II-2 to II-11 were prepared according to the same procedure as described for Intermediate II-1, starting from the corresponding starting materials.

[0604] Table 1: Intermediates II-2 to II-11

[0605]

[0606]

[0607] General reaction conditions for amide formation (taking II-1 as an example).

[0608]

[0609] A suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq.) in anhydrous DMF (1 M) and DCM (0.5 M) was treated with intermediate II-1, followed by 1-hydroxybenzotriazole hydrate (1.1 eq.). After the suspension was clarified, the appropriate amine R in dichloromethane (2.5 M) was added. 81 R 82 NH (1.5 eq.). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to remove DMF. The residue was purified by chromatography in a suitable eluent, if necessary, to give the desired product as a solid, or the residue was tested without further treatment.

[0610] Alternatively, a solution of 2-[4-[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]piperazin-1-yl]acetic acid (Intermediate II-1, 2.5 mg, 0.005 mmol) in NMP (0.75 mL) was added to a substrate tube containing TMP (0,004 mL, 0.025 mmol, 5 eq) and T3P (0.003 mL, 0.05 mmol, 1 eq). After 1 hour, the appropriate amine R 81 R 82NH (0.005mmol, 1 equivalent) and T3P (0.003mL, 0.005mmol, 1 equivalent) were added to the mixture and stirred at room temperature for 16 hours (using BioShake IQ, speed 1800rpm). The crude product was then concentrated to dryness (using GenevaCEZ-2Plus, medium boiling point, 65°C, 7 hours). The compound was tested without further purification. Alternative acid activation methods known in the art can also be used.

[0611] General reaction conditions for removal of -BoC protecting groups

[0612] When amine R 81 R 82 When the NH contains an additional nitrogen protected by a -BoC group, the following general procedure is used to generate the free amine:

[0613] The BoC protected derivative (1 eq) in anhydrous dioxane (0.35 M) was added to a 50 ml flask, 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 triturated in EtO to give the desired product.

[0614] Alternatively, using TFA: the BoC protected derivative (1 eq) in anhydrous DCM (1.7 M) was added to a 50 ml flask, 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 then concentrated under reduced pressure and triturated in Et2O to give the desired product.

[0615] Alternatively, the substrate tube containing the BoC protected derivative was dissolved in anhydrous DCM (0.02 M), then TFA (250 eq.) was added dropwise and the mixture was stirred at 40° C. (using BioShake IQ at 1800 rpm). When the reaction was judged complete by LC-MS, heating was stopped, and the mixture was concentrated to dryness (using GenevaCEZ-2Plus, medium boiling point, 65° C., 7 hours) and placed under vacuum for 4 days to give the desired product.

[0616] Alternatively, the substrate tube containing the BoC protected derivative was dissolved in NMP (0.02 M), then aqueous HCl (37%) was added dropwise and the mixture was stirred at 80° C. When the reaction was judged complete by LC-MS, heating was stopped and the mixture was concentrated to dryness (using Geneva CEZ-2 Plus, medium boiling point, 65° C., 7 hours) and placed under vacuum for 4 days to give the desired product.

[0617] Example 1: 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperidin [1,5-a]quinazolin-5-one (Compound 1)

[0618]

[0619] Compound 1 was obtained according to the general scheme for amide formation from intermediate II-1 described above, using pyrrolidine as the amine partner. The title product was isolated as a beige solid (HPLC purity 100%, Method A2); or

[0620] Intermediate I-1 (30 mg, 0.0692 mmol, 1 eq.), 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (27.3 mg, 0.138 mmol, 2 eq.), Pd2dba3 (2 mg, 0.00346 mmol, 5 mol%), Cs2CO3 (34 mg, 0.104 mmol, 1.5 eq.) and RuPhos (3.23 mg, 0.00692 mmol, 10 mol%) were added to a round bottom flask, followed by DMF (0.035 M). The mixture was degassed with Ar purge, then equipped with a reflux condenser and stirred overnight at 120° C. in a preheated heating block. Afterwards, the mixture was cooled to room temperature, diluted with MeOH, filtered on celite, and concentrated under reduced pressure. The crude product was purified by flash chromatography with 100% DCM until DCM-MeOH (95-5) to afford 13 mg of the title product as a beige solid (yield 34%, HPLC purity 100%, method A2). LC T R =1.87, [ES+MS]m / z550.3(MH+).

[0621] Example 2: 3-(2,4-dimethylphenyl)sulfonyl-8-[4-(2-morpholino-2-oxo-ethyl)piperazine-1- 4H-triazolo[1.5-a]quinazolin-5-one (Compound 2)

[0622]

[0623] Compound 2 was prepared according to the same procedure as compound 1 starting from 2-morpholino-1-piperazin-1-yl-ethanone. The title product was isolated as a white solid (HPLC purity 100%, method A2). LC T R =1.82, [ES+MS] m / z 566.2 (MH+).

[0624] Compounds 3 to 175 of the present invention were prepared from the corresponding intermediates shown in Table 2 below according to the above appropriate general schemes.

[0625] Table 2: Exemplary compounds of the invention

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644] Example 3: AgrA reporter assay

[0645] The USA300 strain UAMS-1625 of Staphylococcus aureus was transformed with a plasmid expressing the reporter gene lacZ, which is controlled by the P3 promoter, which is regulated by AgrA. The resulting reporter strain was used to measure AgrA inhibitory activity as shown below. The cells from the overnight culture plate were resuspended in 0.9% (w / v) saline solution and cultured in LB medium at 5x10 5CFU / ml Bacterial inoculum was prepared. 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 at 37 °C with shaking. After 18 h of incubation, 100 μL was transferred to a new clear 96-well plate and the OD was measured using a TECAN Infinite F200 microplate reader. 600 , to control for growth inhibition. Another 100 μL was transferred to a new black 96-well plate containing 30 μL of lysis buffer (20 mM Tris / HCl, 3 mM MgCl, 0.5% Tween 20 (v / v), 0.5% NP-40 (v / v)), and the plate was incubated at 37°C with shaking for 60 minutes. 20 μL, 0.25 mg / ml of substrate MUG (4-methylumbelliferyl β-D-galactoside) was added, and after incubation at 37°C with shaking for 3 hours, fluorescence was measured using a TECAN Infinite F200 microplate reader (excitation: 360 nm, emission: 450 nm). After normalization to the DMSO control, GraphPad PRISM was used to determine the IC50.

[0646] Determine the IC in the presence of human serum albumin (HAS, 40 mg / mL) by supplementing the LB medium used for inoculum preparation 50 .

[0647] The activities of the compounds of the present invention in the absence and presence of human serum albumin are listed below:

[0648] In Table 3, the corresponding data of compound 45 in WO 2020 / 109350 under the same conditions are also provided.

[0649]

[0650] Table 3: Reporter assay results

[0651] IC 50 (without HSA):+++:IC 50 ≤1μg / mL, ++:1μg / mL <IC 50 ≤5 μg / mL

[0652] IC 50 (including HSA):+++:IC 50 ≤10μg / mL, ++:10μg / mL <IC 50 ≤50μg / mL, +:IC 50 >50

[0653] μg / mL

[0654] IC 50 (When HSA is present) / IC 50 Ratio (when HSA is not present): +++: ratio ≤ 25; ++: 25 < ratio ≤ 125; +: ratio > 125

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate or tautomer thereof: Where: R 1 are independently selected from -H, halogen, -C1-C6 alkyl and -C1-C6 alkoxy, wherein, The alkyl group and the alkoxy group may each be optionally substituted with one or more R 11 replace; R 3 independently selected from -H, halogen, -C1-C6 alkyl, -C1-C6 alkoxy and -C3-C6 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally substituted by one or more R 11 replace; Each occurrence of R 8A and R 8B Each is independently -H or -CH3; Each occurrence of R 81 and R 82 Each is independently selected from -H, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 4 to 8 membered heterocycloalkyl, -C1-C6 alkylene-(4 to 8 membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 wherein the alkyl group is optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl); wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 85 replace; Each occurrence of R 83 and R 84 Independently selected from -H and -C1-C6 alkyl; Each occurrence of R 85 independently selected from -C1-C6 alkyl, halogen, -OH, -N(R 83 )(R 84 ), -C1-C6 alkoxy, -C6-C 10 Aryl and oxo; Or, R 81 and R 82 Together with the nitrogen atom to which they are attached, they form a 4- to 11-membered heterocycloalkyl group, wherein the 4- to 11-membered heterocycloalkyl group is optionally substituted by one or more R 86 replace; Each occurrence of R 86 independently selected from -C1-C6 alkyl, halogen, -OH, -C1-C6 alkylene-OH, -N(R 83 )(R 84 )、-C1-C6 alkylene-N(R 83 )(R 84 ), -C3-C6 cycloalkyl and oxo; Each occurrence of R 11 are independently halogen or -OH; m is independently 1 or 2; and n is independently 0 or 1.

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

3. The compound according to claim 1 or 2, wherein R 3 It is -CH3.

4. A compound according to any one of the preceding claims, wherein R 8A and R 8B All are -H.

5. A compound according to any one of the preceding claims, wherein n is 0 and m is 1.

6. A compound according to any one of the preceding claims, wherein Each occurrence of R 81 and R 82 Each is independently selected from -H and -C1-C6 alkyl, the alkyl being optionally substituted with one or more -C2-C6 alkynyl, halogen, -OH, -(OCH2-CH2) 1-2 -OH, -C1-C6 alkoxy, -N(R 83 )(R 84 ) or -S(C1-C6 alkyl).

7. The compound according to any one of claims 1 to 5, wherein R 81 Selected from -C3-C8 cycloalkyl and -C1-C6 alkylene-(C3-C8 cycloalkyl).

8. The compound according to any one of claims 1 to 5, wherein R 81 Selected from 4- to 8-membered heterocycloalkyl and -C1-C6 alkylene-(4- to 8-membered heterocycloalkyl).

9. The compound according to any one of claims 1 to 5, wherein R 81 Selected from -C6-C 10 Aryl and -C1-C6 alkylene-(C6-C 10 aryl).

10. The compound according to any one of claims 1 to 5, wherein R 81 is selected from 5- to 10-membered heteroaryl and -C1-C6 alkylene-(5- to 10-membered heteroaryl).

11. A compound according to any one of the preceding claims, wherein R 82 is -H or C1-C6 alkyl, R 82 Preferably -H or C1-C2 alkyl, R 82 More preferably, it is H.

12. The compound according to any one of claims 1 to 5, wherein R 81 and R 82 are combined together with the nitrogen atom to which they are attached to form a 4- to 11-membered heterocycloalkyl group, which may be optionally substituted by one or more R 86 replace.

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

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