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

Abstract

The present invention provides compounds according to formula (I), wherein R and R are independently H, halogen, hydroxyl, NO, CN, C-C-alkyl optionally substituted by one or more R, C-C-alkoxy optionally substituted by one or more R, C-C-cycloalkyl optionally substituted by one or more R, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2 and heterocycles optionally substituted by one or more R17, where R3 is selected from halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OCn -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2 and heterocycles optionally substituted by one or more R17, R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11, R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and heterocycles optionally substituted by one or more R17, wherein R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11, wherein the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently H, C1-C6-alkyl optionally substituted by one or more R11; or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, wherein one or more R17 are independently selected from halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, wherein R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and heterocycle optionally substituted by one or more R17, wherein R1, R2, R4, R5, R6, R7, and pharmaceutically acceptable salts, stereoisomers, enantiomers, tautomers of compounds of formula (I), and pharmaceutical compositions thereof, and their use in methods for reducing the pathogenicity of bacteria expressing AgrA, for preventing or treating diseases such as skin or lung infections or atopic dermatitis caused by or exacerbated by bacteria, preferably Staphylococcus aureus. JPEG2022508268000076.jpg85170

Description

[Technical Field]

[0001] The present invention relates to 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives and pharmaceutical compositions thereof, and their use in methods for reducing the virulence of bacteria expressing accessory gene regulator A (AgrA) or an ortholog of AgrA, in methods for inhibiting quorum sensing in bacteria, preferably Staphylococcus aureus, and in methods for preventing or treating diseases caused by or exacerbated by bacteria, preferably Staphylococcus aureus, such as skin or lung infections, atopic dermatitis, or psoriasis in a subject. Accordingly, the present invention relates to antipathogenic compositions and methods for treating, ameliorating, and / or preventing diseases caused by or exacerbated by bacteria, preferably Staphylococcus aureus, and more specifically, to compositions and methods for reducing the virulence of bacteria expressing AgrA or an ortholog of AgrA, preferably AgrA.

[0002] Related technologies Staphylococcus aureus is a human commensal and a notorious opportunistic pathogen that causes serious community-acquired and hospital-acquired infections. It can cause a variety of infections, ranging from mild superficial skin infections to severe systemic life-threatening conditions, such as endocarditis, pneumonia, and sepsis (Lee AS, et al. (2018) Nat Rev Dis Primers, Vol 4, Article 18033 pp 1-23 (doi:10.1038 / nrdp.2018.33)). Furthermore, Staphylococcus aureus has been implicated in allergic skin conditions, such as atopic dermatitis (Geoghegan JA, et al. (2018) Trends Microbiol 26(6):484-497). The success of Staphylococcus aureus in causing such a wide variety of diseases is the result of an extensive arsenal of virulence factors, produced in combination with β-lactam resistance and, in most clones, resistance to other antibiotic classes. Clinically relevant antibiotic resistance has evolved against nearly every antibiotic available, but the discovery and development of novel antibiotic classes has lagged behind in causing the antibiotic resistance crisis we face today. Therefore, alternative strategies for treating or preventing Staphylococcus aureus-mediated bacterial infections that are effective against multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are needed (Dickey SW, et al. (2017) Nat Rev Drug Discov 16(7):457-471).

[0003] One of these strategies is the antipathogenic approach, which targets only traits related to virulence, but not traits related to survival / fitness. In contrast to common antibiotic therapy, antipathogenic drugs are not bacteriostatic (inhibiting bacterial growth) or bactericidal (killing bacteria) per se. This approach focuses on disarming pathogenic bacteria by blocking expression or neutralizing virulence factors, ultimately interfering with bacterial virulence mechanisms and thereby facilitating pathogen clearance by the host immune system. Because antipathogenic drugs do not interfere with essential mechanisms of bacterial growth and survival, they are thought to reduce the pressure on pathogens to develop resistance. An additional benefit is that certain antipathogenic drugs can maintain a healthy host microbiota and ultimately help counter microbial dysbiosis by modulating the aggressiveness of pathogens such as Staphylococcus aureus. Importantly, antivirulence approaches increase the repository of pharmacological targets and therefore offer the possibility of generating alternative antibacterial agents with novel mechanisms of action (Muhlen S and Dersch P (2016) Curr Top Microbiol Immunol 398:147-183).

[0004] How virulence factors are regulated in Staphylococcus aureus: The agr operon is a bacterial quorum-sensing system that controls cell density-dependent expression of virulence factors in Staphylococcus aureus. It consists of two distinct promoters, P2 and P3. P2 is responsible for the production of components of the quorum-sensing system (AgrB, D, C, and A; see Figure 1). The precursor peptide AgrD is processed by AgrB to form the mature autoinducing peptide (AIP), which is secreted across the bacterial membrane. AIP binds to the histidine kinase AgrC and activates the transcriptional regulator AgrA by phosphorylation, promoting expression from P2 and P3. There are four allelic variants of agr (types I–IV), each encoding a distinct AIP, which functions as a specific ligand for AgrC in its own cell but as an inhibitor of other AgrC variants. P3, together with AgrA, produces the agrA effector molecule RNAIII, which is involved in the transcriptional regulation of approximately 200 genes, including multiple virulence factors and metabolic pathways involved in stationary-phase growth (Khan BA, et al. (2015) Expert Opin Investig Drugs 24(5):689-704). Examples of virulence factors regulated by AgrA include cell surface-associated proteins such as protein A (SpA) and fibronectin-binding proteins, secreted toxins such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble modulins (PSMs), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), and leukotoxin G and H (LukGH), or secreted proteases such as SspA or aureolysin. Taken together, the large number of multifunctional virulence determinants makes Staphylococcus aureus pathogenesis particularly complex and provides the pathogen with mechanisms to either inflict damage on the host or to evade and avoid the host's immune defenses.It is important to note that most AgrA-regulated virulence factors are responsible for the virulence of Staphylococcus aureus in skin and soft tissue infections (SSTIs), pulmonary infections, and have also been shown to contribute to chronic inflammatory skin diseases such as atopic dermatitis (Oliveira D et al. (2018) Toxins 10:252 (doi:10.3390 / toxins10060252), Geoghegan JA, et al. (2018) Trends Microbiol 26(6):484-497).

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

[0006] Recently, an AgrA inhibitor called savirin was discovered by Sully and colleagues in a screen of 24,087 compounds selected for inhibition of cyclic thiolactone peptide pheromone (AIP)-induced AgrA in the context of research related to acute bacterial skin and soft tissue infections caused by Staphylococcus aureus (Sully EK, et al. (2014) PLoS Pathog 10(6):e1004174). Savirin was shown to be a potent modulator of AgrA-regulated toxin gene transcription, including hla, psmα, and pvl, across all four AgrA groups without affecting S. aureus viability. Savirin suppressed exotoxin-induced red blood cell (RBC) lysis. Resistance did not develop after multiple passages in savirin. This molecule was shown to disrupt AgrA-DNA interactions and prevent the upregulation of virulence genes. Multiple doses of Savirin were observed to significantly reduce abscess size and skin necrosis in mice infected with MRSA USA300 type strain.

[0007] Despite recent discoveries, there remains a great need for compounds that can reduce the virulence of AgrA-expressing bacteria, preferably Staphylococcus aureus, and / or inhibit quorum sensing in bacteria, preferably Staphylococcus aureus, and thus prevent or treat bacterial infections and / or diseases caused by or exacerbated by bacteria, preferably Staphylococcus aureus, such as skin or lung infections, atopic dermatitis or psoriasis. Summary of the Invention

[0008] We have now surprisingly identified a series of novel compounds that interact with AgrA and inhibit the expression of virulence factors regulated by AgrA. In particular, qRT-PCR has demonstrated that the compounds of the present invention can reduce the expression of RNAIII, the most central regulatory RNA controlling the expression of most virulence factors, such as α-hemolysin. Using qRT-PCR, we demonstrated that the expression of psmα was significantly reduced by the compounds of the present invention. The compounds of the present invention reduce RNAIII and psmα expression more effectively than savirin. Furthermore, incubation of MRSA with the compounds of the present invention and an AgrA inhibitor, respectively, prevented red blood cell (RBC) damage as monitored by a hemolysis assay. The compounds of the present invention are more potent than savirin in preventing RBC lysis. The compounds of the present invention are typically not antibacterial or non-cytotoxic to mammalian cells. Therefore, the compounds of the present invention are classified as antivirulence inhibitors, i.e., compounds that regulate the levels of bacterial, preferably Staphylococcus aureus, virulence factors but do not directly prevent bacterial growth or kill the bacteria.

[0009] In a first aspect, the present invention provides at least one compound according to formula (I) JPEG0007743306000001.jpg91170 (in the formula, R1 and R5 are independently H, halogen, hydroxyl, NO 2、 CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O)m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n-Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; At least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H and pharmaceutical compositions comprising pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of formula (I).

[0010] In a further aspect, the present invention provides a compound of formula (I) JPEG0007743306000002.jpg90170 (in the formula, R1 and R5 are independently H, halogen, hydroxyl, NO 2、 CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkoxy optionally substituted by one or more R11, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m-C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; At least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H; however, When R3 is methyl and R1 is methyl, at least one of R2, R4 to R9 is not H. When R3 is methyl, R1 is methyl, and R5 is methyl, at least one of R2, R4, and R6 to R9 is not H. When R3 is methyl and R2 is methyl, R7 is not Cl. When R3 is methyl and R7 is Cl, at least one of R1, R2, R4, R5, R6, R8, and R9 is not H. When R3 is methyl and R7 and R8 are both methoxy, at least one of R1, R2, R4 to R6, and R9 is not H. When R3 is Cl and R7 and R8 are both methoxy, at least one of R1, R2, R4 to R6, and R9 is not H. When R3 is F and R7 is methyl, at least one of R1, R2, R4 to R6, and R9 is not H. When R3 is methyl and R2 is methyl, at least one of R1, R4 to R9 is not H. When R3 is ethyl and R7 is Cl, at least one of R1, R2, R4 to R6, and R8 to R9 is not H. When R3 is methoxy and R2 is methoxy, at least one of R1, R4 to R9 is not H. When R1 is Cl and R3 is Cl, at least one of R2, R4 to R9 is not H. and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of formula (I).

[0011] The present invention therefore provides di-, tri- or poly-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, preferably di- and tri-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, in which at least one further substituent is present next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl group, either on the phenyl ring or on the benzene ring of the quinazoline moiety, and which is not hydrogen.

[0012] In a further aspect, the present invention relates to a compound according to formula (I) for use in a method of reducing the virulence of a bacterium, preferably a bacterium expressing AgrA or an orthologue of AgrA, preferably AgrA, more preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, even more preferably Staphylococcus aureus. JPEG0007743306000003.jpg88170 (in the formula, R1 and R5 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n-Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; at least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H; and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of formula (I).

[0013] In a further aspect, the present invention provides a compound according to formula (I) for use in a method for preventing or treating a disease, preferably an infectious or inflammatory disease, more preferably a bacterial infection or an inflammatory skin disease caused or exacerbated by bacteria. JPEG0007743306000004.jpg87170 (in the formula, R1 and R5 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-Cn -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; at least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H; and pharmaceutically acceptable salts, stereoisomers, enantiomers and tautomers of the compounds of formula (I), wherein preferably the bacterium is selected from the genera Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably the bacterium is Staphylococcus aureus.

[0014] Further aspects and embodiments of the present invention will become apparent as this description continues. [Brief explanation of the drawings]

[0015] [Figure 1]This figure shows the quorum-sensing signaling pathway in Staphylococcus to control the production of virulence factors. The precursor peptide AgrD is processed by AgrB, and the mature autoinducing peptide (AIP) is secreted through the bacterial membrane. AIP binds to the histidine kinase AgrC in its own cell or in other bacterial cells. AgrC then activates the response regulator AgrA by phosphorylation. Phospho-AgrA binds to the agr P2 and P3 promoters and the promoter of the psm operon to activate transcription (RNAIII-independent AgrA regulation). Classical targets of AgrA are under RNAIII-dependent control and include several toxins and proteases, which are upregulated, and several surface-associated proteins, such as protein A, which are downregulated. Small molecule inhibitors that bind to the DNA-binding domain of AgrA prevent its binding to the P2 and P3 promoters, blocking the continued production of AIP (P2-driven) and virulence factors (P3-driven), but also block the expression of RNAIII-independent AgrA-regulated pathways, such as the production of PSMs. [Figure 2] The chemical shift perturbations observed upon binding of the compound to AgrAc are shown. The H,N-HSQC spectrum of N-AgrAc (100 μM) was recorded in the absence (gray) or presence (black) of 1.6 mM of compound 34 of the present invention. Addition of compound 34 resulted in perturbations in the chemical shifts corresponding to the backbone amides of several residues at the C-terminus of the protein. These perturbations clearly indicate an interaction between compound 34 and AgrAc. DETAILED DESCRIPTION OF THE INVENTION

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The embodiments, preferred embodiments, and highly preferred embodiments described and disclosed herein should apply to all aspects and other embodiments, preferred embodiments, and highly preferred embodiments, regardless of whether they are specifically recited or their repetition is avoided for the sake of brevity.

[0017] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. As used herein, the word "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0018] As used herein, "C1-C6-alkyl" refers to straight-chain or branched C1-C6-alkyl, i.e., alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms, and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl. Preferred C1-C6-alkyl is C1-C4-alkyl, more preferably C1-C3-alkyl.

[0019] As used herein, "C n- "Alkyl" refers, depending on the value of n, to a bond if n=0, or to a straight or branched hydrocarbon chain if n is not 0, thus C n -Alkyl refers to a straight or branched chain hydrocarbon defined as C1-C6-alkyl.

[0020] As used herein, "C1-C6-alkoxy" refers to a "substituted hydroxyl" of the formula (-OR'), where R' is an optionally substituted C1-C6-alkyl as defined herein, and the oxygen moiety is directly attached to the parent molecule, so that the term "C1-C6-alkoxy" as used herein refers to straight-chain or branched C1-C6-alkoxy, which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight-chain or branched pentoxy, straight-chain or branched hexyloxy. Preferred C1-C8-alkoxy is C1-C4 alkoxy.

[0021] As used herein, "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). Preferably, it refers to fluorine, chlorine, or bromine. This also applies correspondingly to halogen in combination with other meanings, such as haloalkyl.

[0022] As used herein, "C1-C6-haloalkyl" refers to the C1-C6-alkyl as defined above, which is substituted with one or more halogen atoms, preferably 1, 2 or 3 halogen atoms, preferably fluorine or chlorine atoms.Preferably, C1-C8-haloalkyl is C1-C4-alkyl, which is substituted with 1, 2 or 3 fluorine or chlorine atoms.Preferred examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoroethyl.

[0023] The term "cycloalkyl" as used herein refers to a monocyclic or bicyclic form, typically and preferably a monocyclic form, and preferably contains 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Specific and preferred examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclohexyl. The term "C3-C6 cycloalkyl" as used herein refers to a monocyclic form containing 3 to 6 carbon atoms, particularly cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0024] The term "aryl" as used herein refers to any C-C alkyl group, such as phenyl or naphthyl, anthranyl or phenanthryl. 14 Monocyclic or polycyclic aryl, preferably C6-C 14 It refers to monocyclic aryl, and most preferably phenyl.

[0025] As used herein, the term "heterocycle" refers to an aromatic, partially saturated, or fully saturated, 4- to 14-membered ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, provided that each ring system cannot contain more than two oxygen atoms and more than two sulfur atoms. As used herein, a heterocycle can be a single ring or two or more fused rings in which at least one ring contains a heteroatom. Preferably, as used herein, the term "heterocycle" refers to an aromatic, partially saturated, or fully saturated, 5- to 7-membered, preferably 4- to 6-membered, single ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, provided that each ring system cannot contain more than two oxygen atoms and more than two sulfur atoms. Typical and preferred examples of the monocyclic aromatic heterocycle of the present invention include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyran, pyrrolyl, pyridinyl, triazolyl, tetrazolyl, imidazolidinyl and pyrazolyl. Typical and preferred examples of the monocyclic partially saturated or fully saturated heterocycle of the present invention include azetidine, oxetane, dioxolane, pyrrolidine, pyrrolidin-2-one, piperidine, morpholine, piperazine, homopiperazine and tetrahydropyran.

[0026] When a group is said to be optionally substituted, preferably there are 1 to 5 optional substituents, more preferably 1 to 3 optional substituents, and even more preferably 1 or 2 optional substituents, and most preferably 1 substituent. When a group is said to be optionally substituted, and for any substitution of the group there are two or more substituents, the two or more substituents may be either the same or different.

[0027] The term "ortholog" as used herein refers to the familiar meaning of the term. In the art, an ortholog is a gene from different species that evolved from a common ancestral gene. Due to their separation after a speciation event, orthologs may diverge, but typically share similarities at the sequence and structural levels. Furthermore, orthologs typically share the same function. Orthology is a type of homology. In this application, the term ortholog is used to include orthologous genes (DNA or RNA) or the peptide / protein products of orthologs. The peptide / protein products of orthologs may be referred to as "orthologous products" or simply "orthologs." The meaning is clear from the context (e.g., an antipathogenic composition of the present invention may contain an antipathogenic agent capable of reducing the pathogenicity of bacteria expressing a peptide or protein that may be referred to as an ortholog of AgrA, i.e., the product of an orthologous gene of Staphylococcus aureus AgrA from another bacterium, such as Streptococcus pyogenes). In particular embodiments, orthologs of AgrA produce proteins / peptides that share greater than about 70%, about 80%, or about 90% identity with the amino acid sequence of the gene product of AgrA.

[0028] The terms "reducing" and "inhibiting" have their commonly understood meaning of lessening or decreasing.

[0029] As used herein, the phrase "reducing the virulence of AgrA-expressing bacteria" typically and preferably refers to inhibiting the synthesis of one or more virulence factors by the bacteria using a compound of formula (I) or a composition of the present invention, preferably a pharmaceutical composition comprising a compound of formula (I). Examples of virulence factors regulated by AgrA include cell surface-associated proteins such as protein A (SpA) and fibronectin-binding proteins, secreted toxins such as α-hemolysin / α-toxin (Hla), δ-hemolysin (Hld), phenol-soluble modulins (PSMs), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), and leukotoxin G and H (LukGH), or secreted proteases such as SspA or aureolysin. In preferred examples and embodiments of the present invention, reducing the virulence of AgrA-expressing bacteria involves inhibiting the synthesis of one or more virulence factors selected from PSMα, RNAIII, and their downstream targets. In preferred examples and embodiments of the present invention, reducing the virulence of AgrA-expressing bacteria is by inhibiting the synthesis of PSMα. In preferred examples and embodiments of the present invention, reducing the virulence of AgrA-expressing bacteria is by inhibiting the synthesis of RNAIII and / or its downstream targets, preferably RNAIII.

[0030] The term "inhibiting the synthesis of one or more virulence factors" as used herein refers to a complete or partial inhibition (preferably more than 20%, more preferably more than 30%, more preferably more than 50%, more preferably more than 90%, even more preferably more than 95%, or even more preferably more than 99%) of the synthesis of one or more virulence factors by the bacterium in the presence of a compound of the present invention of formula (I) or a composition of the present invention, preferably a pharmaceutical composition comprising a compound of the present invention, or in comparison to a method of the present invention in which such a compound of the present invention of formula (I) or a composition of the present invention, preferably a composition comprising a compound of the present invention of formula (I), is not applied or used.

[0031] Virulence factors contemplated herein include any molecule expressed and secreted by bacteria to promote colonization and / or adhesion in a host subject, promote inflammation in host tissues, promote evasion of the host immune response, and obtain nutrients from the host subject. Virulence factors may include both exotoxins and endotoxins. Non-limiting examples of virulence factors inhibited by the compounds of formula (I) or compositions of the present invention, preferably pharmaceutical compositions of the present invention comprising the compounds of formula (I) described herein, include one or more toxins (e.g., α, β, γ, γ-mutant, and δ-hemolysin, PSMs (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B), exfoliative toxins), proteases (e.g., serine proteases, metalloproteases, cysteine ​​proteases), nucleases, lipases, coagulases, hyaluronidases, fibronectin-binding proteins, aggregation 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.

[0032] Antipathogenic agents may be combined with therapeutic agents such as antibiotics and are typically used to prevent and treat infections caused by bacteria such as staphylococci, primarily Staphylococcus aureus.

[0033] The antipathogenic agent can be combined with a therapeutic agent typically and preferably used in the prevention and treatment of chronic inflammatory skin diseases (e.g., atopic dermatitis) exacerbated by bacteria such as staphylococci, primarily Staphylococcus aureus.

[0034] As used herein, the term "antibiotic" refers to an antibacterial 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 certain preferred examples thereof include penicillins, cephalosporins, polymyxins, rifamycins, lipiamycins, quinolones, sulfonamides, macrolides, oxazolidinones, lincosamides, and tetracyclines.

[0035] As used herein, the terms "treating," "treatment," or "therapy" refer to a means of obtaining a desired physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease or condition and / or symptoms caused by the disease or condition. The term refers to inhibiting a disease or condition, i.e., preventing its occurrence, or ameliorating a disease or condition, i.e., causing regression of the disease or condition.

[0036] As used herein, the term "prophylaxis" refers to a measure of preventing or delaying the onset of a disease or condition and / or symptoms resulting from the disease or condition.

[0037] The compounds of the present invention of formula (I), and pharmaceutical compositions of the present invention comprising the compounds of formula (I) as described herein, can be used in the prophylactic and therapeutic treatment of diseases, preferably infectious or inflammatory diseases, more preferably bacterial infectious or inflammatory skin diseases caused or exacerbated by a bacterium, preferably the bacterium is selected from the genera Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably the bacterium is Staphylococcus aureus.

[0038] As used herein, the term "subject" or "animal" or "patient" or "mammal" refers to any subject for whom diagnosis, prognosis, prevention or treatment is desired, particularly a mammalian subject, e.g., a human or a domestic animal such as a dog, cat, horse, or food animal such as a cow, sheep, pig, preferably a human. Thus, in a preferred embodiment of the invention, the subject is a human.

[0039] The term "pharmaceutically acceptable" or "therapeutically acceptable" refers to a material that does not interfere with the effectiveness or biological activity of the active ingredients and that is not toxic to the host.

[0040] A "pharmaceutically acceptable salt" of a compound of Formula (I) refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. For example, the salt may be an acid addition salt. One embodiment of an acid addition salt is a hydrochloride salt. Pharmaceutically acceptable salts can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company, 1990).

[0041] As used herein, the term "for use" as used in "a composition for use in the treatment or prevention of a disease" is intended to also disclose the corresponding method of treatment or prevention and the use of the preparation for the manufacture of a medicament for the treatment or prevention of the corresponding disease."

[0042] A "therapeutically effective amount" is an amount of a compound or pharmaceutical composition according to the present invention that elicits the biological or medical response desired by a researcher, veterinarian, physician, or other clinician in a subject, preferably a human subject. As used herein, the term "therapeutic administration" refers to the administration of a therapeutically effective amount. In particular, the terms "effective," "effective amount," and "therapeutically effective amount" as used herein typically and preferably refer to the amount of a compound of the present invention of formula (I) or a composition of the present invention, preferably a pharmaceutical composition containing a compound of the present invention of formula (I), that reduces bacterial virulence or results in improved symptoms or prolonged survival in a subject with a bacterial-related disease or disorder. The term "effective amount" is generally used herein to refer to the amount of a given compound, or, in the case of a mixture, the total amount of the mixture components that provides a measurable effect on the described function. It will be understood by those skilled in the art that for a given application, the effective amount can be determined by routine experimentation without undue experimentation using methods described herein or known in the art. The term "therapeutically effective amount" is used generally herein to refer to an amount of a given compound, or in the case of a mixture, the total amount of components of the mixture, that provides a measurable effect when administered to an individual, including a human or non-human animal, to at least partially ameliorate the symptoms of such disease, disorder, or condition, conferring a therapeutic effect for the described disease, disorder, or condition. The outcome of treatment can be partial or complete alleviation, inhibition, prevention, amelioration, and / or relief of the disorder, condition, or one or more symptoms thereof.

[0043] In a first aspect, the present invention provides a compound of formula (I) JPEG0007743306000005.jpg89170 (in the formula, R1 and R5 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n-Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n-alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; at least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H; and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of formula (I).

[0044] In one embodiment, when R3 is methyl and R1 is methyl, at least one of R2, R4-R9 is not H. In another embodiment, when R3 is methyl, R1 is methyl, and R5 is methyl, at least one of R2, R4, R6-R9 is not H. In another embodiment, when R3 is methyl and R2 is methyl, R7 is not Cl. In another embodiment, when R3 is methyl and R7 is Cl, at least one of R1, R2, R4, R5, R6, R8-R9 is not H. In another embodiment, when R3 is methyl and R7 and R8 are both methoxy, at least one of R1, R2, R4-R6, R9 is not H. In another embodiment, when R3 is Cl, and R7 and R8 are both methoxy, at least one of R1, R2, R4-R6, R9 is not H. In another embodiment, when R3 is F and R7 is methyl, at least one of R1, R2, R4-R6, and R9 is not H. In another embodiment, when R3 is methyl and R2 is methyl, at least one of R1, R4-R9 is not H. In another embodiment, when R3 is ethyl and R7 is Cl, at least one of R1, R2, R4-R6, R8, and R9 is not H. In another embodiment, when R3 is methoxy and R2 is methoxy, at least one of R1, R4-R9 is not H. In another embodiment, when R1 is Cl and R3 is Cl, at least one of R2, R4-R9 is not H.

[0045] The present invention therefore provides di-, tri- or poly-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, preferably di- and tri-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, in which next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl, there is at least one further substituent on either the phenyl ring or the benzene ring of the quinazoline moiety, which is not hydrogen.

[0046] In a further preferred embodiment, one, two, three, four, or five of R1, R2, and R4-R9 are independently not H, and the others of R1, R2, and R4-R9 are independently H. In a further preferred embodiment, one, two, three, or four of R1, R2, and R4-R9 are independently not H, and the others of R1, R2, and R4-R9 are independently H. In a further preferred embodiment, one, two, or three of R1, R2, and R4-R9 are independently not H, and the others of R1, R2, and R4-R9 are independently H. Again, in a preferred embodiment, one or two of R1, R2, and R4-R9 are independently not H, and the others of R1, R2, and R4-R9 are independently H.

[0047] Thus, in a preferred embodiment, the present invention provides di-, tri-, tetra-, or penta-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives. In a preferred embodiment, the present invention provides di-, tri-, or tetra-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives. In a further preferred embodiment, the present invention provides di- and tri-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives. In a further preferred embodiment, one, two, three, or four of R1, R2, and R4 to R9 are independently not H, and thus the di-, tri-, tetra-, or penta-substitution is (i) one of R1, R2, R4, and R5 is independently not H, (ii) one of R6, R7, R8, and R9 is independently not H, (iii) one of R1, R2, R4, and R5 is independently not H, and R6, R7 , one of R8 and R9 is independently not H, (iv) two of R6, R7, R8 and R9 are independently not H, (v) one of R1, R2, R4 and R5 is independently not H and two of R6, R7, R8 and R9 are independently not H, (vi) two of R1, R2, R4 and R5 are independently not H and two of R6, R7, R8 and R9 are independently not H. In a further preferred embodiment, one or two of R1, R2, and R4 to R9 are independently not H, and thus the di- and tri-substitutions are selected from: (i) one of R1, R2, R4, and R5 is independently not H; (ii) one of R6, R7, R8, and R9 is independently not H; (iii) one of R1, R2, R4, and R5 is independently not H, and one of R6, R7, R8, and R9 is independently not H; (iv) one of R1, R2, R4, and R5 is independently not H, and two of R6, R7, R8, and R9 are independently not H; and (v) two of R6, R7, R8, and R9 are independently not H.In a further preferred embodiment, one or two of R1, R2, and R4 to R9 are independently not H, and thus the di- and tri-substitutions are selected from: (i) one of R1, R2, R4, and R5 is independently not H; (ii) one of R6, R7, R8, and R9 is independently not H; (iii) one of R1, R2, R4, and R5 is independently not H, and one of R6, R7, R8, and R9 is independently not H; and (iv) two of R6, R7, R8, and R9 are independently not H.

[0048] Thus, in a preferred embodiment, the present invention provides di-, tri-, tetra- or penta-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which one or two further substituents are present on the phenyl ring next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl group, and / or are not present anywhere, and one or two substituents are present on the benzene ring of the quinazoline moiety and are not H. In a preferred embodiment, the present invention provides di- and trisubstituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which, next to the 4- or para-position (R3) of the phenyl ring bonded to the sulfonyl group, there is one further substituent on either the phenyl ring or the benzene ring of the quinazoline moiety which is not hydrogen, or one further substituent on the phenyl ring and the benzene ring of the quinazoline moiety, or two substituents on the benzene ring of the quinazoline moiety which are not H.

[0049] In a further preferred embodiment, the one or two of R1, R2, and R4 to R9 that are not independently H are selected from: (i) one of R1, R2, R4, and R5 is independently not H; (ii) one of R6, R7, R8, and R9 is independently not H; (iii) one of R1, R2, R4, and R5 is independently not H, and one of R6, R7, R8, and R9 is independently not H.

[0050] In a further preferred embodiment, at least one of R1, R2, R4, and R5 is not H. In a further highly preferred embodiment, one or two of R1, R2, R4, R5 are not H, and R1, R2, R4, R5 are H. In a further highly preferred embodiment, exactly one of R1, R2, R4, R5 is not H, and the other of R1, R2, R4, R5 is H.

[0051] Accordingly, these preferred embodiments of the present invention provide di-, tri- or polysubstituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which at least two, preferably two or three, more preferably exactly two, substituents are present on the phenyl ring attached to the sulfonyl group and are not hydrogen.

[0052] In a further preferred embodiment, R1 or R5 is not H. In a further preferred embodiment, one of R1 and R5 is H, and the other of R1 and R5 is not H. Thus, when R1 is H, R5 is not H, and when R5 is H, R1 is not H.

[0053] Thus, these preferred embodiments of the present invention provide di-, tri-, or poly-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl group there is at least one, preferably one, additional substituent on the phenyl ring that is not hydrogen and is in the ortho-position (R1 or R5). In these preferred embodiments, the two ortho-positions, i.e., R1 and R5, are indistinguishable.

[0054] In a further highly preferred embodiment, one of R1, R2, R4, and R5 is independently not H, the other of R1, R2, R4, and R5 is H, and R6-R9 are H. In a further highly preferred embodiment, one of R1 and R5 is independently not H, the other of R1 and R5 is H, and R2, R4, and R6-R9 are H. Thus, when R1 is H, R5 is not H, and when R5 is H, R1 is not H.

[0055] These preferred embodiments of the present invention provide disubstituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which, next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl group, there is another substituent on the phenyl ring that is not hydrogen, and that further substitution is at the ortho-position (R1 or R5), and the benzene ring of the quinazoline moiety is unsubstituted. In these preferred embodiments, the two ortho-positions, R1 and R5, are indistinguishable.

[0056] In a further highly preferred embodiment, at least one of said R6 to R9 is not H. In a further preferred embodiment, exactly one of said R6 to R9 is not H.

[0057] Thus, these preferred embodiments of the present invention provide di-, tri-, or poly-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives in which at least one, and preferably exactly one, additional substituent on the benzene ring of the quinazoline moiety is present next to the 4- or para-position (R3) of the phenyl ring bonded to the sulfonyl group and is not hydrogen. In a further highly preferred embodiment, one of R6, R7, R8, and R9 is independently not H, the other of R6, R7, R8, and R9 is H, and R1, R2, R4, and R5 are H.

[0058] In a further highly preferred embodiment, one of R6, R7, R8, and R9 is not H, the other of R6, R7, R8, and R9 is H, and at least one, preferably one or two, and more preferably exactly one of R1, R2, R4, and R5 is not H. In a further highly preferred embodiment, at least two of R1, R2, R4, R5, R6, R7, R8, or R9 are not H. In a further highly preferred embodiment, at least one of R1, R2, R4, R5, R6, R7, R8, or R9 is not H. In a further highly preferred embodiment, at least one of R1, R2, R4, R5 is not H, and at least one of R6-R9 is not H.

[0059] These preferred embodiments of the present invention therefore provide tri- or polysubstituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, preferably di- and tri-substituted 3-(phenylsulfonyl)-[1,2,3]triazolo[1,5a]quinazolin-5(4H)-one derivatives, in which next to the 4- or para-position (R3) of the phenyl ring attached to the sulfonyl group there are at least two, preferably exactly two, substituents which are not hydrogen and at least one further substituent is present either on the phenyl ring or on the benzene ring of the quinazoline moiety which is not hydrogen.

[0060] In a further preferred embodiment, R1 or R5 is not H, and at least one of R6-R9 is not H. In a further highly preferred embodiment, R1 or R5 is not H, and exactly one of R6-R9 is not H. In a further highly preferred embodiment, exactly one of R1 and R5 is H, and the other of R1 and R5 is not H. In a further highly preferred embodiment, exactly one of R1 and R5 is H, R1 and R5 is not H, and at least one of R6-R9 is not H. In yet a further highly preferred embodiment, R2 and R4 are H, exactly one of R1 and R5 is H, the other of R1 and R5 is not H, and at least one of R6-R9 is not H. In a further highly preferred embodiment, one of R1 and R5 is independently not H, one of R6, R7, R8 and R9 is independently not H, the other of R1 and R5 is H, and the other of R6, R7, R8 and R9 is H.

[0061] In a further highly preferred embodiment, R1 and R5 are independently selected from C1-C6-alkyl, halogen or C1-C6-alkoxy, optionally substituted by one or more R11.In a further highly preferred embodiment, R1 and R5 are independently selected from H, halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11.In a further highly preferred embodiment, R1 and R5 are independently selected from H, halogen, C1-C3-alkyl optionally substituted by one or more R11, or C1-C3-alkoxy.

[0062] In a further highly preferred embodiment, R1 and R5 are independently selected from H, halogen, C1-C3-alkyl, CF3, or C1-C3-alkoxy. In a further highly preferred embodiment, R1 and R5 are independently selected from H, halogen, methyl, ethyl, CF3, methoxy, and isopropoxy.

[0063] In a further highly preferred embodiment, R1 and R5 are independently selected from H, methyl, ethyl, CF3, F, Cl, Br, or methoxy. In a further highly preferred embodiment, R1 and R5 are independently selected from H, methyl, ethyl, CF3, F, Cl, or Br. In a further highly preferred embodiment, R1 and R5 are independently selected from H, methyl, ethyl, CF3, Cl, or Br. In a further highly preferred embodiment, R1 and R5 are independently selected from methyl, ethyl, CF3, F, Cl, or Br, and the other of R1 and R5 is H.

[0064] In a further highly preferred embodiment, said R1 or said R5 is independently hydrogen.

[0065] In a further highly preferred embodiment, said R1 or said R5 is independently methyl.

[0066] In a further highly preferred embodiment, said R1 or said R5 is independently ethyl.

[0067] In a further highly preferred embodiment, said R1 or said R5 is independently CF3.

[0068] In a further highly preferred embodiment, said R1 or said R5 is independently F.

[0069] In a further highly preferred embodiment, said R1 or said R5 is independently Cl.

[0070] In a further highly preferred embodiment, said R1 or said R5 is independently Br.

[0071] In a further highly preferred embodiment, said R1 or said R5 is independently methoxy.

[0072] In a further highly preferred embodiment, one of R1 and R5 is independently selected from H, halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently selected from H, halogen, C1-C3-alkyl optionally substituted by one or more R11, or C1-C3-alkoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently selected from H, halogen, C1-C3-alkyl, CF3, or C1-C3-alkoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently selected from H, halogen, methyl, ethyl, CF3, methoxy, and isopropoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently selected from H, methyl, ethyl, CF3, F, Cl, Br, or methoxy, and the other of R1 and R5 is H.

[0073] In a further highly preferred embodiment, R1 or R5 is independently hydrogen. In a further highly preferred embodiment, R1 is hydrogen. In a further highly preferred embodiment, R5 is hydrogen. In a further highly preferred embodiment, one of R1 and R5 is independently methyl, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently ethyl, and the other of R1 and R5 is independently H. In a further highly preferred embodiment, one of R1 and R5 is independently CF3, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently F, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently Cl, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently Br, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is independently methoxy and the other of R1 and R5 is H.

[0074] In a further highly preferred embodiment, R1 and R5 are independently selected from H, halogen, and C1-C2-alkyl optionally substituted by one or more R11. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl optionally substituted by one or more R11. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl optionally substituted by one or more halogen. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl optionally substituted by one or more F. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl optionally substituted by one or more F. In a further highly preferred embodiment, one of R1 and R5 is independently selected from Cl, Br, and CH3 and CF3, and the other of R1 and R5 is H.

[0075] In a further highly preferred embodiment, one of R1 or R5 is independently selected from C1-C6-alkyl, halogen or C1-C6-alkoxy, optionally substituted by one or more R11, and the other one of R1 or R5 is H, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, one of R1 or R5 is independently selected from C1-C3-alkyl, halogen or C1-C3-alkoxy, optionally substituted by one or more R11, and the other one of R1 or R5 is H, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl, optionally substituted by one or more F, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, and CH3 and CF3, and at least one of R6-R9 is not H.

[0076] In a further highly preferred embodiment, one of R1 or R5 is independently selected from C1-C3-alkyl, CF3, halogen or C1-C2-alkoxy, the other of R1 or R5 is H, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R1 or R5 is selected from Cl, Br, and C1-C2-alkyl optionally substituted with one or more F, the other of R1 and R5 is H, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, CH3 and CF3, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, one of R1 or R5 is selected from Cl, Br, CH3 and CF3, the other of R1 and R5 is H, and at least one of R6 to R9 is not H.

[0077] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from C1-C6-alkyl, halogen, or C1-C6-alkoxy, optionally substituted by one or more R11, the other of R1 or R5 is H, and at least one, preferably exactly one, of R6 to R9 is not H.

[0078] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from C1-C3-alkyl, halogen, or C1-C3-alkoxy, optionally substituted by one or more R11, the other one of R1 or R5 is H, and at least one, preferably exactly one, of R6 to R9 is not H.

[0079] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from C1-C3-alkyl, CF3, halogen or C1-C2-alkoxy, the other one of R1 or R5 is H, and at least one, preferably exactly one, of R6 to R9 is not H.

[0080] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from methyl, ethyl, CF3, F, Cl, Br, or methoxy, the other one of R1 or R5 is H, and at least one, preferably exactly one, of R6-R9 is not H.

[0081] In a further highly preferred embodiment, R2 and R4 are H, R1 and R5 are independently selected from H, Cl, Br, and C1-C2-alkyl optionally substituted with one or more F, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R2 and R4 are H, R1 and R5 are independently selected from H, Cl, Br, CH3, and CF3, and at least one of R6 to R9 is not H. In a further highly preferred embodiment, R2 and R4 are H, R1 or R5 are selected from C1, Br, and C1-C2-alkyl optionally substituted with one or more F, and the other one of R1 and R5 is H, and at least one, preferably one or two, more preferably exactly one of R6 to R9 is not H. In a further highly preferred embodiment, R2 and R4 are H, R1 and R5 are independently selected from H, Cl, Br, CH3 and CF3, and at least one, preferably one or two, more preferably exactly one of R6-R9 is not H. In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is selected from Cl, Br, CH3 and CF3, the other of R1 and R5 is H, and at least one, preferably one or two, more preferably exactly one of R6-R9 is not H.

[0082] In a further highly preferred embodiment, one of R1 or R5 is independently selected from C1-C6-alkyl, halogen, or C1-C6-alkoxy, optionally substituted by one or more R11, the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0083] In a further highly preferred embodiment, one of R1 or R5 is independently selected from C1-C3-alkyl, halogen or C1-C3-alkoxy optionally substituted by one or more R11, the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0084] In a further highly preferred embodiment, one of R or R is independently C-C 3- alkyl, CF3, halogen or C1-C2-alkoxy, wherein the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0085] In a further highly preferred embodiment, one of R1 or R5 is independently selected from methyl, ethyl, CF3, F, Cl, Br or methoxy, the other one of R1 or R5 is H, and one of R6-R9 is not H.

[0086] In a further highly preferred embodiment, said R2 is H.

[0087] In a further highly preferred embodiment, said R4 is H.

[0088] In a further highly preferred embodiment, said R2 and said R4 are H.

[0089] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from C1-C6-alkyl, halogen or C1-C6-alkoxy optionally substituted by one or more R11, the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0090] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from C1-C3-alkyl, halogen or C1-C3-alkoxy optionally substituted by one or more R11, the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0091] In a further highly preferred embodiment, R2 and R4 are H and one of R1 or R5 is independently C1-C3- alkyl, CF3, halogen or C1-C2-alkoxy, wherein the other one of R1 or R5 is H, and exactly one of R6 to R9 is not H.

[0092] In a further highly preferred embodiment, R2 and R4 are H, one of R1 or R5 is independently selected from methyl, ethyl, CF3, F, Cl, Br or methoxy, the other one of R1 or R5 is H, and exactly one of R6-R9 is not H.

[0093] In a further highly preferred embodiment, R1, R2, R4 and R5 are H and at least one of R6-R9 is not H, preferably at least one of R6-R9 is not H.

[0094] In a further highly preferred embodiment, R1, R2, R4 and R5 are H and exactly one of R6-R9 is not H.

[0095] In a further preferred embodiment, R3 is selected from the group consisting of halogen, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and heterocycles optionally substituted by one or more R17, preferably the heterocycle is aromatic, partially saturated or fully saturated and contains 1 to 4 nitrogen heteroatoms and at most 1 oxygen atom.

[0096] In a further preferred embodiment, R3 is selected from the group consisting of halogen, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic, partially saturated or fully saturated and contains 1-4 nitrogen heteroatoms and at most 1 oxygen atom.

[0097] In a further highly preferred embodiment, R3 is selected from the group consisting of halogen, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m-C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1-4 nitrogen heteroatoms and at most 1 oxygen atom.

[0098] In a further highly preferred embodiment, said R3 is selected from the group consisting of halogen, CN, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10 (m=0-3), -OR16, -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1-4 nitrogen heteroatoms and at most 1 oxygen atom.

[0099] In a further highly preferred embodiment, said R3 is selected from the group consisting of halogen, CN, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10 (m=0-3), -OR16, -NH-C n -Alkyl-R18(n=0-3), -OCn -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1-4 nitrogen heteroatoms and at most one oxygen atom, and R10 is H or methyl.

[0100] In a further highly preferred embodiment, R3 is selected from the group consisting of F, Cl, Br, CN, C1-C3-alkyl optionally substituted by one or more F or hydroxyl, C1-C3-alkoxy optionally substituted by one or more F, C3-C6-cycloalkyl, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10 (m=0-3), -OR16, -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1-4 nitrogen heteroatoms and at most one oxygen atom, and preferably R10 is H or methyl.

[0101] In a further highly preferred embodiment, R3 is selected from F, Cl, Br, CN, C1-C3-alkyl optionally substituted by one or more F or hydroxyl, C1-C3-alkoxy optionally substituted by one or more F, C3-C6-cycloalkyl, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1 to 4 nitrogen heteroatoms and at most one oxygen atom.

[0102] In a further highly preferred embodiment, R3 is selected from F, Cl, Br, CN, C1-C3-alkyl optionally substituted by one or more F or hydroxyl, C1-C3-alkoxy optionally substituted by one or more F, C3-C5-cycloalkyl, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, and a 5-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic and contains 1 to 4 nitrogen heteroatoms.

[0103] In a further highly preferred embodiment, said R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, OCF3, cyclopropyl, -C(O)NH2, -NHCOCH3, -C(O)OC2H5, 5-methyl-triazolyl, triazolyl and tetrazolyl.

[0104] In a further highly preferred embodiment, said R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, -NHCOCH3, and cyclopropyl.

[0105] In a further highly preferred embodiment, said R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy and cyclopropyl.

[0106] In a further highly preferred embodiment, R3 is selected from methyl, ethyl, isopropyl, and C3-C5-cycloalkyl optionally substituted by one or more R11. In a further highly preferred embodiment, R3 is selected from methyl, ethyl, isopropyl, and C3-C5-cycloalkyl. In a further highly preferred embodiment, R3 is selected from methyl, ethyl, isopropyl, and cyclopropyl. In a further highly preferred embodiment, R3 is selected from methyl, ethyl, and isopropyl.

[0107] In a further highly preferred embodiment, said R3 is F.

[0108] In a further highly preferred embodiment, said R3 is Cl.

[0109] In a further highly preferred embodiment, said R3 is Br.

[0110] In a further highly preferred embodiment, said R3 is CN.

[0111] In a further highly preferred embodiment, said R3 is methyl.

[0112] In a further highly preferred embodiment, said R3 is ethyl.

[0113] In a further highly preferred embodiment, said R3 is isopropyl.

[0114] In a further highly preferred embodiment, said R3 is CF3.

[0115] In a further highly preferred embodiment, said R3 is methoxy.

[0116] In a further highly preferred embodiment, said R3 is isopropoxy.

[0117] In a further highly preferred embodiment, R3 is OCF3.

[0118] In a further highly preferred embodiment, said R3 is cyclopropyl.

[0119] In a further highly preferred embodiment, said R3 is -C(O)NH2.

[0120] In a further highly preferred embodiment, said R3 is -NHCOCH3.

[0121] In a further highly preferred embodiment, said R3 is -C(O)OC2H5.

[0122] In a further highly preferred embodiment, said R3 is triazolyl.

[0123] In a further highly preferred embodiment, R3 is 5-methyl-triazolyl.

[0124] In a further highly preferred embodiment, said R3 is tetrazolyl.

[0125] In a further highly preferred embodiment, R1 and R5 are independently selected from H, C1-C3-alkyl optionally substituted by one or more R11, halogen or C1-C3-alkoxy, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, OCF3, cyclopropyl, -C(O)NH2, -NHCOCH3, C(O)OC2H5, 5-methyl-triazolyl, triazolyl and tetrazoyl.

[0126] In a further highly preferred embodiment, R1 and R5 are independently selected from H, C1-C3-alkyl, CF3, halogen or C1-C2-alkoxy, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, -NHCOCH3 and cyclopropyl.

[0127] In a further highly preferred embodiment, R1 and R5 are independently selected from H, methyl, ethyl, CF3, F, Cl, Br, or methoxy, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, and cyclopropyl.

[0128] In a further highly preferred embodiment, R1 or R5 is selected from Cl, Br and C1-C2-alkyl optionally substituted by one or more F, the other of R1 and R5 is H, and R3 is selected from methyl, ethyl, isopropyl, C3-C5-cycloalkyl optionally substituted by one or more R11. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, CH3 and CF3, and R3 is selected from methyl, ethyl, isopropyl, C3-C5-cycloalkyl. In a further highly preferred embodiment, R1 or R5 is selected from Cl, Br, CH3 and CF3, the other of R1 and R5 is H, and R3 is methyl, ethyl, isopropyl and cyclopropyl, preferably R3 is selected from methyl, ethyl and cyclopropyl.

[0129] In a further highly preferred embodiment, R1 and R5 are independently selected from H, C1-C3-alkyl optionally substituted by one or more R11, halogen or C1-C3-alkoxy, R2 and R4 are H, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, OCF3, cyclopropyl, -C(O)NH2, -NHCOCH3, -C(O)OC2H5, and triazolyl and tetrazolyl.

[0130] In a further highly preferred embodiment, R1 and R5 are independently selected from H, C1-C3-alkyl, CF3, halogen or C1-C2-alkoxy, R2 and R4 are H, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, -NHCOCH3, and cyclopropyl.

[0131] In a further highly preferred embodiment, R1 and R5 are independently selected from H, methyl, ethyl, CF3, F, Cl, Br or methoxy, R2 and R4 are H, and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy and cyclopropyl.

[0132] In a further highly preferred embodiment, R1 or R5 is selected from Cl, Br and C1-C2-alkyl optionally substituted by one or more F, the other of R1 and R5 is H, R2 and R4 are H, and R3 is selected from methyl, ethyl, isopropyl, C3-C5-cycloalkyl optionally substituted by one or more R11. In a further highly preferred embodiment, R1 and R5 are independently selected from H, Cl, Br, CH3 and CF3, R2 and R4 are H, and R3 is selected from methyl, ethyl, isopropyl, C3-C5-cycloalkyl. In a further highly preferred embodiment, one of R1 or R5 is selected from Cl, Br, CH3 and CF3, the other of R1 and R5 is H, R2 and R4 are H, and R3 is selected from methyl, ethyl, isopropyl and cyclopropyl, preferably R3 is selected from methyl, ethyl, and cyclopropyl.

[0133] In a further highly preferred embodiment, said R10 is H or methyl.

[0134] In a further highly preferred embodiment, R is independently selected from F and hydroxy. In a further highly preferred embodiment, R is independently Cl. In a further highly preferred embodiment, R is independently F. In a further highly preferred embodiment, R is independently hydroxy.

[0135] In a further preferred embodiment, R12, R13, R14, R15 and R16 are independently selected from H, C1-C3-alkyl optionally substituted by one or more R11, or R12 and R13, together with the nitrogen to which they are attached, form a 4-6 membered heterocycle optionally substituted by one or more R17. In a further preferred embodiment, R12, R13, R14, R15 and R16 are independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl, or R12 and R13, together with the nitrogen to which they are attached, form a 4-6 membered heterocycle optionally substituted by one or more R17. In a further preferred embodiment, R12 is independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl, or R12 and R13 together with the nitrogen to which they are attached form a 4-6-membered heterocycle optionally substituted by one or more R17. In a further preferred embodiment, R13 is independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl, or R12 and R13 together with the nitrogen to which they are attached form a 4-6-membered heterocycle optionally substituted by one or more R17. In a further highly preferred embodiment, R14 is independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl. In a further highly preferred embodiment, R15 is independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl. In a further highly preferred embodiment, said R16 is independently selected from H, C1-C3-alkyl optionally substituted by one or more F, and hydroxyl.

[0136] In a further preferred embodiment, the one or more R17 are independently selected from halogen, CN, —N(R12)(R13), —C(O)—R16, —C(O)—OR16, —C n-alkyl-OR16 (n=0-3), C1-C3-alkyl optionally substituted by one or more R11, and C1-C3-alkoxy optionally substituted by one or more R11. In a further highly preferred embodiment, the one or more R17 are independently selected from C1-C3-alkyl optionally substituted by one or more R11, and C1-C3-alkoxy optionally substituted by one or more R11. In a further highly preferred embodiment, the one or more R17 are independently selected from C1-C3-alkyl, optionally substituted by one or more F, and C1-C3-alkoxy. In a further highly preferred embodiment, the one or more R17 are independently selected from C1-C3-alkyl and C1-C3-alkoxy.

[0137] In a further preferred embodiment, said R18 is selected from -N(R12)(R13), -OR10, and a 4-6 membered heterocycle optionally substituted by one or more R17.

[0138] In a further highly preferred embodiment, R1, R2, R4 and R5 are H and R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, OCF3, cyclopropyl, -C(O)NH2, -NHCOCH3, -C(O)OC2H5, and triazolyl and tetrazolyl, and at least one of R6-R9 is not H.

[0139] In a further highly preferred embodiment, R1, R2, R4 and R5 are H and R3 is F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, OCF3, cyclopropyl, -C(O)NH2, -NHCOCH3, -C(O)OC2H 5、 and triazolyl and tetrazolyl, wherein exactly one of R6-R9 is not H.

[0140] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, -NHCOCH3 and cyclopropyl, and at least one of R6-R9 is not H.

[0141] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy, -NHCOCH3 and cyclopropyl, and exactly one of R6-R9 is not H.

[0142] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy and cyclopropyl, and one of R6-R9 is not H.

[0143] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, methoxy, isopropoxy and cyclopropyl, and exactly one of R6-R9 is not H.

[0144] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is cyclopropyl, and at least one of R6-R9 is not H.

[0145] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is cyclopropyl, and exactly one of R6-R9 is not H.

[0146] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is isopropyl and at least one of R6-R9 is not H.

[0147] In a further highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is isopropyl, and exactly one of R6-R9 is not H.

[0148] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently selected from H, halogen, CN, C1-C3-alkyl optionally substituted by one or more F or hydroxyl, C1-C3-alkoxy optionally substituted by one or more F, C3-C 6- Cycloalkyl, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0 to 3).

[0149] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17.

[0150] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently selected from H, halogen, CN, C1-C3-alkyl optionally substituted with one or more F, C1-C3-alkoxy optionally substituted with one or more F, C3-C6-cycloalkyl.

[0151] In a further highly preferred embodiment, said R6, R7, R8 and R9 are independently selected from H, halogen, CN, C1-C3-alkoxy optionally substituted by one or more F.

[0152] In a further highly preferred embodiment, said R6, R7, R8 and R9 are independently selected from H, halogen, CN, C1-C3-alkoxy.

[0153] In a further highly preferred embodiment, said R6, R7, R8 and R9 are independently selected from H, F, Cl, Br, CN, methoxy and ethoxy.

[0154] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently H. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently halogen. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently CN. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently C1-C3-alkyl, optionally substituted by one or more F or hydroxyl. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently hydroxyl. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently C1-C3-alkyl, optionally substituted by one or more F. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently C1-C3-alkoxy, optionally substituted by one or more F. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently CF3. In a further highly preferred embodiment, said R6, R7, R8 and R9 are independently C3-C6-cycloalkyl.

[0155] In a further highly preferred embodiment, R, R, R and R are independently -O(C-C-alkyl-O) m -C1-C3-alkyl-OR10 (m=0-3), preferably m=1 or 2. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -O(C2-alkyl-O) m -C1-C3-alkyl-OR10 (m=0-3), preferably m=1 or 2. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -O(C2-alkyl-O) m -C2-alkyl-OR10 (m=0 to 3), preferably m=1 or 2.

[0156] In a further highly preferred embodiment, said R6, R7, R8 and R9 are independently C1-C3-alkyl-O-C1-C3-alkyl.

[0157] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -NH-C n -alkyl-R18 (n=0-3), preferably n=1 or 2. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -NH-C n -alkyl-R18 (n=0-3), preferably n=0, 1 or 2, wherein R18 is a heterocycle optionally substituted by one or more R17. Preferably, the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing one or two heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, the heterocycle is selected from piperidine, morpholine and tetrahydropyran, optionally substituted by one or two R17, preferably C1-C2-alkyl.

[0158] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=0-3), preferably n=1, 2 or 3. In a further highly preferred embodiment, R18 is selected from -OR10, -C(O)-R16, -C(O)-OR16, CN, and a heterocycle optionally substituted with one or more R17, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered monocyclic ring system containing one or two heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably the heterocycle is dioxolane optionally substituted with one or two R17, preferably R17 is CH3. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently selected from -OC n-alkyl-R18 (n=0-3), preferably n=1, 2 or 3. In a further highly preferred embodiment, R18 is selected from -OR10, -C(O)-OR16, CN, and a heterocycle optionally substituted by one or more R17, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, and preferably the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing one or two heteroatoms selected from nitrogen and oxygen.

[0159] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, and preferably R10 is selected from H or CH3. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=1 or 2), wherein R18 is a heterocycle optionally substituted by one or more R17, wherein the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing one or two heteroatoms selected from nitrogen and oxygen; more preferably, the heterocycle is a dioxolane optionally substituted by one or two R17, preferably two R17, wherein R17 is preferably CH3.

[0160] In a further highly preferred embodiment, R6, R7, R8, and R9 are independently a heterocycle optionally substituted by one or more R17, preferably the heterocycle is a fully saturated 4-6 membered monocyclic ring system containing one or two heteroatoms selected from nitrogen and oxygen. In a further highly preferred embodiment, R6, R7, R8, and R9 are independently a heterocycle optionally substituted by one or more R17, preferably the heterocycle is azetidine.

[0161] In a further highly preferred embodiment, R6, R7, R8 and R9 are independently C1-C3-alkoxy. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently F. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently Cl. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently Br. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently I. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently CN. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently methoxy. In a further highly preferred embodiment, R6, R7, R8 and R9 are independently ethoxy.

[0162] In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently selected from halogen, CN, C1-C3-alkyl optionally substituted by one or more F or hydroxyl, C1-C3-alkoxy optionally substituted by one or more F, C3-C6-cycloalkyl, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), wherein the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from halogen, CN, C1-C3-alkyl optionally substituted with one or more F or hydroxyl, C1-C3-alkoxy optionally substituted with one or more F, C3-C6-cycloalkyl, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR11(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0 to 3), and the other of R6, R7, R8 and R9 is H.

[0163] In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently selected from halogen, CN, C1-C3-alkyl optionally substituted with one or more F, C1-C3-alkoxy optionally substituted with one or more F, C3-C6-cycloalkyl, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from halogen, CN, C1-C3-alkyl optionally substituted with one or more F, C1-C3-alkoxy optionally substituted with one or more F, C3-C6-cycloalkyl, and the other of R6, R7, R8 and R9 is H.

[0164] In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently selected from halogen, CN, C1-C3-alkoxy optionally substituted with one or more F, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from halogen, CN, C1-C3-alkoxy optionally substituted with one or more F, and the other of R6, R7, R8 and R9 is H.

[0165] In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently selected from halogen, CN, C1-C3-alkoxy, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from halogen, CN, C1-C3-alkoxy, and the other of R6, R7, R8 and R9 is H.

[0166] In a further highly preferred embodiment, one or two of R6, R7, R8, and R9 are independently selected from F, Cl, Br, CN, methoxy, and ethoxy, and the other of R6, R7, R8, and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8, and R9 is independently selected from F, Cl, Br, CN, methoxy, and ethoxy, and the other of R6, R7, R8, and R9 is H.

[0167] In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from halogen, CN, C1-C3-alkoxy optionally substituted by one or more R11, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently selected from F, Cl, CN, methoxy and ethoxy, and the other of R6, R7, R8 and R9 is H.

[0168] In a further highly preferred embodiment, one or two of R6, R7, R8, and R9 are independently -OC n -alkyl-R18 (n=0-3), preferably n=1, 2 or 3, and R6, R7, R8 and R9 are H. Preferably, R18 is selected from -OR10, -C(O)-OR16, CN, and a heterocycle optionally substituted by one or more R17, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, and preferably the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing 1 or 2 heteroatoms selected from nitrogen and oxygen.

[0169] In a further highly preferred embodiment, one or two of R6, R7, R8, and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, preferably R10 is selected from H or CH3, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently -OC n-Alkyl-R18 (n=1 or 2), wherein R18 is a heterocycle optionally substituted by one or more R17, wherein the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing one or two heteroatoms selected from nitrogen and oxygen, and more preferably, the heterocycle is a dioxolane optionally substituted by one or two R17, preferably two R17, wherein preferably R17 is CH3 and the other of R6, R7, R8 and R9 is H.

[0170] In a further highly preferred embodiment, exactly one of R6, R7, R8, and R9 is independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, preferably R10 is selected from H or CH3, and the other of R6, R7, R8, and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8, and R9 is independently -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3, and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN and the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently -OC n -alkyl-R18 (n=1 or 2), wherein R18 is a heterocycle optionally substituted by one or more R17, wherein the heterocycle is a fully saturated 5- or 6-membered, preferably 6-membered, monocyclic ring system containing one or two heteroatoms selected from nitrogen and oxygen, and more preferably, the heterocycle is a dioxolane optionally substituted by one or two R17, preferably two R17, wherein R17 is preferably CH3 and the other of R6, R7, R8 and R9 is H.

[0171] In a further highly preferred embodiment, one or two of R6, R7, R8 and R9 are independently halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R7, R8 and R9 are H, and more preferably the other of R6, R7, R8 and R9 is H. In a further highly preferred embodiment, exactly one of R6, R7, R8 and R9 is independently halogen, hydroxyl, methoxy, ethoxy, -OC n -Alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R7, R8 and R9 are H, and more preferably the other of R6, R7, R8 and R9 is H.

[0172] In a further highly preferred embodiment, R6 is halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R7, R8 and R9 are H, more preferably R7, R8 and R9 are H.

[0173] In a further highly preferred embodiment, R7 is halogen, hydroxyl, methoxy, ethoxy, -OC n-alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R8 and R9 are H, more preferably R6, R8 and R9 are H.

[0174] In a further highly preferred embodiment, R8 is halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R7 and R9 are H, more preferably R6, R7 and R9 are H.

[0175] In a further highly preferred embodiment, R9 is halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=1, 2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R7 and R8 are H, more preferably R6, R7 and R8 are H.

[0176] In a further highly preferred embodiment, R6 is halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, and preferably R10 is selected from H or CH3. 、 At least two of R7, R8 and R9 are H, preferably R7, R8 and R9 are H. In a further highly preferred embodiment, R6 is selected from the group consisting of halogen, hydroxyl, methoxy, ethoxy, -OC n-alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3, and at least two of R7, R8 and R9 are H, preferably R7, R8 and R9 are H. In a further highly preferred embodiment, R6 is selected from halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN, and at least two of R7, R8 and R9 are H, preferably R7, R8 and R9 are H.

[0177] In a further highly preferred embodiment, R7 is selected from the group consisting of halogen, hydroxyl, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, preferably R10 is H, and at least two of R6, R8 and R9 are H, preferably R6, R8 and R9 are H. In a further highly preferred embodiment, R7 is selected from the group consisting of halogen, hydroxyl, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is H, and at least two of R6, R8 and R9 are H, preferably R6, R8 and R9 are H. In a further highly preferred embodiment, R7 is selected from the group consisting of halogen, hydroxyl, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN, and at least two of R6, R8 and R9 are H, preferably R6, R8 and R9 are H.

[0178] In a further highly preferred embodiment, R8 is halogen, hydroxyl, methoxy, ethoxy, -OC n-alkyl-R18 (n=2 or 3), wherein R18 is -OR10, preferably R10 is selected from H or CH3, and at least two of R6, R7 and R9 are H, preferably R6, R7 and R9 are H. In a further highly preferred embodiment, R8 is selected from halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3, and at least two of R6, R7 and R9 are H, preferably R6, R7 and R9 are H. In a further highly preferred embodiment, R8 is selected from halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN, and at least two of R7, R8 and R9 are H, preferably R6, R7 and R9 are H.

[0179] In a further highly preferred embodiment, R9 is halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, preferably R10 is selected from H or CH3, and at least two of R6, R7 and R8 are H, preferably R6, R7 and R8 are H. In a further highly preferred embodiment, R9 is selected from halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -C(O)-OR16, preferably R16 is selected from H or CH3, and at least two of R6, R7 and R8 are H, preferably R6, R7 and R8 are H. In a further highly preferred embodiment, R9 is selected from halogen, hydroxyl, methoxy, ethoxy, -OC n -alkyl-R18 (n=2 or 3), wherein R18 is CN, and at least two of R6, R7 and R8 are H, preferably R6, R7 and R8 are H.

[0180] In a further highly preferred embodiment, R8 is selected from Cl, F, CN and methoxy, and R6, R7, and R9 are H. In a further highly preferred embodiment, R8 is methoxy, and R6, R7, and R9 are H. In a further highly preferred embodiment, R8 is Cl, F, methoxy, hydroxy, or -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, -C(O)-OR16 or CN, preferably R10 is selected from H or CH3, preferably R16 is selected from H or CH3, preferably at least two of R6, R7 and R9 are H, more preferably R6, R7 and R9 are H.

[0181] In a further highly preferred embodiment, R6 is Cl and R7, R8 and R9 are H. In a further highly preferred embodiment, R6 is Cl, OH or methoxy and two of R7, R8 and R9 are H. In a further highly preferred embodiment, R6 is Cl, OH or methoxy and R7, R8 and R9 are H.

[0182] In a further highly preferred embodiment, R7 is Cl or methoxy, and R6, R8, and R9 are H. In a further highly preferred embodiment, R7 is Cl, F, hydroxy, or -OC n -alkyl-R18 (n=2 or 3), wherein R18 is -OR10, -C(O)-OR16, or CN, preferably R10 is selected from H, preferably R16 is H, preferably at least two of R6, R8, and R9 are H, and more preferably R6, R8, and R9 are H.

[0183] In a further highly preferred embodiment, R9 is Cl, OH or methoxy and two of R6, R7 and R8 are H. In a further highly preferred embodiment, R6 is Cl, OH or methoxy and R6, R7 and R8 are H.

[0184] In a further preferred embodiment, R6 to R9 are H and at least one of R1, R2, R4 and R5 is not H. In a further highly preferred embodiment, R6 to R9 are H and exactly one of R1, R2, R4 and R5 is not H. In a further highly preferred embodiment, R6 to R9 are H, R1 or R5 is C1-C6-alkyl optionally substituted with one or more R11, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R1 or R5 is C1-C3-alkyl optionally substituted with one or more R11, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R1 or R5 is C1-C3-alkyl, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R1 or R5 is methyl, ethyl, cyclopropyl or isopropyl, and R2 and R4 are H.

[0185] In a further highly preferred embodiment, R6 to R9 are H, R3 is C1-C6-alkyl optionally substituted by one or more R11, R1 or R5 is C1-C6-alkyl optionally substituted by one or more R11, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R3 is C1-C3-alkyl optionally substituted by one or more R11, R1 or R5 is C1-C3-alkyl optionally substituted by one or more R11, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R3 is C1-C3-alkyl, R1 or R5 is C1-C3-alkyl, and R2 and R4 are H. In a further highly preferred embodiment, R6 to R9 are H, R3 is methyl, ethyl or isopropyl, R1 or R5 is methyl, ethyl, cyclopropyl or isopropyl, and R2 and R4 are H.

[0186] In a further highly preferred embodiment, one of R1 and R5 is selected from halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is selected from halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is selected from halogen, methyl, ethyl, trifluoromethyl, methoxy and ethoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, one of R1 and R5 is selected from F, Cl, Br, methyl, ethyl, trifluoromethyl and methoxy, and the other of R1 and R5 is H.

[0187] In a further highly preferred embodiment, R2 and R4 are H, one of R1 and R5 is selected from halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, and the other of R1 and R5 is H. In a further highly preferred embodiment, R2 and R4 are H, one of R1 and R5 is selected from halogen, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, R2 and R4 are H, one of R1 and R5 is selected from halogen, methyl, ethyl, trifluoromethyl, methoxy and isopropoxy, and the other of R1 and R5 is H.

[0188] In a further highly preferred embodiment, R2 and R4 are H, one of R1 and R5 is selected from F, Cl, Br, methyl, ethyl, trifluoromethyl, and methoxy, and the other of R1 and R5 is H. In a further highly preferred embodiment, R2 and R4 are H, one of R1 and R5 is selected from F, Cl, Br, methyl, trifluoromethyl, and methoxy, and the other of R1 and R5 is H.

[0189] In a further highly preferred embodiment, said R3 is selected from the group consisting of halogen, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle may be aromatic, partially saturated or fully saturated and contains 1-4 heteroatoms selected from nitrogen, oxygen, with the proviso that each ring system cannot contain more than two oxygen atoms, and preferably the heterocycle contains at least one nitrogen heteroatom.

[0190] In a further highly preferred embodiment, said R3 is selected from the group consisting of halogen, CN, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted with one or more R17, and a 4-6 membered heterocycle optionally substituted with one or more R17, wherein the heterocycle may be aromatic, partially saturated or fully saturated and contains 1-4 heteroatoms selected from nitrogen and oxygen, with the proviso that each ring system cannot contain more than two oxygen atoms, and preferably the heterocycle contains at least one nitrogen heteroatom.

[0191] In a further highly preferred embodiment, said R3 is selected from the group consisting of halogen, CN, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n-Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is selected from tetrazole, pyrazole, pyrrole, oxazole, thiazole, imidazole, triazole, pyrrolidine, pyrrolidin-2-one, piperidine and morpholine. In a further highly preferred embodiment, R3 is selected from halogen, CN, C1-C3-alkyl optionally substituted by one or more R11, C1-C3-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10 (m=0-3), -OR16, -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4- to 6-membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is selected from tetrazole, pyrazole, pyrrole, oxazole, thiazole, imidazole, triazole, pyrrolidine, pyrrolidin-2-one, piperidine, and morpholine.

[0192] In a further highly preferred embodiment, R3 is selected from the group consisting of F, Cl, Br, CN, C1-C2-alkyl-O-C1-C2-alkyl, C1-C3-alkyl, trifluoromethyl, C1-C2-alkoxy, -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C3-alkyl-O) m -C1-C3-alkyl-OR11 (m=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is selected from triazole and tetrazole.

[0193] In a further highly preferred embodiment, R3 is selected from the group consisting of F, Cl, Br, CN, CH2-O-CH3, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, -N(R14)-C(O)-R15, -C(O)-OR16, -O(C1-C 3- Alkyl-O) m -C1-C 3- and alkyl-OR11 (m=0-3), -OPO(OR10)2, -PO(OR10)2, and a 4-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is selected from triazole and tetrazole.

[0194] In another highly preferred embodiment, R1, R2, and R4 are H, R3 is selected from methyl, ethyl, cyclopropyl, and isopropyl, R5 is selected from H, Cl, Br, CF3, and methyl, and at least one of R6-R9 is not H.

[0195] In another highly preferred embodiment, said R3 is isopropyl and at least one of R6, R7, R8 or R9 is not H.

[0196] In another highly preferred embodiment, R1, R2, R4 and R5 are H, R3 is isopropyl, and at least one of R6, R7, R8 or R9 is not H.

[0197] In another highly preferred embodiment, R1 is methyl, R2, R4 and R5 are H, R3 is methyl and at least one of R6, R7, R8 or R9 is not H.

[0198] In a further highly preferred embodiment, the compound of formula (I) is selected from: JPEG0007743306000006.jpg216170JPEG0007743306000007.jpg247170JPEG0007743306000008.jpg30170Preferably, the compound is selected from the following: JPEG0007743306000009.jpg122170

[0199] In a further highly preferred embodiment, the compound is selected from: JPEG0007743306000010.jpg59170JPEG0007743306000011.jpg136170

[0200] In a further highly preferred embodiment, the compound is 7-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 6-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 9-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazoline-8-carbonitrile, 3-(2,4-dimethylphenyl)sulfonyl-8-fluoro-4H-triazolo[1,5-a]quinazolin-5-one, 6-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 9-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-(2-methoxy-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-isopropoxy-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-bromo-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-fluoro-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-(4-methoxy-2-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, N-[4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-phenyl]acetamide, 3-(4-fluoro-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[2-methyl-4-(trifluoromethoxy)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-chloro-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-cyclopropylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzonitrile, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzoic acid, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzoate ethyl 8-methoxy-3-[4-(trifluoromethyl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[4-methyl-2-(trifluoromethyl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-cyclopropyl-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-ethyl-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]benzonitrile, 3-(2,4-dimethylphenyl)sulfonyl-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[2-methyl-4-(2H-tetrazol-5-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzamide, 8-methoxy-3-[2-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, and 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(3-methoxypropoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanenitrile, 3-(2,4-dimethylphenyl)sulfonyl-8-iodo-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4,5-dimethyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-(azetidin-1-yl)-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-morpholinoethylamino)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(tetrahydropyran-4-ylamino)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4,6-dimethyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4,6-dimethyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 2-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]acetonitrile, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoate methyl, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanamide, 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4H-triazolo[1,5-a]quinazolin-5-one, 8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, and 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one.

[0201] In a further highly preferred embodiment, the compound is 7-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 6-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 9-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 6-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 9-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[4-methyl-2-(trifluoromethyl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(3-methoxypropoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanenitrile, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(tetrahydropyran-4-ylamino)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoate methyl, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, and 8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one.

[0202] In a further highly preferred embodiment, the compound is 7-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 6-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 8-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 9-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 6-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 9-chloro-3-(4-isopropylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2-chloro-4-methylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2-bromo-4-methylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one. In another highly preferred embodiment, the compound is 8-methoxy-3-[4-methyl-2-(trifluoromethyl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one.In another highly preferred embodiment, the compound for use is 3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one.In another highly preferred embodiment, the compound for use is 3-(2-chloro-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one.In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2-bromo-4-methylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 8-bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-(3-methoxypropoxy)-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanenitrile. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one. In another highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-9-methoxy-4H-triazolo[1,5-a]quinazolin-5-one.In another highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-(tetrahydropyran-4-ylamino)-4H-triazolo[1,5-a]quinazolin-5-one.In another highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-9-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one.In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoate methyl. In a further highly preferred embodiment, the compound is 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one. In a further highly preferred embodiment, the compound is 8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one.

[0203] In a further aspect, the present invention provides compounds according to Formula (I), and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of Formula (I) disclosed herein, for use in a method of reducing the virulence of a bacterium, preferably a bacterium expressing AgrA or an orthologue of AgrA, preferably a bacterium expressing AgrA, even more preferably a bacterium of a genus selected from Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. In a further highly preferred embodiment, the bacterium expresses AgrA or an orthologue of AgrA. In a further highly preferred embodiment, the bacterium expresses AgrA. In a further highly preferred embodiment, the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium. In a further highly preferred embodiment, the bacterium is of the genus Staphylococcus. In a further highly preferred embodiment, the bacterium is Staphylococcus aureus. The herein described and disclosed embodiments, preferred embodiments and highly preferred embodiments of compounds of formula (I) shall apply to the methods of the present invention, regardless of whether they are specifically mentioned again or their repetition is avoided for the sake of brevity.

[0204] In a further aspect, the present invention provides compounds according to Formula (I), and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of compounds of Formula (I) disclosed herein, for use in a method for preventing or treating a disease, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, wherein the bacterium is selected from the genus Staphylococcus, Streptococcus, or Clostridium, more preferably Staphylococcus, and even more preferably the bacterium is Staphylococcus aureus. In a further highly preferred embodiment, the disease is an infectious or inflammatory disease. In a further highly preferred embodiment, the disease is an infectious disease. In a further highly preferred embodiment, the disease is a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium. In a further highly preferred embodiment, the disease is a bacterial infection and the bacterium is selected from the genus Staphylococcus, Streptococcus, or Clostridium. In a further highly preferred embodiment, the disease is exacerbated by bacteria of a genus selected from Staphylococcus, preferably Staphylococcus aureus. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by bacteria selected from the genus Staphylococcus. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by Staphylococcus aureus. In a further highly preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis. In a further highly preferred embodiment, the disease is an inflammatory skin disease, preferably atopic dermatitis exacerbated by Staphylococcus aureus. The embodiments, preferred and highly preferred embodiments described and disclosed herein of compounds of formula I shall apply to the method of the present invention, regardless of whether they are specifically mentioned again or their repetition is avoided for the sake of brevity.

[0205] In a further aspect, the present invention relates to a compound according to formula (I) for use in a method for inhibiting quorum sensing, preferably AgrA quorum sensing, in a bacterium, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. JPEG0007743306000012.jpg90170 (in the formula, R1 and R5 are independently H, halogen, hydroxyl, NO 2、 CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C optionally substituted by one or more R11 6- Cycloalkyl, -C n- Alkyl-N(R12)(R13)(n=0-3), -C n- Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n-Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently H, halogen, C1-C10 optionally substituted by one or more R11 6- alkyl, R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n-alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17, wherein at least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H; and pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers of the compound of formula (I). In a further preferred embodiment, the bacterium is selected from Streptococcus pyogenes, Clostridium difficile, or Staphylococcus aureus, and preferably, the bacterium is Staphylococcus aureus. In a highly preferred embodiment, the bacterium is Staphylococcus aureus.

[0206] In a further aspect, the present invention provides at least one compound according to formula (I) JPEG0007743306000013.jpg87170 (in the formula, R1 and R5 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R3 is halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m-C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R2 and R4 are independently selected from H, halogen, C1-C6-alkyl optionally substituted by one or more R11; R6, R7, R8 and R9 are independently selected from H, halogen, hydroxyl, NO2, CN, C1-C6-alkyl optionally substituted by one or more R11, C1-C6-alkoxy optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -C n -Alkyl-N(R12)(R13)(n=0-3), -C n -Alkyl-C(O)N(R12)(R13)(n=0-3), -SO2-N(R12)(R13), -SO2-N(R14)-C(O)-R15, -C n -Alkyl-N(R14)-C(O)-R15 (n=0-3), -C n -Alkyl-C(O)-OR16 (n=0-3), -O(C1-C3-alkyl-O) m -C1-C3-Alkyl-OR10(m=0-3), -C n -Alkyl-OR16(n=0-3), -NH-C n -Alkyl-R18(n=0-3), -OC n -alkyl-R18 (n=0-3), -OPO(OR10)2, -PO(OR10)2, and a heterocycle optionally substituted by one or more R17; R10 is selected from H and C1-C6-alkyl optionally substituted by one or more R11; the one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently selected from H, C1-C6-alkyl optionally substituted by one or more R11, C3-C6-cycloalkyl optionally substituted by one or more R11, -SO2-C1-C6-alkyl optionally substituted by one or more R11, or R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17, The one or more R17 may be halogen, hydroxy, NO2, CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C n -alkyl-OR16 (n=0-3), C1-C6-alkyl optionally substituted by one or more R11, and C1-C6-alkoxy optionally substituted by one or more R11, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; at least one of R1, R2, R4, R5, R6, R7, R8 or R9 is not H, and Pharmaceutical compositions comprising pharmaceutically acceptable salts, stereoisomers, enantiomers, tautomers of compounds of formula (I) and pharmaceutically acceptable excipients are provided.

[0207] In a further preferred embodiment, the bacterium is selected from Streptococcus pyogenes, Clostridium difficile or Staphylococcus aureus, preferably the bacterium is Staphylococcus aureus.

[0208] In a preferred embodiment, the pharmaceutical composition further comprises at least one antibiotic active against bacteria, preferably against bacteria of a genera selected from Staphylococcus, Streptococcus or Clostridium, more preferably against Staphylococcus, and even more preferably against Staphylococcus aureus. In a highly preferred embodiment, the pharmaceutical composition further comprises at least one antibiotic active against Staphylococcus aureus.

[0209] Thus, the compositions and compounds of the present invention represent an antipathogenic therapy that can be used as a standalone treatment to enhance the host's self-defense and self-healing capabilities by reducing tissue damage, reducing inflammation, reducing disease dissemination, and enhancing immune responses and recurrence rates. If the host is unable to adequately eliminate disarmed pathogens, combination therapy with conventional antibiotics (in the case of infections caused by Staphylococcus aureus) or anti-inflammatory agents (in the case of diseases exacerbated by Staphylococcus aureus) may be considered, ultimately optimizing the timeliness and / or dosage of treatment (Dickey SW, et al. (2017) Nat Rev Drug Discov 16(7):457-471).

[0210] In a preferred embodiment, the pharmaceutical composition further comprises at least one anti-inflammatory agent, preferably at least one anti-inflammatory agent for treating chronic inflammatory skin diseases.

[0211] In a further aspect, the present invention provides a combination product comprising at least one compound according to formula (I) and at least one antibiotic active against bacteria, preferably against bacteria of a genera selected from Staphylococcus, Streptococcus, or Clostridium, more preferably against Staphylococcus, and even more preferably against Staphylococcus aureus. Thus, in another embodiment, the compounds of formula (I) of the present invention can be administered in combination with an antibiotic. Exemplary antibiotics include colloidal silver, penicillins (including penicillin G, ampicillin, amoxicillin, methicillin, oxacillin, dicloxacillin, flucloxacillin, amoxicillin / clavulanate, ampicillin / sulbactam), carbapenems (including imipenem, meropenem, ertapenem, doripenem, imipenem-cilastatin), cephalosporins (including cephalothin, cefazolin, cephalexin, cephradine, cefamandole, cefoxitin, and third-generation cephalosporins), glycopeptides (including vancomycin, teicoplanin, oritavancin, telavancin, dalbavancin), oxazolidinones (including linezolid, tedizolid), lipopeptides (including daptomycin, ramoplanin), lincosamides (including clindamycin and lincomycin). These include, but are not limited to, benzodiazepines (including benzocaine), macrolides (including erythromycin, spiramycin, roxithromycin, clarithromycin, azithromycin), aminoglycosides (including streptomycin, gentamicin, amikacin, kanamycin, neomycin, tobramycin), ketolides (including telithromycin, solithromycin), bacitracin, ansamycins (including rifampicin), tetracyclines (including doxycycline, minocycline), glycylcyclines (including tigecycline), quinolones (including ciprofloxacin, moxifloxacin, levofloxacin, ofloxacin), streptogramins (including quinupristin / dalfopristin), trimethoprim-sulfamethoxazole (TMP-SMX), and topical mupirocin.

[0212] In a further aspect, the present invention provides a combination product comprising at least one compound according to formula (I) and at least one agent, preferably an anti-inflammatory agent, typically and preferably used to treat inflammatory diseases, preferably chronic inflammatory skin diseases, which diseases are exacerbated by bacteria of a genus selected from Staphylococcus, preferably Staphylococcus aureus.

[0213] The combination therapy described herein may involve simultaneous or sequential administration of a compound of formula (I) of the present invention and at least one antibiotic or at least one other drug, preferably an anti-inflammatory drug typically and preferably used to treat inflammatory diseases. The combination of a compound of formula (I) of the present invention with at least one antibiotic or at least one other drug in the methods, compositions, or combinations of the present invention can reduce the amount of either drug compound required for a therapeutically effective dosage, thereby reducing the negative side effects that the antibiotic or drug may induce in vivo. Furthermore, the combination of a compound of formula (I) of the present invention with at least one antibiotic or at least one other drug in the methods, compositions, or combinations of the present invention can shorten the duration of in vivo treatment. Furthermore, the combination of a compound of formula (I) of the present invention with at least one antibiotic in the methods, compositions, or combinations of the present invention can reduce the effective dose or shorten the time required for successful antibiotic treatment, which in turn reduces the chance of microbial resistance to a particular antibiotic.

[0214] The compounds, pharmaceutical compositions, or combination products of the present invention of formula (I) can be administered to any subject who can experience the beneficial effects of the compounds, compositions, or products of the present invention, as described herein. More preferably, the subject is a human. The compounds, compositions, or products of the present invention described herein can be administered by any means that achieves their intended purpose. For example, administration can be parenteral, topical, local, subcutaneous, oral, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, or intradermal delivery, or by transdermal, buccal, oral mucosal, ocular route, or by inhalation. In a preferred embodiment, administration to the subject is systemic. In other embodiments, administration to the subject is local, such as a topical solution, topical ointment, or topical cream. More preferably, the subject is a human.

[0215] In a further aspect, the present invention provides the use of a compound of formula (I), pharmaceutical composition or combination product according to the present invention for the manufacture of a medicament for reducing the virulence of a bacterium, preferably a bacterium expressing AgrA or an orthologue of AgrA, preferably AgrA, further preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. In a further highly preferred embodiment, the bacterium expresses AgrA. In a further highly preferred embodiment, the bacterium is of a genus selected from Staphylococcus, Streptococcus or Clostridium. In a further highly preferred embodiment, the bacterium is of the genus Staphylococcus. In a further highly preferred embodiment, the bacterium is Staphylococcus aureus.

[0216] In a further aspect, the present invention provides the use of a compound of formula (I), pharmaceutical composition or combination product according to the present invention for the manufacture of a medicament for preventing or treating a disease, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, wherein the bacterium is preferably selected from the genera Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by a bacterium selected from the genera Staphylococcus, Streptococcus, or Clostridium. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by a bacterium selected from the genus Staphylococcus. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by a bacterium selected from the genus Staphylococcus. In a further highly preferred embodiment, the disease is an infectious disease caused or exacerbated by Staphylococcus aureus.

[0217] In a further aspect, the present invention provides the use of a compound of formula (I), a pharmaceutical composition or a combination product according to the present invention for the manufacture of a medicament effective for the inhibition of quorum sensing, preferably AgrA quorum sensing, in bacteria, preferably bacteria of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably against Staphylococcus, and even more preferably against Staphylococcus aureus. In a further aspect, the present invention provides the use of a pharmaceutical composition according to the present invention for the manufacture of a medicament for the inhibition of quorum sensing, preferably AgrA quorum sensing, in bacteria, preferably bacteria of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably against Staphylococcus, and even more preferably against Staphylococcus aureus.

[0218] In a further aspect, the present invention provides a method for reducing the virulence of a bacterium, preferably a bacterium expressing AgrA or an orthologue of AgrA, preferably AgrA, more preferably Staphylococcus aureus, comprising administering to a subject an amount of a compound of formula (I) according to the present invention, pharmaceutical composition, or combination product, preferably a compound of formula (I), effective to inhibit the synthesis of one or more virulence factors by the bacterium. In a further highly preferred embodiment, the bacterium expresses AgrA. In a further highly preferred embodiment, the bacterium is of a genus selected from Staphylococcus, Streptococcus, and Clostridium. In a further highly preferred embodiment, the bacterium is of the genus Staphylococcus. In a further highly preferred embodiment, the bacterium is Staphylococcus aureus. The herein described and disclosed embodiments, preferred embodiments, and highly preferred embodiments of compounds of formula I shall apply to the method of the present invention, regardless of whether they are specifically mentioned again or their repetition is avoided for the sake of brevity.

[0219] In a further preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the synthesis of one or more bacterial virulence factors, wherein the one or more virulence factors are selected from the group consisting of one or more toxins (e.g., α, β, γ, γ-mutant, and δ-hemolysin, PSMs (e.g., PSMα), Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxins (e.g., enterotoxin B), exfoliative toxins), proteases (e.g., serine proteases, metalloproteases, and cysteine ​​proteases), nucleases, lipases, coagulases, hyaluronidases, clumping factors, pyrogenic toxin superantigens (e.g., TSST-1), and combinations thereof. Thus, in a further preferred embodiment of the method of the present invention, the one or more toxins are selected from α, β, γ, γ-mutant, and δ-hemolysin. In a further preferred embodiment of the method of the present invention, the PSM is PSMα. In a further preferred embodiment of the method of the present invention, the enterotoxin is enterotoxin B or an exfoliative toxin. In a further preferred embodiment of the method of the present invention, the protease is selected from a serine protease, a metalloprotease, and a cysteine ​​protease. In a further preferred embodiment of the method of the present invention, the pyrogenic toxin superantigen is TSST-1. In a further preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the synthesis of one or more bacterial virulence factors, wherein the one or more virulence factors are selected from the group consisting of α, β, γ, γ-mutant, and δ-hemolysin, PSMα, Panton-Valentine leukocidin (PVL), leukotoxin E and D (LukED), leukotoxin G and H (LukGH), enterotoxin B, exfoliative toxins, serine proteases, metalloproteases, cysteine ​​proteases, nucleases, lipases, coagulase, hyaluronidase, clumping factors, TSST-1, and any combination of one or more of any specific virulence factor or general group of virulence factors. In a further highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits the expression of PSMα, RNAIII, and / or any of its downstream targets.In a further highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of PSMα. In a further highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of RNAIII. In a further highly preferred embodiment of the method of the present invention, the compound of formula (I) inhibits expression of a downstream target of RNAIII. In a further highly preferred embodiment, the method further comprises administering an antibiotic or anti-inflammatory agent to the subject, preferably the human. In a further highly preferred embodiment, the method further comprises administering an antibiotic to the subject, preferably the human. In a further highly preferred embodiment, the method further comprises administering an anti-inflammatory agent to the subject, preferably the human.

[0220] In a further aspect, the present invention provides a method for preventing or treating a disease in a subject, preferably an infectious or inflammatory disease, more preferably a bacterial infection or inflammatory skin disease caused or exacerbated by a bacterium, wherein the bacterium is preferably selected from the genera Staphylococcus, Streptococcus, or Clostridium, more preferably a bacterium of the genus Staphylococcus, and even more preferably, the bacterium is Staphylococcus aureus, the method comprising administering to a subject in need of such prevention or treatment an effective amount of a compound of Formula (I), pharmaceutical composition, or combination product, preferably Formula (I). In a further highly preferred embodiment, the disease is an infectious or inflammatory disease. In a further highly preferred embodiment, the disease is an infectious disease. In a further highly preferred embodiment, the disease is a bacterial infection. In a further highly preferred embodiment, the disease is an inflammatory skin disease caused or exacerbated by a bacterium. Preferably, the infection, preferably the bacterial infection, is caused by a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably by Staphylococcus, and even more preferably by Staphylococcus aureus. In a further highly preferred embodiment, the infection, preferably the bacterial infection, comprises an antibiotic-resistant Staphylococcus infection, preferably the antibiotic-resistant Staphylococcus infection comprises a methicillin-resistant Staphylococcus aureus infection.

[0221] Thus, the compounds of formula (I) or compositions of the present invention described herein, preferably pharmaceutical compositions of the present invention comprising compounds of formula (I), can be administered to a subject to inhibit the activity of AgrA, thereby preventing the production of virulence factors that aid in the development of bacterial infections or conditions or disorders associated with bacterial infections. Examples of diseases and disorders associated with bacterial infections that respond to treatment with the compounds and / or compositions of the present invention include, but are not limited to, skin and soft tissue infections, pulmonary infections, or chronic inflammatory skin diseases such as atopic dermatitis.

[0222] In a further aspect, the present invention provides a method for inhibiting quorum sensing, preferably AgrA quorum sensing, in a bacterium, preferably a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, comprising administering to a subject an effective amount of a compound of formula (I), pharmaceutical composition or combination product, preferably a compound of formula (I).

[0223] In a further preferred embodiment of the present invention, the compound of formula (I) is provided in a topical composition together with a pharmaceutically acceptable carrier and topically administered to a subject, preferably the subject has a disease or disorder associated with a bacterial infection, the bacterial infection being an infection caused or exacerbated by a bacterium, preferably Staphylococcus aureus. In a further preferred embodiment, the infection caused or exacerbated by a bacterium is a subcutaneous steroid infection (SSTI) or atopic dermatitis. In a further preferred embodiment, the bacterial infection is a subcutaneous steroid infection (SSTI) or atopic dermatitis.

[0224] Thus, the compounds of formula (I) or compositions of the present invention or combination products of the present invention, preferably compounds of formula (I) or compositions of the present invention comprising the compounds of formula (I) described herein, can be used to prevent or treat infections in a subject caused by any bacterial species that utilize the AgrA response regulator in quorum sensing and virulence factor production. The compounds and compositions of the present invention are typically and preferably administered to subjects with or at risk of having an infection, preferably a bacterial infection, such as a staphylococcal and / or streptococcal infection. For example, subjects who may benefit from treatment with the compounds or compositions of the present invention described herein may be hospitalized patients at risk of developing a hospital-acquired infection, or subjects known to be infected with or exposed to antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-intermediate-susceptible Staphylococcus aureus, and vancomycin-resistant Staphylococcus aureus. Methods for detecting the presence of a staphylococcal bacterial infection are well known and can be used, for example, by culturing a sample from the subject, e.g., blood cultures.

[0225] In a further aspect, the present invention provides a method for the treatment of a subject suffering from an infection or inflammatory disease, preferably a bacterial infection or an inflammatory skin disease, caused by bacteria of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably Staphylococcus, and even more preferably Staphylococcus aureus, the method comprising administering to the subject a compound of formula (I) according to the present invention and at least one antibiotic active against bacteria, preferably against bacteria of a genus selected from Streptococcus or Clostridium, and even more preferably against Staphylococcus aureus.

[0226] In a further aspect, the present invention provides a method for preventing or treating a bacterial infection in a subject, comprising the step of administering to a subject in need of such prevention or treatment an effective amount of a compound of formula (I) according to the present invention. Preferably, the bacterial infection is caused by a bacterium of a genus selected from Staphylococcus, Streptococcus or Clostridium, more preferably the genus Staphylococcus, and even more preferably Staphylococcus aureus.

[0227] In a further aspect, the present invention provides a method for preventing or treating a disease caused or exacerbated by Gram-positive quorum-sensing bacteria, comprising administering to a subject in need of such prevention or treatment an effective amount of a compound of formula (I) according to the present invention.

[0228] Preparation of compounds The compounds of the present invention can be prepared by a variety of methods, including standard chemistry. Previously defined substituents will continue to have their previously defined meanings unless otherwise specified. Exemplary general synthetic methods are shown in the following schemes and can be readily adapted to prepare other compounds of the present invention. Certain preferred compounds of the present invention can be prepared according to the experimental procedures disclosed in the Examples section.

[0229] The general procedures used to synthesize compounds of formula (I) are set forth below in Reaction Schemes 1-3 and are provided in the Examples section.

[0230] Preparation of Compounds of Formula (I) The compounds of formula (I) of the present invention (wherein R1 to R9 are as defined above) can be prepared according to Scheme 1. An appropriately substituted anthranilic acid ester (III) can be prepared by the addition of sodium azide. 1or trimethylsilyl azide, and was readily converted to the corresponding 2-azidobenzoate (II) by diazotization and substitution with trimethylsilyl azide (Barral, K., et al. Org. Lett. 2007, 9(9), 1809-1811). Treatment of (II) with substituted arylsulfonylacetonitrile (IV) in the presence of base afforded the desired triazoloquinazolinone of formula (I) (Lee, K., et al. Bioorganic Med. Chem. Lett. 2010, 20(5), 1767-1770; Jones, P., et al. Tetrahedron 2002, 58(50), 9973-9981). JPEG0007743306000014.jpg66170

[0231] Preparation of intermediate compounds Intermediates of formula (IV) can be prepared according to Scheme 2 by reacting the corresponding commercially available arylsulfonyl chlorides of formula (V) with chloroacetonitrile in the presence of sodium sulfite. JPEG0007743306000015.jpg74170

[0232] Alternatively, the intermediate of formula (IV) can be prepared by oxidizing the sulfide of formula (VI) in the presence of mCPBA (Anderson, MO, et al. J. Med. Chem. 2012, 55(12), 5942-5950) or hydrogen peroxide (Tsui, GC, et al. Org. Lett. 2011, 13(2), 208-211) according to Scheme 3. The intermediate of formula (VI) can be prepared by alkylating the commercially available aryl thiol of formula (VII) with bromoacetonitrile in the presence of potassium carbonate (Anderson, MO, et al. J. Med. Chem. 2012, 55(12), 5942-5950). Alternatively, compounds of formula (VI) can be prepared from commercially available anilines of formula (VIII) and bromoacetonitrile by a copper-catalyzed S-transfer reaction (Li, Y., et al. Org. Lett. 2014, 16(10), 2692-2695). JPEG0007743306000016.jpg78170

[0233] Highly preferred compounds of formula (I) of the present invention are listed in Table 1 by providing the compound number, chemical structure and name. JPEG0007743306000017.jpg248170JPEG0007743306000018.jpg239170JPEG0007743306000019.jpg254170JPEG00077433060 00020.jpg236170JPEG0007743306000021.jpg233170JPEG0007743306000022.jpg232170JPEG0007743306000023.jpg209170

[0234] The synthesis and physical data characterization of particularly preferred compounds are described in the Examples section. Compound 34 was purchased from AK Scientific. [Example]

[0235] The present invention is illustrated by the following non-limiting examples. Specific embodiments of the present invention are described below, but those skilled in the art will understand that various changes and modifications can be made. References to preparations carried out in a manner similar to, or in accordance with the general method of, other preparations may include variations in routine parameters such as time, temperature, post-treatment conditions, slight changes in reagent amounts, etc.

[0236] Abbreviation The following list provides definitions of certain abbreviations and symbols used herein. It will be understood that the list is not exhaustive, but the meaning of abbreviations and symbols not defined below will be readily apparent to one of ordinary skill in the art. In describing this invention, chemical elements will be identified according to the Periodic Table of the Elements. JPEG0007743306000024.jpg247170

[0237] Proton nuclear magnetic resonance ( 1H NMR spectra were recorded on a Bruker DPX 300 MHz spectrometer equipped with a 5 mm BBI probe, a Bruker AV 400 MHz spectrometer equipped with a 5 mm PABBI probe, a Bruker DRX 500 MHz spectrometer equipped with a 5 mm PABBI probe, or a Bruker Avance III 600 spectrometer equipped with a 5 mm room temperature BBI probe. Samples were recorded at 25 °C using DMSO-D6, C5D5N, CD2Cl2, Pyr-d5, or CDCl3 as solvents unless otherwise noted.

[0238] 2D 1 H, 15 N HSQC spectra were acquired at 298 K on a Bruker Avance IIIHD 600 MHz NMR spectrometer equipped with a cryogenic triple resonance probe (Bruker, Karlsruhe, Germany). Proton chemical shifts were referenced using the methyl signal of sodium 3-trimethylsilyl-[2,2,3,3-d4]-propionate at 0 ppm. Spectra were processed with the Bruker TopSpin software package 3.5 and analyzed with Sparky software. AgAc assignments were estimated from entry 18598 in the Biomolecular Magnetic Resonance Research Bank (BMRB). Chemical shifts are reported in ppm downfield from the internal standard tetramethylsilane (TMS). NMR data abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, sep = septuplet, m = multiplet, app = apparent, br = broad. Mass spectra were obtained using electrospray (ES) ionization techniques. All temperatures are reported in degrees Celsius. Microwave heating was performed using a Biotage Initiator™ equipped with a Robot Sixty.

[0239] Intermediate VI Intermediate VI-1: 2-[2-methyl-4-(trifluoromethoxy)phenyl]sulfanylacetonitrile A mixture of sodium thiosulfate pentahydrate (Fluorochem, 1818 mg, 7.3 mmol), 2-bromoacetonitrile (Fluorochem, 878.5 mg, 7.3 mmol), copper(II) sulfate pentahydrate (Kemika, 26.12 mg, 0.105 mmol), and 2,2'-dipyridyl (Fluorochem, 16.34 mg, 0.105 mmol) in MeOH / HO (10 mL / 20 mL) was stirred at 80 °C for 2 h, then 2-methyl-4-(trifluoromethoxy)aniline (ArkPharm, 200 mg, 1.05 mmol) and tert-butyl nitrite (Fluorochem, 186.7 μL, 1.57 mmol) was added and stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure and DCM (30 mL) was added. The organic phase was extracted and evaporated in vacuo to give 150 mg of a brown oily residue, which was purified by flash chromatography (eluent cHex: EtOAc 7:3) to give the title compound (97 mg, 37.5%) as a yellowish oil. 1 H NMR (300MHz, CDCl3) δ ppm:7.57(d, J=8.6Hz, 1H), 7.17-7.06(m, 2H), 3.52(s, 2H), 2.51(s, 3H).

[0240] Intermediates VI-2 to VI-8 were prepared similarly as described for VI-1, replacing 2-methyl-4-(trifluoromethoxy)aniline with those shown in the table below. Variations in the protocol and purification steps are also indicated. JPEG0007743306000026.jpg203170

[0241] Intermediate IV Intermediate IV-1: 2-(2,4-dimethylphenyl)sulfonylacetonitrile 2-Bromoacetonitrile (Alfa Aesar, 174 μL, 2.50 mmol) was stirred in an ice bath and dissolved in DMF (0.4 M), then treated with 2,4-dimethylbenzenethiol (Enamine, 321 μL, 2.38 mmol) and KCO (691 mg, 5.00 mmol) and stirred at 0 °C for 2 h. The reaction mixture was taken up in excess HO and extracted three times with EtO. The combined organic extracts were washed twice with water and NaCl (saturated aqueous solution) and then concentrated in vacuo to produce 2-(2,4-dimethylphenyl)sulfanylacetonitrile in approximately 90% yield. Next, 2-(2,4-dimethylphenyl)sulfanylacetonitrile (380 mg, 2.14 mmol) was dissolved in DCM (0.4 M) and treated in portions with mCPBA (77.0%, 961 mg, 4.29 mmol) at 0 °C. The reaction was stirred under argon at room temperature for 3 days. The reaction mixture was quenched with excess sodium sulfite solution and extracted twice with DCM. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to yield the title compound (300 mg, 67%). 1 H NMR (300MHz, CD2Cl2) δ ppm:7.95(d, J=8.0Hz, 1H), 8.32-8.25(m, 2H), 4.15(s, 2H), 2.69(s, 3H), 2.45(s, 3H). [ES-MS]m / z 208(MH-).

[0242] Intermediate IV-2: 2-(4-chloro-2-methyl-phenyl)sulfonylacetonitrile 2-Bromoacetonitrile (Aldrich, 159 mg, 1.33 mmol) was stirred in an ice bath, dissolved in DMF (0.4 M), and then treated with 4-chloro-2-methylbenzene (Fluorochem, 200 mg, 1.26 mmol) and K2CO3 (348 mg, 2.52 mmol) and stirred at 0 °C for 1 h. The reaction mixture was taken up in excess H2O and extracted three times with Et2O. The combined organic extracts were washed twice with water and NaCl (saturated aqueous solution), dried over MgSO4, filtered, and then concentrated in vacuo to produce 2-(4-chloro-2-methylphenyl)sulfanylacetonitrile in 23% yield. 2-(4-Chloro-2-methylphenyl)sulfanylacetonitrile was dissolved in glacial acetic acid (5 mL) and 30% H2O2 in water (413 μL) and added. The solution was heated at 110 °C for 1.5 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. Water was added and the residue was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound (107 mg, 92%). 1 H NMR (300MHz, DMSO-d6) δ ppm: 7.94 (d, J=8.47Hz, 1H), 7.70 (d, J=2.16Hz, 1H), 7.63 (dd, J=8.44, 2.07Hz, 1H), 5.22 (s, 2H), 2.64 (s, 3H). [ES-MS]m / z 227(MH-).

[0243] Intermediate IV-3: 2-(2-methoxy-4-methylphenyl)sulfonylacetonitrile A mixture of 2-methoxy-4-methyl-benzenesulfonyl chloride (Santa Cruz, 200 mg, 0.906 mmol), sodium sulfite (183 mg, 1.45 mmol), and sodium bicarbonate (122 mg, 1.45 mmol) was suspended in a mixture of water (2.0 mL) and i-PrOH (0.5 mL). The resulting suspension was heated at 120 °C for 30 minutes using microwave irradiation. 2-Chloroacetonitrile (Aldrich, 2.72 mmol, 172 μL) was added to the reaction mixture, which was then heated at 120 °C for 20 minutes using microwave irradiation. Next, NH4Cl (saturated aqueous solution, 15 mL) was added, and the resulting suspension was extracted with EtOAc (3 × 10 mL). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (cHex: EtOAc 4:1) to afford the title compound (177 mg, 87%) as a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ ppm: 7.71 (d, J=8.1Hz, 1H), 7.20 (s, 1H), 7.05-7.60 (m, 1H), 5.08 (s, 2H), 3.94 (s, 3H), 2.42 (s, 3H). [ES-MS]m / z 224(MH-).

[0244] Intermediates IV-4 to IV-14 were prepared similarly as described for IV-3, substituting 2-methoxy-4-methyl-benzenesulfonyl chloride with the starting material shown in the table below. Variations in the purification steps are also indicated. JPEG0007743306000030.jpg82170JPEG0007743306000031.jpg221170

[0245] Intermediate IV-15: 2-[2-methyl-4-(trifluoromethoxy)phenyl]sulfonylacetonitrile Intermediate VI-1 (93 mg, 0.38 mmol) was dissolved in DCM (5 mL) and mCPBA (Apollo Scientific, 204 mg, 1.18 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature overnight. mCPBA (Apollo Scientific, 102 mg, 1 equiv.) was added and stirring was continued at room temperature for 72 h. Saturated aqueous NaSO (10 mL) was added to the reaction mixture. The aqueous layer was extracted with DCM (10 mL × 2). The combined organic layers were washed with saturated aqueous NaHCO, water, then brine, dried over MgSO, filtered, and concentrated in vacuo to give the title compound (84 mg, 80%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ ppm: 8.07 (d, J=8.8Hz, 1H), 7.63-7.51 (m, 2H), 5.26 (s, 2H), 2.69 (s, 3H). [ES-MS]m / z 278(MH-).

[0246] Intermediates IV-16 to IV-17 were prepared similarly as described for IV-15, substituting intermediate VI-1, 2-[2-methyl-4-(trifluoromethoxy)phenyl]sulfanylacetonitrile, for the starting material indicated in the table below. Modifications to the protocol and purification steps are also indicated. JPEG0007743306000033.jpg62170

[0247] Intermediate IV-18: 2-[4-methyl-2-(trifluoromethyl)phenyl]sulfonylacetonitrile JPEG0007743306000034.jpg89170 Intermediate VI-4 (167 mg, 0.63 mmol) was dissolved in glacial acetic acid (5 mL) and 30% H2O2 in water (513 μL, 5 mmol) was added. The solution was heated at 110 °C for 5 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. Water was added and the residue was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluent cHex: EtOAc 8:2) to produce the title compound (98 mg, 54%). 1 H NMR (300MHz, DMSO-d6) δ ppm: 8.15 (d, J=8.2Hz, 1H), 7.97 (s, 1H), 7.85 (d, J=8.3Hz, 1H), 5.21 (s, 2H), 2.52 (s, 3H, under solvent). [ES-MS]m / z 262(MH-).

[0248] Intermediates IV-19 to IV-22 were prepared similarly as described for IV-18, replacing intermediate VI-4 with the starting material indicated in the table below. Modifications to the protocol and purification steps are also indicated. JPEG0007743306000035.jpg105170

[0249] (Intermediate II) Intermediate II-1: Methyl 2-azido-5-chlorobenzoate JPEG0007743306000036.jpg109170 Methyl 2-amino-5-chlorobenzoate (Enamine, 400 mg, 2.16 mmol) was dissolved in dry ACN (2 mL) and cooled to 0 °C. Tert-butyl nitrite (Sigma-Aldrich, 388 μL, 3.23 mmol) was added, and the reaction mixture was stirred for 5 minutes. Azido(trimethyl)silane (Acros, 343 μL, 2.59 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give the title compound (391 mg, 86%) as an orange solid, which was used in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ ppm: 7.77 (d, J=2.5Hz, 1H), 7.69 (dd, J=8.6 & 2.6Hz, 1H), 7.44 (d, J=8.6Hz, 1H), 3.82 (s, 3H).

[0250] Intermediates II-2 to II-4 were prepared in a similar manner to that described for II-1, substituting the methyl 2-amino-5-chlorobenzoate shown in the table below. JPEG0007743306000037.jpg82170

[0251] Intermediate II-5: 2-Azido-4-methoxy-benzoic acid methyl ester To an ice-cooled suspension of methyl 2-amino-4-methoxybenzoate (1 g, 5.4 mmol) was added a solution of sodium nitrite (564 mg, 8.2 mmol) in HCl (aqueous, 6 M, 27 mL) in water (7.0 mL) under a N atmosphere. The resulting yellow solution was stirred at 0 °C for 20 min. The resulting solution was added dropwise to an ice-cooled solution of sodium azide (703 mg, 11 mmol) and sodium acetate (4437 mg, 54 mmol) in water (30 mL) under a N atmosphere. The resulting solution was stirred at 0 °C for 15 min and then allowed to reach room temperature spontaneously for 2 h. The reaction mixture was extracted with EtO (3 × 80 mL). The combined organic layers were washed with NaHCO3 (saturated aqueous solution, 2 x 100 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title product (1.1 g, 94%) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ ppm: 7.83-7.58 (m, 1H), 6.89-6.80 (m, 2H), 3.85 (s, 3H), 3.78 (s, 3H).

[0252] Intermediate II-6: Methyl 2-azidobenzoate To an ice-cooled suspension of methyl 2-aminobenzoate (0.5 g, 3.3 mmol) in HCl (aqueous, 6 M, 17 mL) was added a solution of sodium nitrite (345 mg, 5 mmol) in water (4.0 mL) under a N atmosphere. The resulting yellow solution was stirred at 0 °C for 20 min and then added dropwise to an ice-cooled solution of sodium azide (430 mg, 6.6 mmol) and sodium acetate (2713 mg, 33 mmol) in water (18 mL) under a N atmosphere. The resulting solution was stirred at 0 °C for 30 min and then allowed to reach room temperature spontaneously for 1.5 h. The reaction mixture was extracted with EtO (3 × 50 mL). The combined organic layers were washed with NaHCO3 (saturated aqueous solution, 3 x 50 mL), dried over Na2SO4, filtered and evaporated in vacuo to give the title product (413 mg, 70%) as a yellow oil. 1H NMR (300MHz, DMSO-d6) δ ppm:7.76(d, J=7.8Hz, 1H), 7.63(t, J=7.6Hz, 1H), 7.40(d, J=8.4Hz, 1H) 7.28(t, J=7.6Hz, 1H), 3.81(s, 3H).

[0253] Intermediate II-7: 2-Azido-4-bromo-benzoic acid methyl ester To an ice-cooled suspension of methyl 2-amino-4-bromobenzoate (0.5 g, 2.2 mmol) in HCl (aqueous, 6 M, 17 mL) was added a solution of sodium nitrite (226 mg, 3.3 mmol) in water (3.0 mL) under a N atmosphere. The resulting yellow solution was stirred for 20 min at 0 °C and then added dropwise to an ice-cooled solution of sodium azide (212 mg, 3.3 mmol) and sodium acetate (3.57 g, 43 mmol) in water (22 mL) under a N atmosphere. The resulting solution was stirred at 0 °C for 20 min and then allowed to reach room temperature spontaneously for 2 h. The reaction mixture was extracted with EtO (3 × 50 mL). The combined organic layers were washed with NaHCO3 (saturated aqueous solution, 3 x 50 mL), dried over Na2SO4, filtered and evaporated in vacuo to give the title product (410 mg, 74%) as a yellow oil.

[0254] Intermediate II-8: 2-Azido-6-methoxy-benzoic acid methyl ester To an ice-cooled suspension of methyl 2-amino-6-methoxybenzoate (0.25 g, 1.4 mmol) in HCl (aqueous, 6 M, 8 mL) was added a solution of sodium nitrite (144 mg, 2.1 mmol) in water (1.5 mL) under a N atmosphere. The resulting yellow solution was stirred at 0 °C for 20 min and then added dropwise to an ice-cooled solution of sodium azide (135 mg, 2.1 mmol) and sodium acetate (2.26 g, 28 mmol) in water (10 mL) under a N atmosphere. The resulting solution was stirred at 0 °C for 20 min and then allowed to reach room temperature spontaneously for 1 h. The reaction mixture was extracted with EtO (3 × 50 mL). The combined organic layers were washed with NaHCO3 (saturated aqueous solution, 3 x 50 mL), dried over Na2SO4, filtered and evaporated in vacuo to afford the title product (260 mg, 91%) as a yellow oil, which was used in the next step without further purification.

[0255] Intermediates II-9 to II-12 were prepared in a similar manner to that described for II-8, substituting methyl 2-amino-6-methoxybenzoate as shown in the table below. JPEG0007743306000042.jpg162170

[0256] Intermediate II-13: 2-Azido-5-methoxy-4-(2-methoxyethoxy)benzoic acid methyl ester JPEG0007743306000043.jpg67170 To a solution of intermediate II-11 (130 mg, 0.58 mmol) in DMF (2 mL), 1-bromo-2-methoxyethane (82.1 μL, 0.87 mmol) and K2CO3 (242 mg, 1.75 mmol) were added, and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated brine. The mixture was washed with NH4Cl solution and saturated brine, dried over Na2SO4, filtered, and evaporated in vacuo to give the title product (170 mg, 100%).

[0257] Intermediate II-14: 2-Azido-4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzoic acid methyl ester JPEG0007743306000044.jpg43170 To a solution of intermediate II-12 (75 mg, 0.39 mmol) in DMF (1 mL), 1-[2-(2-bromoethoxy)ethoxy]-2-methoxyethane (135 μL, 0.78 mmol) and K2CO3 (215 mg, 1.55 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and washed with saturated brine. The mixture was washed with NH4Cl solution and saturated brine, dried over Na2SO4, filtered, and evaporated in vacuo to give the title product (130 mg, 98%).

[0258] Intermediate II-15: 2-Azido-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]benzoic acid methyl ester JPEG0007743306000045.jpg87170 To a solution of intermediate II-12 (75 mg, 0.39 mmol) in DMF (1 mL) was added 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (66 μL, 0.47 mmol) and K2CO3 (215 mg, 1.55 mmol), and the reaction mixture was stirred at 50 °C for 4 days. The reaction mixture was diluted with EtOAc (150 mL) and washed with saturated brine. The mixture was washed with NH4Cl solution and saturated brine, dried over Na2SO4, filtered, and evaporated in vacuo to give the title product (85 mg, 71%).

[0259] Intermediate II-16: Methyl 2-azido-4-(2-hydroxyethoxy)-5-methoxy-benzoate JPEG0007743306000046.jpg67170 To a solution of intermediate II-11 (120 mg, 0.54 mmol) in DMF (2 mL) was added 2-bromoethanol (153 μL, 2.1 mmol) and K2CO3 (594 mg, 4.3 mmol), and the reaction mixture was stirred at room temperature for 6 days. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated brine. The mixture was washed with NH4Cl solution and saturated brine, dried over Na2SO4, filtered, and evaporated in vacuo to give the title product (144 mg, 100%).

[0260] Compounds of Formula I Compound 1: 7-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one JPEG0007743306000047.jpg107170 Sodium methoxide solution was carefully prepared in situ by dissolving sodium (27.2 mg, 1.18 mmol) in anhydrous MeOH (0.1 M) under argon. To this solution was added intermediate IV-1 (112 mg, 0.536 mmol), and the solution was stirred at room temperature for 20 min. Intermediate II-1 (100 mg, 0.47 mmol) was added in portions, and the resulting orange solution was stirred at room temperature overnight. After concentration under reduced pressure, the residue was suspended in HO and acidified to pH 2 with 1N HCl. The precipitate was filtered and washed with water. The yellow solid was heated in EtOH and filtered to give the title compound (80.0 mg, 43.5%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ ppm:12.63(br s, 1H), 8.32 (d, J=8.7Hz, 1H), 8.19 (d, J=8.2Hz, 1H), 8.14 (d, J=1.9Hz, 1H), 8 .1-7.9(m, 1H), 7.28(d, J=8.2Hz, 1H), 7.22(s, 1H), 2.59(s, 3H), 2.33(s, 3H). [ES+MS]m / z 389(MH + ).

[0261] Compounds 2-30 of formula (I) of the present invention were prepared by methods similar to those described for compound 1, replacing intermediates IV-1 and II-1 with the corresponding intermediates IV and II shown in the table below. Modifications to the protocol and purification steps are also shown. JPEG0007743306000048.jpg234170JPEG0007743306000049.jpg248170JPEG0007743306000050.jpg212170

[0262] Compound 31: 8-Methoxy-3-[2-methyl-4-(2H-tetrazol-5-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one Compound 31 can be prepared from compound 22 by [3+2] cycloaddition using sodium azide and copper(II) sulfate as described in Akhlaghinia, B. et al. J. Braz. Chem. Soc. 2012, 23(12), 2197-2203.

[0263] A mixture of compound 22 (0.0910 mmol, 40.0 mg), copper(II) sulfate pentahydrate (Kemika, 0.0018 mmol, 0.5 mg), and sodium azide (Sigma-Aldrich, 0.091 mmol, 5.9 mg) in DMSO (0.4 mL) was stirred and heated at 140 °C for 1 h. The reaction mixture was poured into HCl (aqueous 4 M), and the resulting suspension was extracted with EtOAc (3 × 30 mL). The aqueous layer was neutralized with NaHCO (saturated aqueous solution) and re-extracted with DCM / i-PrOH (7:2). The combined organic layers were dried over NaSO, filtered, and evaporated in vacuo to give the crude product, which was subjected to preparative HPLC purification (high pH, ​​Method B) to afford the title compound (6.3 mg, 15.5%) as a white solid. 1 H NMR (500MHz, Pyr-d5) δ ppm: 8.58-8.48(m, 2H), 8.48-8.42(m, 2H), 7.83(d, J=2.2Hz, 1H), 7.20-7.15(m, 1H, under solvent), 3.78(s, 3H), 2.94(s, 3H). [ES+MS]m / z 439(MH + ).

[0264] Compound 32: 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzamide Compound 32 can be prepared by hydrolysis of compound 22 using acetamide and palladium(II) chloride as described in Maffioli, S. Et al. Org. Lett. 2005, 7, (13), 5237-5239.

[0265] To a solution of compound 22 (0.06 mmol, 25.0 mg) in a mixture of water / THF 1:3 (1.3 mL), acetamide (15 mg, 0.25 mmol) and PdCl2 (2.2 mg, 0.012 mmol) were added, and the mixture was stirred at room temperature for 5 hours. A 1N solution of NaOH (0.1 mL) was added, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was evaporated in vacuo. Water was added to the residue, and the pH was adjusted to pH 2, giving a brown precipitate. The precipitate was purified by flash chromatography (eluent DCM:MeOH 10:0.05) to give the title compound (6.39 mg, 24%) as a beige solid. 1 H NMR (500MHz, Pyr-d5) δ ppm:9.07(br s., 1H), 8.66(br s., 1H), 8.54-8.50(m, 1H), 8.45-8.20(m, 1H), 8.25-8.20(m, 2H), 7.84(d, J=2.1Hz, 1H), 3.80(s, 3H), 2.92(s, 3H). [ES+MS]m / z 414(MH+).

[0266] Compound 33: 8-Methoxy-3-[2-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one Compound 33 can be prepared by copper-catalyzed oxidative cyclization of compound 22 using acetamide and palladium(I) bromide as described in Ueda, S. et al. J. Am. Chem. Soc. 2009 131(42), 15080-15081.

[0267] To a mixture of compound 22 (0.601 mmol, 25.0 mg), copper(I) bromide (0.003 mmol, 0.43 mg), cesium carbonate (0.180 mmol, 58.7 mg), and acetamidine hydrochloride (0.0901 mmol, 8.52 mg) was added DMSO (0.19 mL). The resulting mixture was stirred and heated at 120 °C for 6 h. The reaction mixture was cooled to room temperature and diluted with a mixture of EtOAc (5 mL) and saturated aqueous NaHCO3 (10 mL). The resulting suspension was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (reverse phase, eluent: aqueous NH4HCO3 / MeCN 8:2) to give the title compound (5.5 mg, 19.5%) as a white solid. 1 H NMR (500MHz, Pyr-d5) δ ppm:8.58-8.53(m, 1H), 8.49-8.39(m, 3H), 7.83(d, J=1.95Hz, 1H), 7.24-7.17(m, 1H, under solvent), 3.79(s, 3H), 2.99(s, 3H), 2.49(s, 3H). [ES+MS]m / z 452(MH+).

[0268] Compound 35: 3-(2-chloro-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one A 20% solution of sodium ethoxide (0.655 mL, 1.69 mmol), diluted with anhydrous EtOH (2 mL) containing 3 Å molecular sieves and stirred under a nitrogen atmosphere for 2 h, was added to a suspension of intermediate IV-5 (194.5 mg, 0.85 mmol) in anhydrous EtOH (3 mL) and 4 Å molecular sieves under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 min. Next, a solution of intermediate II-6 (100 mg, 0.56 mmol) in dry EtOH was slowly prepared, and the resulting yellowish solution was stirred at room temperature overnight. After filtration and concentration under reduced pressure, the residue was purified by flash chromatography (DCM to 1% MeOH in DCM). The residue was dissolved in MeOH and precipitated with EtO. The residue was dried to afford the title compound (8 mg, 4%) as a white solid.1 H NMR (500MHz, CDCl3) δ ppm:9.58(bs, 1H), 8.46-8.60(m, 2H), 8.34(d, J=8.3Hz, 1H), 7.97(t, J=8.0Hz , 1H), 7.72(t, J=7.8Hz, 1H), 7.35(d, J=8.6Hz, 1H), 7.31(s, 1H), 2.43(s, 3H). [ES+MS]m / z 375(MH+).

[0269] Compound 36: 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one Compound 36 can be prepared by demethylation of the methoxy group of compound 5 using sodium hydroxide and 1-dodecanethiol, as described in Chae, J. Arch. Pharm. Res. 2008, 31(3), 305-309.

[0270] Compound 5 (40 mg, 0.102 mmol) and NaOH (12.2 mg, 0.306 mmol) were dissolved in NMP (0.4 mL), and 1-dodecanethiol (37 μL, 0.153 mmol) was added to the solution. The reaction mixture was stirred at 130 °C for 15 min. Ethyl acetate (30 mL) was added to the reaction mixture and washed with 3 × 30 mL of water. The organic layer was dried over MgSO, filtered, and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NH (90:9:1.5) 10-100%) to give the title compound (8 mg, 21%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ ppm:12.13(bs, 1H), 11.27(s, 1H), 8.18(d, J=8.0Hz, 1H), 8.04(d, J=8.5Hz, 1H), 7.54(d, J=2.8Hz , 1H), 7.27(d, J=8.2Hz, 1H), 7.07(dd, J=8.8, 2.3Hz, 1H), 7.31(s, 1H), 2.57(s, 3H), 2.32(s, 3H). [ES+MS]m / z 371(MH+).

[0271] Compounds 46 and 50 of formula (I) of the present invention were prepared by a method similar to that described for compound 36, replacing compound 5 as the starting material with those shown in the table below. Variations in the protocol and purification steps are also shown. JPEG0007743306000056.jpg48170

[0272] Compound 37: 3-(2-bromo-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one A sodium ethoxide solution was carefully prepared in situ by dissolving sodium (13 mg, 0.56 mmol) in anhydrous EtOH (2 mL) cooled in an ice bath under nitrogen. To this solution, intermediate IV-10 (61.3 mg, 0.22 mmol) was added, and the solution was stirred for 15 min. Intermediate II-6 (33 mg, 0.19 mmol) dissolved in dry EtOH (0.5 mL) was added, and the resulting yellowish solution was stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by flash chromatography (DCM to DCM:MeOH:NH3 (90:9:1.5) 3–100%) and then by preparative HPLC (ACN / HCOOH (1% v / v in water), 30 / 70–80 / 20, 14 min) to give the title compound (1.1 mg, 1.4%) as an orange solid. 1 H NMR (500MHz, CDCl3) δ ppm:9.60(bs, 1H), 8.48-8.36(m, 3H), 7.98(t, J=7.5Hz, 1H), 7.73(t, J=8.2Hz, 1H), 7.53(s, 1H), 7.41(d, J=8.4Hz, 1H), 7.43(s, 3H). [ES+MS]m / z 419, 421(MH + ).

[0273] Compound 38: 3-(2-bromo-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one To a solution of intermediate IV-1 (20.4 mg, 0.1 mmol) in dry EtOH (0.5 mL), a 20% solution of NaOEt in EtOH (75.5 μL, 0.2 mmol) was added, and the resulting solution was stirred at room temperature for 20 min. Next, a solution of intermediate II-7 (25 mg, 0.1 mmol) in dry EtOH (0.5 mL) was added, and the resulting yellowish solution was stirred at room temperature for 1 h. The ethanol was evaporated, and the residue was dissolved in water (3 mL). The pH was adjusted to approximately 2, and then extracted with EtOAc (approximately 100 mL). The organic layer was dried over NaSO and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NH (90:9:1.5) 0-100%) to afford the title compound (13 mg, 31%) as a white solid. 1 H NMR (400MHz, CDCl3) δ ppm:9.51(br.s, 1H), 8.54(d, J=1.6Hz, 1H), 8.22(d, J=8.8Hz, 1H), 8.06(d, J=8.4Hz, 1H) , 7.79(dd, J=8.4, 1.6Hz, 1H), 7.19(d, J=8Hz, 1H), 7.12(s, 1H), 2.68(s, 3H), 2.36(s, 3H). [ES+MS]m / z 433, 435(MH + ).

[0274] Compound 39: 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one To a solution of intermediate IV-1 (150 mg, 0.7 mmol) in dry EtOH (2.5 mL), a 20% solution of NaOEt in EtOH (543 μL, 1.4 mmol) was added, and the resulting solution was stirred at room temperature for 20 min. Next, a solution of intermediate II-8 (174.6 mg, 0.84 mmol) in dry EtOH (2 mL) was added, and the resulting yellowish solution was stirred at room temperature overnight. The ethanol was evaporated, and the residue was dissolved in water (6 mL). The pH was adjusted to approximately 2, and then extracted with EtOAc (approximately 100 mL). The organic layer was dried over NaSO and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NHOH (90:9:1.5) 0-100%) to afford the title compound (60 mg, 22%) as a white solid. 1 H NMR (400MHz, CDCl3) δ ppm:9.25(br.s, 1H), 8.06(d, J=8.4Hz, 1H), 7.96(d, J=8.4Hz, 1H), 7.81(t, J=8.4Hz , 1H), 7.18(d, J=8Hz, 1H), 7.09-7.12(m, 2H), 4.05(s, 3H), 2.68(s, 3H), 2.35(s, 3H). [ES+MS]m / z 385(MH + ).

[0275] Compounds 42, 44, 47, 51, 52, 57, 59 and 60 of formula (I) of the present invention were prepared by a method similar to that described for compound 39, replacing intermediates IV-1 and II-8 with the corresponding intermediates IV and II shown in the table below. Variations in the protocol and purification steps are also shown. JPEG0007743306000060.jpg184170

[0276] Compound 40: 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one To a solution of compound 36 (50 mg, 0.1 mmol) in DMF (1 mL), 1-bromo-3-methoxypropane (12 μL, 0.1 mmol) and potassium carbonate (43.7 mg, 0.3 mmol) were added, and the resulting solution was stirred at room temperature overnight. Since the starting material was not completely consumed, 1-bromo-3-methoxypropane (12 μL, 0.1 mmol) and potassium carbonate (43.7 mg, 0.3 mmol) were added, and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3 × 30 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were collected, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NH4OH (90:9:1.5) 0-100%) to give the title compound (20 mg, 40%) as a white solid. 1 H NMR (400MHz, CDCl3) δ ppm:9.59(bs, 1H), 8.38(d, J=8.88Hz, 1H), 8.21(d, J=7.99Hz, 1H), 7.89(s, 1H), 7.35-7.21(m, 3H), 4.3 8(t, J=6.22Hz, 2H), 3.69(t, J=5.86Hz, 2H), 3.48(s, 3H), 2.81(s, 3H), 2.49(s, 3H), 2.31-2.18(m, 2H). [ES+MS]m / z 443(MH + ).

[0277] Compounds 41, 43, 54, and 55 of formula (I) of the present invention were prepared by methods similar to those described for compound 40, replacing 1-bromo-3-methoxypropane with those shown as starting materials in the table below. Variations in the protocol and purification steps are also shown. JPEG0007743306000062.jpg95170

[0278] Compound 45: 8-(azetidin-1-yl)-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one To a solution of compound 42 (40 mg, 0.08 mmol) in dioxane (1.5 mL), azetidine (8.25 μL, 0.12 mmol), sodium tert-butoxide (11.8 mg, 0.12 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl t-butyl ether adduct (RuPhos precatalyst, 6.6 mg, 0.008 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos, 3.8 mg, 0.008 mmol) were added. The reaction mixture was heated at 120 °C for 3 h. The solvent was evaporated and the residue was purified by flash chromatography (DCM to DCM:MeOH:NH4OH (90:9:1.5) 0-100%) to give the title compound (20 mg, 59%) as a white powder. 1 H NMR (300MHz, CDCl3) δ ppm:9.18(br.s, 1H), 8.07(d, J=8.7Hz, 2H), 7.17(d, J=8.1Hz, 1H), 7.09(s, 1H), 7.00(d, J=2.4Hz, 1 H), 6.50(dd, J=8.7, 2.4Hz, 1H), 4.12(t, J=7.5Hz, 4H), 2.66(s, 3H), 2.45-2.55(m, 2H), 2.35(s, 3H). [ES+MS]m / z 410(MH+).

[0279] Compounds 48 and 49 of formula (I) of the present invention were prepared by methods similar to those described for compound 45, replacing azetidine with those shown as starting materials in the table below. Variations in the protocol and purification steps are also shown. JPEG0007743306000064.jpg51170

[0280] Compound 53: 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one To a solution of compound 36 (150 mg, 0.4 mmol) in DMF (1 mL), 2-bromoethyl acetate (100 mg, 0.6 mmol) and potassium carbonate (222 mg, 1.6 mmol) were added, and the resulting solution was stirred at room temperature overnight. Since the starting material was not completely consumed, 2-bromoethyl acetate (33.5 mg, 0.2 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added, and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (2 × 10 mL). The organic layer was dried over NaSO and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NHOH (90:9:1.5) 0–100%). The residue was washed with EtO and dried under vacuum. It was then suspended in water, acidified to pH ∼2, extracted with DCM, dried over sodium sulfate, evaporated to dryness and washed with diethyl ether to give ethyl 2-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]acetate (86 mg, 46%). [ES+MS] m / z 457 (MH + ).

[0281] To a solution of ethyl 2-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]acetate (20 mg, 0.043 mmol) in MeOH:water (2 mL, 1:1) was added lithium hydroxide (10.3 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 2 h. MeOH was evaporated in vacuo, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The organic layer was dried over NaSO and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NHOH (90:9:1.5) 0-100%) to give the title compound (17 mg, 92%) as a white powder. 1H NMR (300MHz, DMSO-d6) δ ppm:12.27(bs, 1H), 8.14(d, J=8.21Hz, 1H), 8.08(d, J=8.86Hz, 1H), 7.66(d, J=2.38Hz, 1H), 7.29-7.1 5(m, 3H), 4.97(t, J=5.50Hz, 1H), 4.21(t, J=4.35Hz, 2H), 3.81-3.71(m, 2H), 2.55(s, 3H), 2.32(s, 3H). [ES+MS]m / z 415(MH + ).

[0282] Compound 56: 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazol-yn-8-yl]oxy]butanamide To a solution of compound 55 (150 mg, 0.3 mmol) in MeOH (20 mL) was added LiOH (27 mg, 0.64 mmol), and the resulting solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in water (2.5 mL) and acidified with 2 N HCl. The precipitate was filtered and dried under vacuum to give 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoic acid (40 mg, 28%). 1 H NMR (300MHz, DMSO-d6) δ ppm:12.26(br.s, 1H), 12.18(br.s, 1H), 8.18(d, J=7.8Hz, 1H), 8.10(d, J=8.1Hz, 1H), 7.68(d, J=2.4Hz, 1H), 7.21-7.29(n, 3H), 4.23(t, J=6.0Hz, 2H), 2.72(s, 3H), 2.41(t, J=7.2Hz, 2H), 2.33(s, 3H), 1.95-2.05(m, 2H).

[0283] A solution of methyl 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoate (20 mg, 0.044 mmol), HOBt (10.1 mg, 0.066 mmol), DIPEA (30.5 μL, 0.175 mmol), and HATU (25 mg, 0.066 mmol) in DMF (1 mL) was stirred at room temperature for 5 min. Next, ammonium chloride (47 mg, 0.088 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine. The NH4Cl solution and saturated brine were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NH4OH (90:9:1.5) 0-100%) to give the title compound (12 mg, 60%) as a white powder. 1 H NMR (300MHz, DMSO-d6) δ ppm:8.15(d, J=8.1Hz, 1H), 8.09(d, J=8.7Hz, 1H), 7.65(d, J=2.4Hz, 1H), 7.20-7.34(m, 4H), 6.79( s, 1H), 4.19(t, J=6.3Hz, 2H), 2.56(s, 3H), 2.32(s, 3H), 2.25(t, J=7.4Hz, 2H), 1.94-2.03(m, 2H). [ES+MS]m / z 456(MH + ).

[0284] Compound 61: 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one To a solution of intermediate IV-1 (100 mg, 0.47 mmol) in dry EtOH (1 mL), a 20% solution of NaOEt in EtOH (362 μL, 0.94 mmol) was added, and the resulting solution was stirred at room temperature for 20 min. Next, a solution of intermediate II-16 (199 mg, 0.47 mmol) in dry EtOH (2 mL) was added, and the resulting yellowish solution was stirred at room temperature overnight. The ethanol was evaporated, and the residue was dissolved in water (6 mL). The pH was adjusted to approximately 2, and then extracted with EtOAc (approximately 250 mL). The organic layer was dried over NaSO and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NHOH (90:9:1.5) 0 to 100%) to give 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one (75 mg, 36%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ ppm:12.38(br.s, 1H), 8.20,(d, J=8.4Hz), 7.75(s, 1H), 7.55(s, 1H), 7.27(d, J=8.7Hz, 1H), 7.21(s , 1H), 4.98(br.s, 1H), 4.22-4.26(m, 2H), 3.92(s, 3H), 3.78-3.80(m, 2H), 2.57(s, 3H), 2.33(s, 3H). [ES+MS]m / z 445(MH + ).

[0285] 3-(2,4-Dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one (50 mg, 0.11 mmol) and NaOH (13.5 mg, 0.34 mmol) were dissolved in NMP (1.5 mL), and 1-dodecanethiol (40.4 μL, 0.17 mmol) was added to the solution. The reaction mixture was stirred at 130 °C for 3 h. The reaction mixture was cooled to room temperature. Ethyl acetate (300 mL) was added to the reaction mixture and washed with 3 × 50 mL of water. The organic layer was dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (DCM to DCM:MeOH:NH3 (90:9:1.5) 10-100%) to give the title compound (7 mg, 14%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ ppm:12.22(br.s, 1H), 10.08(s, 1H), 8.19,(d, J=8.5Hz), 7.72(s, 1H), 7.49(s, 1H), 7.28(d, J=9.0Hz, 1H ), 7.22(s, 1H), 4.96(t, J=6Hz, 1H), 4.24(t, J=4.5Hz, 2H), 3.78-3.81(m, 2H), 2.57(s, 3H), 2.33(s, 3H). [ES+MS]m / z 431(MH+).

[0286] 1 H, 15 N HSQC NMR spectroscopy: 2D 1 H, 15 N HSQC spectra (96 scans) typically consist of 、1 H and 15 Under N, 3072 and 180 points were used, and 100 μM or 200 μM 15 All spectra were acquired in the presence of 3% DMSO-d6.

[0287] For each sample tested, 400 μL of 100 μM PBS in [50 mM NaPi pH 6.3; 100 mM NaCl; 3 mM THP; 5% DO; + TMSP] was used. 15N-AgrAc was mixed with 13 μL of the compound stock solution (dissolved in DMSO-d6). 13 μL of DMSO-d6 was added for the control experiment. In each NMR sample, the final concentration of DMSO-d6 was 3%. After a centrifugation step (approximately 7000 × g for several minutes), the supernatant was transferred to a Shigemi NMR tube. The samples were analyzed on a 600 MHz spectrometer equipped with a sample changer. For each tube, 1D 1 H spectrum and 2D 1 H, 15 N-HSQC was obtained.

[0288] Figure 2 shows that compound 34 binds to AgrA. C We explain the chemical shift perturbations observed upon binding to AgrA and demonstrate that these inhibitors indeed bind to the C-terminal domain of AgrA.

[0289] MIC: Minimum inhibitory concentrations (MICs) were determined by broth microdilution in cation-adjusted Mueller-Hinton (CA-MHB) broth according to CLSI guidelines. From overnight culture plates, cells were resuspended in 0.9% (w / v) saline, and a bacterial inoculum was prepared in CA-MHB at 5x10^5 CFU / ml. Compounds were serially diluted 2-fold in CA-MHB, and 10 μL of this 10x concentrated sample was added to a 96-well plate. Finally, 90 μL of the bacterial suspension was added to the compound. The plate was covered and incubated at 35°C for 18 hours without shaking. All experiments included antibiotics as a quality control. The MIC was determined visually as the lowest concentration of compound that prevented visible bacterial growth, and the plate was scanned for documentation.

[0290] Lethal dose 50% (LD 50 ): Human hepatocellular carcinoma cells (HepG2) engineered for stable expression of human secreted embryonic alkaline phosphatase (hSEAP) were used for LD50 measurements. Cells were cultured in 10 cm Petri dishes in EMEM (EBSS) + 2 mM glutamine + 1% non-essential amino acids (NEAA) + 10% fetal bovine serum (FBS) + 1% penicillin / streptomycin (PS) (Sigma) at 37 °C in a humidified atmosphere with 5% CO2. For LD50 measurements, 20,000 cells per well were seeded into clear 96-well tissue culture plates and incubated overnight at 37 °C with 5% CO2 for cell attachment. The next morning, the medium was replaced with fresh medium containing 2-fold serially diluted compounds ranging from 0.8 to 100 µM or DMSO (solvent control). The plates were incubated at 37 °C with 5% CO2 and humidification for 48 h. For SEAP quantification, culture supernatants were collected and heat-inactivated at 65°C for 15 minutes. Then, 10 μL of heat-inactivated supernatant was mixed with 70 μL of MilliQ and 100 μL of 2× SEAP buffer (20 mM homoarginine, 1 mM MgCl2, 21% diethanolamine, adjusted to pH 9.8 with HCl) in a new 96-well flat-bottom plate (Greiner). Enzyme activity was measured for 25 minutes by measuring absorbance at 405 nm using a microplate reader, and specific SEAP activity was calculated within the linear range of absorbance using the Beer-Lambert law. LD 50 Compounds at >100 μM are considered to be non-cytotoxic. JPEG0007743306000068.jpg52170JPEG0007743306000069.jpg255141JPEG0007743306000070.jpg54170

[0291] Hemolysis assay: The hemolysis assay is a phenotypic assay for measuring red blood cell (RBC) lysis mediated by exotoxins recovered from the supernatant (SN) of Staphylococcus aureus cultures. This assay was developed to evaluate the efficacy of compounds in reducing exotoxin expression through inhibition of AgrA.

[0292] Two hemolysis assays were performed. In the first hemolysis assay (hemolysis assay I), an overnight culture of MRSA (USA300 isolate) was added to a tube containing 1 mL of fresh TSB and either 10 μM compound (primary test, fixed concentration) or 30 / 10 / 3.3 / 1.1 and 0.37 μM compound at an OD of 0.1. 600 (IC 50 The cultures were then diluted with fresh medium to an OD of 6.0, after which the cell density was measured. 600 The culture was adjusted to 0°C and grown at 220 rpm for 8 hours. The culture was passed through a 0.2 μm filter and immediately used in the hemolysis assay. The toxin-containing filtrate was serially diluted in PBS, with dilutions ranging from 1:2 to 1:256 tested. Hemolytic activity was assessed using a modification of the protocol described by Sully et al. Briefly, defibrinated rabbit blood (10% washed pooled cells, Rockland) was diluted 1:5 with PBS to a cell concentration of 2%. The diluted toxin-containing filtrate was mixed 1:1 with red blood cells (100 μL each). PBS- or 0.4% TX-100-treated blood cells were used to determine baselines for no lysis and complete lysis, respectively. The reaction was mixed by gentle pipetting and incubated at 37°C for 1 hour. After incubation, the plate was centrifuged at 1000 x g for 5 minutes at room temperature. A 30 μL aliquot of the supernatant was transferred to a 96-well U-bottom plate and the absorbance at 405 nm was measured. The PBS control values ​​were subtracted from the experimental data, and the difference was normalized to the absorbance value of the TX-100 lysis control. These values ​​were plotted against the extract concentration and fitted to a four-parameter logistic model (EC) using GraphPad. 50 Activity curves were generated by fitting the IC to the IC50 / IC60 / IC70 / IC80 / IC90 / IC90 / IC10 / IC11 / IC12 / IC13. Compounds were further analyzed in the presence of 30 / 10 / 3.3 / 1.1 / 0.37 μM compound. 50 Measurements were performed at an OD of 0.75 for all five concentrations. 600 The absorbance values ​​at 1000 kJ / min were used (Table 3, right column). The lower the value, the more active the compound. Compounds 12, 18, and 26 had IC values ​​of approximately 1 μM. 50 It is the most potent compound with

[0293] For the second hemolysis assay (hemolysis assay II), compounds were serially diluted from 32 μg / ml to 0.0156 μg / ml using two-fold dilutions in Cation-adjusted Mueller Hinton Broth (CA-MHB). DMSO (0.9%, n=6) and BV2985 (16 μg / ml, n=6) were used to determine baselines for no inhibition and complete inhibition of lysis, respectively. 250 μl of the prepared compound dilutions and controls were transferred to a 96-deep-well plate. Staphylococcus aureus MRSA strain (USA300 isolate) was scraped from a fresh orientation agar plate and suspended in saline adjusted to an OD610 of 0.1 (corresponding to a 0.5 McFarland scale). The bacterial suspension was then diluted 100-fold in CA-MHB and mixed 1:1 with the compound dilutions to obtain a two-fold dilution of the compound dilutions. After incubating the plates at 37°C and 600 rpm for 18 hours, the cultures were filter-sterilized using a 96-well, 0.2 μm filter plate (Corning) stacked on top of the receiver plate by centrifugation at 4500 rpm for 2 minutes at room temperature. Hemolytic activity was assessed using a modification of the protocol described by Sully et al. Briefly, defibrinated rabbit blood (10% washed pooled cells, Rockland) was diluted 1:5 with PBS to a cell concentration of 2%. The diluted filtrate containing the toxin was mixed 1:1 with red blood cells (100 μl each). The reaction was mixed by gentle pipetting and incubated at 37°C for 1 hour. After incubation, the plate was centrifuged at 1000 x g for 5 minutes at room temperature. A 30 μL aliquot of the supernatant was transferred to a 96-well U-bottom plate, and the absorbance at 405 nm was measured. The values ​​of the complete inhibition control (HTS007753) were subtracted from the experimental data, and the difference was then normalized to the value of the no-inhibition control (DMSO). These values ​​were plotted against the concentration of test compound to generate inhibitor concentration-response curves, which were then fitted to a four-parameter logistic model (IC50; IC95) using GraphPad. The minimum effective concentration (MEC) was determined directly from the raw data, as the compound concentration yielded an absorbance less than twice the mean of the complete inhibition control. The lower the value, the more active the compound. JPEG0007743306000071.jpg194170

[0294] Quantitative RT-PCR analysis of psma and RNAIII: An overnight culture of MRSA (USA300 isolate) was added to a 100 mL Erlenmeyer flask containing 25 mL of fresh TSB to a starting OD of 0.05. 600 The culture was inoculated at an OD of 0.5. 600に Cells were grown at 37°C and 220 rpm until reaching maturity. One milliliter of mid-logarithmic culture was transferred to each well of a 12-well plate, and 10 μM compound or 1% v / v DMSO was added. Cultures were grown at 37°C with shaking for 2 hours at 300 rpm. Cells were harvested by centrifugation, 500 μL of RNAlater was added to halt cellular metabolism and RNA degradation, and total RNA was extracted using the PureLink RNA Mini Kit (Ambion) according to the manufacturer's recommendations. Residual DNA contamination was removed using the Turbo DNA-free Kit (Ambion). Quantitative reverse transcription PCR (qRT-PCR) was performed using the GoTaq 1-step RT-qPCR System Kit (Promega) on a CFX96 Real-Time PCR Detection System (BioRad). Extracted RNA (25 ng) was mixed with 10 μL of GoTaq MasterMix, 1 μL of 8 μM primer, 0.4 μL of GoScript RT mix, and 0.3 μL of carboxy-X-rhodamine (CXR) standard dye in a total volume of 20 μL. RNA polymerase sigma factor D (rpoD) was quantified as a housekeeping gene, and the expression of psmα and RNAIII was normalized to rpoD using the comparative ΔΔCT (CT is the threshold cycle) method.

[0295] Sequence information of the probes used in qRT-PCR for transcript detection (5'-3'): JPEG0007743306000072.jpg31170JPEG0007743306000073.jpg51170

[0296] The main effector of AgrA is RNAIII, which is under the control of the P3 promoter (see Figure 1). RNAIII itself is involved in the regulation of numerous virulence genes, including α-hemolysin. In contrast, psmα is directly regulated by AgrA. Both genes are significantly less expressed in the presence of potent AgrA inhibitors. Legend: 0 = 0-10 fold downregulation, + downregulation >10 fold (1 log 10 ), ++downward adjustment >100x (2log 10 All compounds tested are significantly more potent than savirin in down-regulating psmα and RNAIII.

[0297] Expression and purification of AgrAc: AgrA (AgrAc) 15 To produce the N-labeled C-terminal domain, Escherichia coli BL21(DE3) cells were grown in an M9-based semi-rich medium, [ 15 N]-NH4Cl (1.5 g / liter), unlabeled D-glucose (4 g / liter), Isogro- 15 Cells were grown in M9 medium supplemented with N powder-growth medium (1 g / liter, 10%; Sigma-Aldrich). When the optical density at 600 nm reached approximately 0.8–1.0, the temperature was lowered to 18°C ​​and protein production was induced with 0.4 mM isopropyl-β-D-1-thiogalactopyranoside. Cells were harvested by centrifugation 20 h after induction, resuspended in lysis buffer [50 mM NaHPO / NaHPO (NaPi) pH 7.8, 500 mM NaCl, protease inhibitor cocktail (completely EDTA-free, Roche)], and lysed using a homogenizer (20,000 psi). After removing cell debris by centrifugation (30,000 × g), the resulting supernatant was resuspended in Ni powder-equilibrated [50 mM NaPi pH 7.8, 500 mM NaCl]. 2+ Affinity chromatography (HisTrap column, 5 ml; GE Healthcare Europe) was performed. AgrAc was eluted with a steep imidazole gradient (0–400 mM), and fractions were analyzed by SDS-PAGE (4–20%). 15Selected fractions containing N-AgrAc were pooled and dialyzed against 50 mM NaPi, pH 6.8, 100 mM NaCl, and 4 mM DTT. The protein was concentrated to 200 μM using a Vivaspin Turbo 4 concentrator (cutoff, 5 kDa, Sartorius Stedim Biotech, Aubagne, France), 0.2 μm filtered, flash-frozen in liquid nitrogen, and stored at -80°C. Protein concentration was estimated based on UV absorbance at 280 nm.

Claims

1. Compounds of Formula I (In the formula, R1 is independently halogen, hydroxyl, NO ２ , CN, C optionally substituted by one or more R １ -C ６ - alkyl, C optionally substituted by one or more R １ -C ６ -alkoxy, C optionally substituted by one or more R ３ -C ６ -cycloalkyl, -C ｎ -alkyl-N(R12)(R13) (n=0 to 3), -C ｎ -Alkyl-C(O)N(R12)(R13) (n=0 to 3), -SO ２ -N(R14)-C(O)-R15, -C ｎ -Alkyl-N(R14)-C(O)-R15 (n=0 to 3), -C ｎ -alkyl-C(O)-OR16 (n=0 to 3), -O(C １ -C ３ -alkyl-O) ｍ -C １ -C ３ -alkyl-OR10 (m=0 to 3), -C ｎ -Alkyl-OR16 (n=0 to 3), -NH-C ｎ -Alkyl-R18 (n=0 to 3), -O-C ｎ -Alkyl-R18 (n = 0 to 3), -OPO(OR10) ２ , PO(OR10) ２ and heterocycle optionally substituted by one or more R17; R5 is H; R3 is halogen, hydroxyl, NO ２ , CN, C optionally substituted by one or more R １ -C ６ - alkyl, C optionally substituted by one or more R １ -C ６ -alkoxy, C optionally substituted by one or more R ３ -C ６ -cycloalkyl, -C ｎ -alkyl-N(R12)(R13) (n=0 to 3), -C ｎ -Alkyl-C(O)N(R12)(R13) (n=0 to 3), -SO ２ -N(R14)-C(O)-R15, -C ｎ -Alkyl-N(R14)-C(O)-R15 (n=0 to 3), -C ｎ -alkyl-C(O)-OR16 (n=0 to 3), -O(C １ -C ３ -alkyl-O) ｍ -C １ -C ３ -alkyl-OR10 (m=0 to 3), -C ｎ -Alkyl-OR16 (n=0 to 3), -NH-C ｎ -Alkyl-R18 (n=0 to 3), -O-C ｎ -Alkyl-R18 (n = 0 to 3), -OPO(OR10) ２ , -PO (OR10) ２ and heterocycle optionally substituted by one or more R17; R2 and R4 are independently H, halogen, C optionally substituted by one or more R11 １ -C ６ - alkyl, R6, R7, R8 and R9 are independently H, halogen, hydroxyl, NO ２ , CN, C optionally substituted by one or more R １ -C ６ - alkyl, C optionally substituted by one or more R １ -C ６ -alkoxy, C optionally substituted by one or more R ３ -C ６ -cycloalkyl, -C ｎ -alkyl-N(R12)(R13) (n=0 to 3), -C ｎ -Alkyl-C(O)N(R12)(R13) (n=0 to 3), -SO ２ -N(R12)(R13), -SO ２ -N(R14)-C(O)-R15, -C ｎ -Alkyl-N(R14)-C(O)-R15 (n=0 to 3), -C ｎ -alkyl-C(O)-OR16 (n=0 to 3), -O(C １ -C ３ -alkyl-O) ｍ -C １ -C ３ -alkyl-OR10 (m=0 to 3), -C ｎ -Alkyl-OR16 (n=0 to 3), -NH-C ｎ -Alkyl-R18 (n=0 to 3), -O-C ｎ -Alkyl-R18 (n = 0 to 3), -OPO(OR10) ２ , -PO (OR10) ２ and heterocycle optionally substituted by one or more R17; R10 is H, and optionally one or more C substituted by R11. １ -C ６ - alkyl, said one or more R11 are independently selected from Cl, F and hydroxy; R12, R13, R14, R15 and R16 are independently H, C optionally substituted by one or more R11 １ -C ６ - alkyl, C optionally substituted by one or more R ３ -C ６ -cycloalkyl, -SO optionally substituted by one or more R ２ -C １ -C ６ -alkyl, or said R12 and R13 together with the nitrogen to which they are attached form a heterocycle optionally substituted by one or more R17; The one or more R17 are independently selected from halogen, hydroxy, NO ２ , CN, -N(R12)(R13), -C(O)-R16, -C(O)-OR16, -C ｎ -alkyl-OR16 (n=0-3), optionally substituted by one or more R11 １ -C ６ - alkyl, and C optionally substituted by one or more R １ -C ６ -alkoxy, R18 is selected from -N(R12)(R13), -OR10, -C(O)-R16, -C(O)-OR16, -C(O)-N(R12)(R13), CN, and a heterocycle optionally substituted by one or more R17; one or two of R6, R7, R8 and R9 are independently not H; Pharmaceutically acceptable salts, stereoisomers, enantiomers and tautomers of the compounds of formula (I).

2. The compound of claim 1, wherein R2 and R4 are H.

3. wherein R1 is independently C optionally substituted by one or more R11 １ -C ６ - alkyl, halogen or C １ -C ６ 3. The compound according to claim 1, wherein the alkoxy group is selected from the group consisting of alkoxy, ...

4. The R1 is independently C １ -C ２ -Alkyl, CF ３ 4. The compound of claim 1, wherein the aryl group is selected from the group consisting of aryl, aryl ether, aryl ethers ...

5. wherein R3 is halogen, CN, C optionally substituted by one or more R11 １ -C ６ - alkyl, C optionally substituted by one or more R １ -C ６ -alkoxy, C optionally substituted by one or more R ３ -C ６ -cycloalkyl, -N(R12)(R13), -C(O)N(R12)(R13), -N(R14)-C(O)-R15, -C(O)-OR16, -O(C １ -C ３ -alkyl-O) ｎ -C １ -C ３ -alkyl-OR10 (n=0 to 3), C １ -C ３ -Alkyl-O-C １ -C ３ -alkyl, -OPO(OR10) ２ , -PO (OR10) ２ and a 5-6 membered heterocycle optionally substituted by one or more R17, wherein the heterocycle is aromatic, partially saturated or fully saturated and contains 1 to 4 nitrogen heteroatoms.

6. R3 is C optionally substituted by 1 to 3 R11 １ -C ３ - alkyl or C ３ -C ５ 6. The compound according to any one of claims 1 to 5, wherein the aryl group is selected from the group consisting of -cycloalkyl.

7. wherein R6, R7, R8 and R9 are independently H, halogen, CN, hydroxyl, optionally substituted by one or more F or hydroxyl; １ -C ３－ alkyl, C optionally substituted by one or more F １ -C ３ -alkoxy, C ３ -C ６ -cycloalkyl, -O(C １ -C ３ -alkyl-O) ｎ -C １ -C ３ -alkyl-OR10 (n=0 to 3), -C ｎ -Alkyl-OR16 (n=0 to 3), -NH-C ｎ -Alkyl-R18 (n=0 to 3), -O-C ｎ -alkyl-R18 (n=0-3), and heterocycle optionally substituted by one or more R17.

8. The compound is 7-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 6-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 8-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 9-chloro-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazoline-8-carbonitrile, 3-(2,4-dimethylphenyl)sulfonyl-8-fluoro-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-(2-methoxy-4-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-isopropoxy-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-chloro-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-bromo-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-fluoro-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-(4-methoxy-2-methyl-phenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, N-[4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-phenyl]acetamide, 3-(4-fluoro-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2-bromo-4-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[2-methyl-4-(trifluoromethoxy)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-chloro-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzonitrile, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzoic acid, ethyl 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzoate, 8-methoxy-3-[4-methyl-2-(trifluoromethyl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-cyclopropyl-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(4-ethyl-2-methyl-phenyl)sulfonyl-8-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-methoxy-3-[2-methyl-4-(2H-tetrazol-5-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 4-[(8-methoxy-5-oxo-4H-triazolo[1,5-a]quinazolin-3-yl)sulfonyl]-3-methyl-benzamide, 8-methoxy-3-[2-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 8-bromo-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-6-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(3-methoxypropoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanenitrile, 3-(2,4-dimethylphenyl)sulfonyl-8-iodo-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 8-(azetidin-1-yl)-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-morpholinoethylamino)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(tetrahydropyran-4-ylamino)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-9-hydroxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 2-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]acetonitrile, 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanoate methyl 4-[[3-(2,4-dimethylphenyl)sulfonyl-5-oxo-4H-triazolo[1,5-a]quinazolin-8-yl]oxy]butanamide, 3-(2,4-dimethylphenyl)sulfonyl-8-hydroxy-7-methoxy-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-methoxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one, 3-(2,4-dimethylphenyl)sulfonyl-8-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4H-triazolo[1,5-a]quinazolin-5-one, 8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-(2,4-dimethylphenyl)sulfonyl-4H-triazolo[1,5-a]quinazolin-5-one, and 3-(2,4-dimethylphenyl)sulfonyl-7-hydroxy-8-(2-hydroxyethoxy)-4H-triazolo[1,5-a]quinazolin-5-one.

9. 9. A medicament for reducing bacterial pathogenicity comprising a compound according to formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, tautomer thereof.

10. The pharmaceutical according to claim 9, wherein the bacterium expresses AgrA.

11. 11. The method of claim 10, wherein the bacterium belongs to a genus selected from Staphylococcus, Streptococcus, and Clostridium.

12. The method of claim 11, wherein the bacterium is of the genus Staphylococcus.

13. The method according to claim 12, wherein the bacterium is Staphylococcus aureus.

14. The pharmaceutical of any one of claims 9 to 13, wherein the compound inhibits the synthesis of one or more virulence factors by the bacterium, and the one or more virulence factors are selected from PSMα and RNAIII.

15. 9. A medicament for preventing or treating a disease in a subject, comprising a compound according to formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, tautomer thereof.

16. The pharmaceutical composition of claim 15, wherein the disease is an infectious disease or an inflammatory disease.

17. The method of claim 16, wherein the infectious or inflammatory disease is a bacterial infection or an inflammatory skin disease caused or exacerbated by bacteria.

18. 18. The method of claim 17, wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium.

19. The method of claim 18, wherein the bacterium is of the genus Staphylococcus.

20. The method of claim 19, wherein the bacterium is Staphylococcus aureus.

21. 16. The method of claim 15, wherein the disease is a bacterial infection, including an antibiotic-resistant staphylococcal infection.

22. 22. The method of claim 21, wherein the antibiotic-resistant Staphylococcus infection comprises a methicillin-resistant Staphylococcus aureus (MRSA) infection.

23. 9. A pharmaceutical composition comprising at least one compound according to formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, tautomer thereof, and a pharmaceutically acceptable excipient.

24. 24. The pharmaceutical composition of claim 23, further comprising at least one antibiotic or anti-inflammatory agent active against bacteria.

25. 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises at least one antibiotic active against bacteria.

26. 26. The pharmaceutical composition of claim 25, wherein the bacterium is of a genus selected from Staphylococcus, Streptococcus, or Clostridium.

27. 27. The pharmaceutical composition of claim 26, wherein the bacterium is of the genus Staphylococcus.

28. 28. The pharmaceutical composition of claim 27, wherein the bacterium is Staphylococcus aureus.

Images