CN118526503A

CN118526503A - Compounds for treating or preventing sepsis or sepsis-related conditions

Info

Publication number: CN118526503A
Application number: CN202310176736.3A
Authority: CN
Inventors: 吴剑平; 莫廉; 陈瑞环
Original assignee: Luoda Pharmaceutical Co ltd; LUODA BIOSCIENCES Inc
Current assignee: Luoda Pharmaceutical Co ltd; LUODA BIOSCIENCES Inc
Priority date: 2023-02-23
Filing date: 2023-02-23
Publication date: 2024-08-23
Also published as: WO2024175053A1

Abstract

The present invention provides compounds for use in the treatment or prevention of sepsis or a condition associated with sepsis, the compounds of the present invention are s-triazine derivatives represented by formula a below, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, wherein R ₁、R₂ and Z are defined herein. The invention also includes corresponding pharmaceutical application and methods for treating and preventing diseases.

Description

Compounds for treating or preventing sepsis or sepsis-related conditions

Technical Field

The present invention relates to compounds for treating or preventing sepsis or sepsis-related conditions.

Background

Sepsis is a life threatening organ dysfunction [Singer et al.The Third International Consensus Definitions for Sepsis and Septic Shock(Sepsis-3).JAMA.2016;315:801-10]. caused by a deregulation of the host's response to infection, in the united states, with over 170 thousands of sepsis cases per year, and thus resulting in 27 thousands of deaths [ www.cdc.gov/sepsis ]; there are about 5000 thousands of sepsis cases and 1100 thousands of deaths worldwide each year, and mortality rates exceeding 20％[WHO.Global report on the epidemiology and burden of sepsis:current evidence,identifying gaps and future directions.Geneva:World Health Organization;2020.Licence:CC BY-NC-SA 3.0IGO]. world health organization has seen sepsis as a global health concern. Unfortunately, over the last thirty years, all drugs used in sepsis experiments have failed to show clinical efficacy, probably because none of these drugs can address the complex pathological processes of the disease [Cavaillon et al.Sepsis therapies:learning from 30years of failure of translational research to propose new leads.EMBO Mol Med.2020;12(4):e10128].

Common pathological features of sepsis include pathogen infection, excessive inflammation, immunosuppression, catabolism (Catabolism), and the like. All sepsis patients routinely use broad-spectrum antibiotics after diagnosis. Although bacteria are the most common infectious pathogen that causes sepsis, fungi, parasites and viruses are also possible causes of sepsis. Medical emergencies have little time to identify causative agents by blood culture, and patients in Intensive Care Units (ICU) often develop Multiple Drug Resistant (MDR) infections, both of which limit the effectiveness of antibiotics in sepsis. Corticosteroids have been used clinically to reduce excessive inflammation in septic patients, but their effectiveness remains uncertain [Lamontagne et al.Corticosteroid therapy for sepsis:aclinical practice guideline.BMJ.2018;362:k3284]. because severe septic patients experience both excessive inflammation and immunosuppression, and corticosteroids reduce inflammation by suppressing the immune system, thus exacerbating the infection. No other anti-inflammatory agent showed any efficacy in the treatment of sepsis. Clinically, the treatment of septicemia is mainly supported or symptomatic treatment such as body fluid supplementation, pressure boosting and the like except antibiotics. At present, no medicine can have anti-inflammatory and anti-immunosuppression effects at the same time, and no medicine can reverse catabolism to normal metabolism. An effective anti-sepsis drug must have multiple effects against the complex pathogenesis of the disease. Vimentin intermediate filaments are involved in many cytopathic processes associated with sepsis pathogenesis [ Ridge et al, roles of VIMENTIN IN HEALTH AND diseases, genes dev.2022;36:391-407]. We demonstrate that targeting vimentin can treat sepsis using small molecule compounds that target vimentin.

Disclosure of Invention

In a first aspect, the present invention provides the use of a s-triazine derivative represented by formula a, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, in the manufacture of a medicament for treating or preventing sepsis or a condition associated with sepsis:

Wherein:

R ₁ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₁₂ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkylamino, di C ₁-C₆ alkylamino, hydroxymethyl or aminomethyl;

R ₂ is-NR ₄R₅,R₄ and R ₅ are independently selected from hydrogen, C ₁-C₆ alkyl and C ₁-C₆ haloalkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O and S, which heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, wherein R ₆ is hydrogen, hydroxy, C ₁-C₆ alkyl or C ₁-C₆ haloalkyl;

Z is aryl or heteroaryl optionally substituted with 1-3R ₃; preferably, the aryl is a 6-14 membered aryl, such as phenyl or naphthyl; the heteroaryl is a 5-10 membered heteroaryl, preferably a nitrogen containing heteroaryl, including but not limited to imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl and tetrazolyl; preferably, Z is phenyl or pyridinyl optionally substituted with 1 or 2R ₃;

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₁₂ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkylamino, di C ₁-C₆ alkylamino, hydroxymethyl, aminomethyl or-COR _a;

R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from hydrogen, C ₁-C₆ alkyl optionally substituted with one or more substituents selected from halogen or NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a4 to 6 membered heterocycle optionally substituted with C ₁-C₆ alkyl optionally containing additional heteroatoms selected from N, O and S;

R ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a4 to 6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; and

X is NH or O, and is connected with the meta position or para position of phenyl.

In a second aspect, the invention provides a method of treating or preventing sepsis or a condition associated with sepsis, the method comprising administering to a subject or individual in need thereof a therapeutically or prophylactically effective amount of a s-triazine derivative represented by formula a herein, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, or a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a s-triazine derivative represented by formula a herein, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof.

In a third aspect, the invention provides a s-triazine derivative, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, of formula a herein, or a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a s-triazine derivative, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, of formula a herein, for use in the treatment or prophylaxis of sepsis or sepsis-related condition.

The compounds of formula A for use in the methods and uses of any of the above aspects herein are preferably compounds described in any of the embodiments below, including in particular the compounds described by formulas I-1, I-2, I-3 and A-1, and each of the specific compounds listed in the tables.

Drawings

Fig. 1: compound C52 significantly reduced the severity and death of CLP-induced sepsis mice. A: experimental protocol. C57BL/6J mice received sham surgery or CLP surgery, and mice were given vehicle or C52 compound (0.2 mg/kg or 1 mg/kg) by oral gavage daily 10 minutes before surgery and on days 1 to 6 post-surgery on the same day, and surviving animals were sacrificed on day 7 post-surgery. B: mice survived 7 days (n=10 per group) P <0.01Log-Rank test. C: disease severity was scored daily for 7 days. Data are expressed as mean ± SEM (initial animals per group 10, animals at different time points reduced by death). * P <0.01, mann-WhitneyU test.

Fig. 2: compound C52 significantly reduced inflammatory factors in the systemic blood circulation of CLP-induced sepsis mice. A: experimental protocol. Sham surgery or CLP surgery was performed on C57BL/6J mice. Mice were given lysozyme or C52 compound (0.2 mg/kg or 1 mg/kg) by oral gavage 10 minutes before surgery and 16 hours after surgery, respectively, and samples were taken 24 hours after surgery. B-C: the concentrations of TNF- α (B) and IL-6 (C) in the serum of mice 24 hours after the operation were determined using ELISA. Data are expressed as mean ± SEM (n=6 per group), P <0.05, P <0.01, mann-WhitneyU test.

Fig. 3: compound C52 significantly reduced the expression of inflammatory factors in specific organs (lungs) of septic mice. a-C: IL-1 beta (A), IL-6 (B) and TNF-alpha (C) mRNA levels in the lungs were assessed by RT-qPCR. Data are expressed as mean ± SEM (n=6 per group), P <0.05, P <0.01, mann-WhitneyU test.

Fig. 4: compound C52 significantly reduced acute injury to lung tissue in septic mice. A: representative lung histopathological images of sham operated mice and CLP operated mice treated with vehicle or compound C52 (1 mg/kg or 0.2 mg/kg). Scale bar: 200 microns. B: h & E stained lung tissue sections were semi-quantitatively scored for bleeding, alveolar hyperemia, neutrophil infiltration, and alveolar space size to assess lung histopathological lesions. C: the severity of pulmonary edema is measured by determining the wet-to-dry weight ratio of the lung tissue. Data are expressed as mean ± SEM (n=6 per group), P <0.01, mann-Whitney U test.

Detailed Description

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute a preferred technical solution.

The inventors have previously developed compounds that bind to vimentin with a core structure of s-triazine (US 10,611,736). The invention selects a specific representative s-triazine derivative, and uses the animal model of Cecal Ligation Perforation (CLP) which is most commonly used and is most relevant to human septicemia to evaluate the anti-septicemia effect of a small molecular compound of the targeting vimentin. The present invention has found that oral administration of compound C52 not only reduces disease severity, but also reduces mortality in animals. Further analysis shows that the compound can reduce the content of inflammatory cytokines TNFa and IL-6 in blood, which are closely related to septicemia, and reduce the gene expression level of TNFa, IL-6 and IL 1-beta in lung tissues, thereby reducing acute lung injury and pulmonary edema. Thus, such s-triazine derivatives have preventive and therapeutic effects on sepsis.

The s-triazine derivative of the present invention preferably has a structural formula represented by the following formula a:

Wherein:

Z is aryl or heteroaryl optionally substituted with 1-3R ₃;

Preferably, in Z of formula A, aryl is a 6-14 membered aryl, such as phenyl or naphthyl; heteroaryl is a 5-10 membered heteroaryl, preferably a nitrogen containing heteroaryl, including but not limited to imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl and tetrazolyl. Preferred Z is phenyl or pyridinyl optionally substituted with 1 or 2R ₃.

The s-triazine derivatives of the present invention are preferably those described in US 16/300,162, the entire contents of which are incorporated herein by reference. More specifically, the s-triazine derivative of the present invention is a2, 4, 6-trisubstituted s-triazine compound having a structure represented by the following formula I:

Wherein:

The s-triazine derivatives used in the present invention also include pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers or solvates of the compounds of formulae A and I.

In formula a and formula I, preferably, R ₁ is hydrogen, halogen or nitro, more preferably H, F, cl or nitro.

In formulas A and I, preferably, R ₂ is-NR ₄R₅,R₄ and R ₅ are independently selected from hydrogen, C ₁-C₆ alkyl and C ₁-C₆ haloalkyl, Or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O and S, which heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, Wherein R ₆ is hydrogen, hydroxy or C ₁-C₆ alkyl. Preferably, R ₄ and R ₅ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form an optionally further group selected from NR ₆, A 4-6 membered saturated heterocyclic ring of heteroatoms of O and S, which heterocyclic ring may be substituted with hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, wherein R ₆ is hydrogen or C ₁-C₆ alkyl. Preferably, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered saturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆ and O, said heterocyclic ring being optionally substituted with a substituent selected from hydroxy and C ₁-C₆ alkyl, Wherein R ₆ is hydrogen or C ₁-C₆ alkyl. The number of substituents on the heterocycle is typically 1, 2 or 3. Preferably, the 4-6 membered saturated heterocyclic ring includes, but is not limited to, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, and azetidinyl.

In formulas A and I, preferably, R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from hydrogen, C ₁-C₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉R₁₀ and C ₁-C₆ alkyl substituted by 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S optionally substituted by C ₁-C₆ alkyl; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form an optionally further group selected from N, O, S are 4-to 6-membered heterocycles of heteroatoms. preferably, R ₃ is halogen, C ₁-C₆ alkoxy or-COR _a,R_a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O optionally substituted by C ₁-C₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O. preferably, the method comprises the steps of, The heterocyclic ring formed by R ₇ and R ₈ together with the nitrogen atom to which they are attached and the heterocyclic ring formed by R ₉ and R ₁₀ together with the nitrogen atom to which they are attached include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, and morpholinyl. Preferably, when R ₃ is a non-H substituent, it is typically located in the meta or para position of the phenyl group.

In formulas A and I, preferably, X is NH, attached to the para or meta position of the phenyl group; or X is O and is connected with para position of phenyl.

In a preferred embodiment, formula a and formula I are shown:

R ₁ is hydrogen, halogen or nitro;

R ₂ is-NR ₄R₅,R₄ and R ₅ are independently selected from hydrogen, C ₁-C₆ alkyl and C ₁-C₆ haloalkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O and S, which heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, wherein R ₆ is hydrogen, hydroxy or C ₁-C₆ alkyl; and

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from hydrogen, C ₁-C₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉R₁₀ and C ₁-C₆ alkyl substituted by 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S optionally substituted by C ₁-C₆ alkyl; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form an optionally further group selected from N, O, S are 4-to 6-membered heterocycles of heteroatoms.

In a preferred embodiment, formula a and formula I are shown:

R ₁ is hydrogen, halogen or nitro;

R ₂ is-NR ₄R₅,R₄ and R ₅ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from NR ₆ and O, said heterocyclic ring optionally being substituted with a substituent selected from hydroxy and C ₁-C₆ alkyl, wherein R ₆ is hydrogen or C ₁-C₆ alkyl;

R ₃ is halogen or-COR _a,R_a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl optionally substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally substituted with C ₁-C₆ alkyl optionally containing a further heteroatom selected from N or O; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O; and

X is NH, and is connected with para position or meta position of phenyl.

In certain embodiments, preferably, in formula a and formula I:

R ₁ is hydrogen, halogen or nitro;

R ₂ is-NR ₄R₅,R₄、R₅ independently selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O, S, which heterocyclic ring may be substituted with hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, wherein R ₆ is hydrogen, hydroxy, C ₁-C₆ alkyl;

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl, -CONR ₇R₈, wherein R ₇、R₈ is independently selected from hydrogen, C ₁-C₆ optionally substituted alkyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; wherein the C ₁-C₆ alkyl group is optionally substituted with one or more substituents selected from halogen, C ₁-C₆ alkylamino and di C ₁-C₆ alkylamino;

X groups are meta-position and para-position NH or O.

In certain embodiments, more preferably, in formula a and formula I:

R ₁ is hydrogen, halogen or nitro;

R ₂ is-NR ₄R₅,R₄、R₅ independently selected from hydrogen, C ₁-C₆ alkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O, S, which heterocyclic ring may be substituted with hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, R ₆ is hydrogen, C ₁-C₆ alkyl;

R ₃ is hydrogen, halogen or-CONR ₇R₈ wherein R ₇、R₈ is independently selected from hydrogen, optionally substituted C ₁-C₆ alkyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; wherein the C ₁-C₆ alkyl group is optionally substituted with one or more substituents selected from the group consisting of C ₁-C₆ alkyl-substituted amino and di C ₁-C₆ alkyl-substituted amino;

X groups are meta-position and para-position NH or O.

In a preferred embodiment, the compounds of formula I herein have the structure shown in formula I-1 or formula I-2 below:

in the method, in the process of the invention,

R ₁ is selected from H, halogen and nitro;

R ₂ is selected from morpholinyl, pyrrolidinyl, piperazinyl, and azetidinyl optionally substituted with hydroxy or C ₁-C₆ alkyl; and

R ₃ is halogen or COR _a; wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally substituted with C ₁-C₆ alkyl optionally containing an additional heteroatom selected from N or O; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O.

Preferably, in formula I-2 above, R ₃ is halogen.

Preferably, in formula I-1 above, R ₁ is selected from H and halogen (preferably Cl); r ₂ is selected from morpholinyl (preferably morpholino); r ₃ is halogen or COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally substituted by C ₁-C₆ alkyl optionally containing a further heteroatom selected from N or O, preferably piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl, more preferably piperidinyl or piperazinyl substituted by C ₁-C₄ alkyl.

In a preferred embodiment, the compounds of formula I herein have the structure shown in formula I-3 below:

in the method, in the process of the invention,

R ₁ is H;

R ₂ is morpholinyl;

R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally substituted with C ₁-C₆ alkyl optionally containing a further heteroatom selected from N or O; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O.

In certain embodiments of formula I-1, R ₁ is selected from H, halogen, and nitro; r ₂ is morpholinyl; r ₃ is halogen or COR _a; Wherein, R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from the group consisting of C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O optionally substituted by C ₁-C₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O. In certain embodiments, in these compounds, R ₁ (when a non-hydrogen substituent) and R ₃ are each independently located meta or para to the phenyl group. In certain embodiments, where R ₁ is a non-hydrogen substituent, R ₃ is located in the meta-position to the phenyl group. in certain embodiments, the saturated heterocyclic ring in these compounds includes, but is not limited to, piperazinyl, piperidinyl, pyrrolidinyl, and morpholinyl.

Preferably, the compound of formula A has the structure shown in formula A-1 below:

Wherein:

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-CONR ₇R₈ wherein R ₇、R₈ is independently selected from hydrogen, C ₁-C₆ optionally substituted alkyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; wherein C ₁-C₆ alkyl may be optionally substituted with one or more substituents selected from halogen, mono-C ₁-C₆ alkyl substituted amino, di-C ₁-C₆ alkyl substituted amino.

Preferably, in formula A-1, R ₃ is H or halogen.

Preferably, the compounds of formula a of the present invention are selected from the following compounds L1-L42 and pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers and solvates:

Compound L42 (C52M):

the compounds of formula a described herein may be prepared by reference to the methods disclosed in US 16/300,162.

Herein, "alkyl" refers to a C ₁-C₁₂ alkyl group, such as a C ₁-C₆ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, and the like.

"Heterocycle" refers to a4 to 6 membered heterocycle optionally containing heteroatoms selected from N, O and S. The heterocycle may be a saturated heterocycle or an unsaturated heterocycle. Exemplary heterocycles include, but are not limited to, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, pyrazolyl, and the like.

"Halogen" includes F, cl, br and I.

"Carboxy" refers to-COOH.

In "3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl", the alkynyl position of C ₂-C₆ alkynyl is generally at position 1. In certain embodiments, the "3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl" is "3- (1-butyn-4-yl) -3H-bisaziridin-3-yl".

Herein, NR ₇R₈ and NR ₉R₁₀ may be mono-C ₁-C₆ alkylamino or di-C ₁-C₆ alkylamino, said C ₁-C₆ alkyl optionally being substituted, for example by one or more halogen, mono-C ₁-C₆ alkylamino or di-C ₁-C₆ alkylamino groups, or by a 4 to 6 membered saturated heterocyclic ring containing N and optionally additional N or O. Such heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and the like. The heterocyclic ring may also be optionally substituted, for example by a C ₁-C₆ alkyl group.

Herein, "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 14 carbon atoms, more preferably having 6 to 10 carbon atoms, e.g., 6, 7, 8, 9, or 10 carbon atoms). Aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. Examples of aryl groups described in the various embodiments herein include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms, for example 1,2, 3,4, 5,6,7, 8, 9 or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups described in the embodiments herein include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, benzindolyl, benzomorpholinyl, benzisoxazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, benzothienyl, indolizinyl, phthalazinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4, 6-tetrahydro [1, 4b ] 1, 4-imidazo [1, 4-b ] 1, 4-triazolo [ 2-b ] 1, 4-b ] 1-triazolo [ 2.

Herein, when a group is substituted, the number of substituents may be, for example, 1, 2, 3, or 4, or not. Typically, unless otherwise indicated, substituents may be selected from halogen, C ₁-C₆ alkyl, hydroxy, carboxy, amino, mono C ₁-C₆ alkylamino, di C ₁-C₆ alkylamino, nitro, 3- (C ₂-C₆ alkynyl) -3H-biazetidinyl, heterocyclyl (e.g., morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, pyrazolyl, and the like), and C ₆-C₁₄ aryl (e.g., phenyl), and the like.

The relative terms such as "isomer," "racemate," "prodrug," "solvate," as used herein do not differ significantly from the ordinary meaning of the terms described in the art. Those of ordinary skill in the art will recognize the meaning of these terms. For example, the term "isomer" refers to one of two or more compounds that have the same molecular composition but different structures and properties. The term "racemate" refers to an equimolar mixture of optically active chiral molecules and their enantiomers. The term "prodrug" also refers to prodrugs, etc., which are compounds that have pharmacological effects after being converted in vivo. The term "solvate" refers to a mixture of a solvent and a compound.

Herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

Herein, "pharmaceutically acceptable acid addition salt" refers to a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

Herein, "pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

Examples of prodrugs of the compounds of the present invention may include simple esters of carboxylic acid-containing compounds (e.g., esters obtained by condensation with a C1-4 alcohol according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C1-4 carboxylic acids, C3-6 diacids, or anhydrides thereof such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of amino-containing compounds (e.g., imines obtained by condensation with C1-4 aldehydes or ketones according to methods known in the art); carbamates of amino-containing compounds, such as those described by Leu et al (J.Med. Chem.,42:3623-3628 (1999)) and Greenwald et al (J.Med. Chem.,42:3657-3667 (1999)). Aldols or ketals of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

The present invention relates to the use of a compound of formula a (including the compound of formula I, the compound of formula I-1, the compound of formula I-2, the compound of formula I-3, and the compound of formula a-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, as described herein, in the manufacture of a medicament for treating or preventing sepsis or a condition associated with sepsis. The invention also relates to a compound of formula a (including the compound of formula I, the compound of formula I-1, the compound of formula I-2, the compound of formula I-3, and the compound of formula a-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, and pharmaceutical compositions thereof, as described herein, for use in treating or preventing sepsis or a condition associated with sepsis. Also included herein are methods of treating or preventing sepsis or a condition associated with sepsis, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula a described herein (including the compound of formula I, compound of formula I-1, compound of formula I-2, compound of formula I-3, and compound of formula a-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, or administering a therapeutically or prophylactically effective amount of a pharmaceutical composition described herein.

Herein, "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium recognized in the art for delivery of a biologically active compound to a mammal (e.g., a human). Such vehicles include all pharmaceutically acceptable carriers, diluents or excipients thereof.

Herein, a "therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result (e.g., decrease disease severity, increase survival) at the requisite dosage and for the requisite period of time. The therapeutically effective amount of the compound can vary depending on factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. The dosing regimen may be adjusted to provide the optimal therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are exceeded by the therapeutically beneficial effect. By "prophylactically effective amount" is meant an amount effective to achieve the desired prophylactic result (e.g., reducing the condition, reducing mortality, reducing inflammation and inflammatory factors, reducing complications and sequelae) at the requisite dosage and for the requisite period of time. Typically, a prophylactic dose is used in a subject prior to or at an early stage of the disease, such that the prophylactically effective amount can be less than the therapeutically effective amount. In preferred embodiments, the amount of the compounds described herein administered is sufficient to exert a therapeutic and prophylactic effect on sepsis or sepsis-related conditions by affecting the structure and function of vimentin intermediate filaments.

As used herein, "treating" encompasses treatment of a disease or condition of interest in a mammal (preferably a human) having the disease or condition of interest, and includes:

(i) Preventing the disease or condition from occurring in a mammal, particularly when the mammal is susceptible to the condition but has not been diagnosed with the condition;

(ii) Inhibiting the disease or condition, i.e., suppressing its development;

(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition; or (b)

(Iv) Alleviating symptoms caused by the disease or condition, i.e., alleviating pain without addressing the underlying disease or condition.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. Methods of administration known in the art may be used in the present invention. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The skilled artisan is familiar with the techniques of administration that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa.

The compounds herein are directed to vimentin-mediated treatment and prevention of sepsis or sepsis-related conditions. Specifically, the compound can inhibit the cytopathic process related to the pathogenesis of the sepsis, which is participated by the vimentin intermediate filament, through combining with the vimentin and/or affecting the structure and the function of the vimentin intermediate filament, thereby achieving the effect of treating or preventing the sepsis or the illness related to the sepsis.

Herein, preferably, the sepsis-associated condition includes, but is not limited to, organic and/or functional damage to tissues, organs, systemic inflammatory cytokine production, and/or cells, tissues, and organs caused by immune disorders resulting from pathogen infection. Herein, the effect of the compounds of the invention on tissue, organ and systemic inflammation is measured by measuring the protein amount of inflammatory cytokines, mRNA expression levels in tissue organs, respectively, in body fluids of sepsis patients. The cytokine is a cytokine that plays a critical role in sepsis, in certain embodiments, the cytokine is IL-1β, TNF- α, and IL-6. The term "body fluid" as used herein includes blood, serum, sweat or urine. In certain embodiments, the bodily fluid is serum. In this context, the organic and/or functional lesions of cells, tissues and organs include pulmonary oedema and/or acute lung injury, such as alveolar effusion, interstitial oedema, hemorrhage, necrosis and immune cell infiltration.

Herein, the pathogen is one or more of bacteria, viruses, fungi and parasites. The pathogen can be identified or difficult to identify clearly by blood culture.

In a preferred embodiment, this document relates to a method of preparing a compound of formula A (including the compound of formula I, the compound of formula I-1, the compound of formula I-2, the compound of formula I-3, and the compound of formula A-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, as described herein, for the treatment or prevention of a pathogen infection or a disease caused by a pathogen infection. The method comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula a described herein (including the compound of formula I, the compound of formula I-1, the compound of formula I-2, the compound of formula I-3, and the compound of formula a-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, or a therapeutically or prophylactically effective amount of a pharmaceutical composition described herein.

Herein, the individual or subject is preferably a mammal, more preferably a human.

Herein, therapeutic benefit may be achieved by simultaneous or sequential administration of at least 1,2,3, or more of the compounds described herein. The compounds or pharmaceutical compositions described herein may also be combined with other therapies to provide a combined therapeutically effective dose. For example, the compounds or pharmaceutical compositions described herein may be administered in combination with other drugs, preferably antibacterial or viral drugs.

The pharmaceutical compositions provided herein may contain a compound of formula a described in any of the embodiments herein (including the compound of formula I, the compound of formula I-1, the compound of formula I-2, the compound of formula I-3, and the compound of formula a-1) or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

Herein, "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, humectant, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by, for example, the U.S. Food and Drug Administration (FDA) for use in humans or farm animals. Typically, the pharmaceutically acceptable carrier is an inert diluent.

The pharmaceutical composition of the invention comprises a compound shown in a formula I-1, pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, tautomer or solvate thereof, wherein R ₁ is selected from H and halogen (preferably Cl), and more preferably H; r ₂ is selected from morpholinyl (preferably morpholino); r ₃ is halogen or COR _a, more preferably halogen; r _a is OH or NR ₇R₈,R₇ and R ₈ together with the nitrogen atom to which they are attached form a4 to 6 membered saturated heterocyclic ring optionally substituted with C ₁-C₆ alkyl optionally containing an additional heteroatom selected from N or O, preferably piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl, more preferably piperidinyl or piperazinyl substituted with C ₁-C₄ alkyl. More preferably, the pharmaceutical composition of the invention contains compounds C50 and/or C52.

The pharmaceutical compositions herein may take a variety of forms to suit the route of administration selected. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable compositions of the compounds described herein. Those skilled in the art will recognize that a wide variety of non-toxic pharmaceutically acceptable solvents can be employed to prepare solvates of the compounds of the present invention.

The pharmaceutical compositions of the present invention may be in a variety of suitable dosage forms including pills, capsules, elixirs, syrups, troches, lozenges and the like. The pharmaceutical compositions of the present invention may be administered by a variety of suitable routes including oral, topical, parenteral, inhalation or spray or rectal administration and the like. The term "parenteral" as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or similar injection or infusion techniques.

Pharmaceutical compositions containing the compounds of the present invention are preferably in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs.

Compositions for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may comprise one or more agents selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives. In order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents including calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The aqueous suspension contains the active substance in admixture with excipients which are suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia. Dispersing or wetting agents, which may be naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptaoctadecanol ethyleneoxycetyl alcohol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene sorbitol monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those described above may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or a mixture of these. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols; anhydrides such as sorbitan monooleate; condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavouring and colouring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions of the invention may also be administered in the form of suppositories, e.g. for rectal administration. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Or the composition may be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffers may be dissolved in the vehicle.

For administration to non-human animals, the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Moreover, it would be convenient to formulate animal feed and drinking water products so that the animals can ingest the appropriate amount of the compound in their diets. For further ease of administration, the compounds may be present in the composition as a premix for addition to feed or drinking water. The composition may also be added as a food or beverage supplement to humans.

Dosage levels useful in the treatment of the above conditions include about 1mg to about 500mg per day, about 5mg to about 150mg per day, more preferably about 5mg to about 100mg per day. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the condition being treated and the particular mode of administration.

The frequency of administration may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most diseases, a dosage regimen of 3 times per day or less is preferred. However, it will be appreciated that the specific dosage level for any particular patient will depend on a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Preferred compounds of the invention will have desirable pharmacological properties including, but not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-life. For compounds used in the treatment of central nervous system disorders, it is necessary to penetrate the blood brain barrier, whereas for the treatment of peripheral disorders it is generally preferred that the compounds have low exposure levels in brain tissue. For the treatment of organ-specific diseases, it is preferred to enrich the exposed compounds in the organ and to expose the smallest compounds in other organs or the whole body.

The amount of composition required for treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the disease being treated and the age and condition of the patient, and will ultimately depend on the attending physician or clinician.

The invention will be illustrated in the form of specific embodiments. It should be understood that these examples are illustrative only and are not intended to limit the scope of the invention. The methods and materials used in the examples, unless otherwise indicated, are those conventional in the art and commercially available.

Preparation example

The compounds of formula A may be prepared by reference to the methods disclosed in U.S. Pat. No. 16/300,162.

The preparation of compound L42 (C52M) is given below by way of example.

Step 1

A solution of 1 (3.0 g,23.3 mmol) in dioxane (50 mL) was cooled to 10deg.C, then DIEA (4.0 g,46.6 mmol) and phenyl chloroformate (4.0 g,25.6 mmol) were added dropwise under nitrogen. After addition, the mixture was warmed to room temperature and stirring continued until complete. The mixture was cooled to 10 ℃ and quenched with saturated aqueous NaHCO ₃. NaHCO ₃ solution (50 mL) was separated and the aqueous layer extracted with EA (100 mL. Times.2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated, and the residue was triturated with MeOH (20 mL) to give the desired product, compound 2 (2.5 g, 43%) as an off-white solid.

Step 2

To a solution of C52 intermediate-C (prepared as described in U.S. Pat. No. 16/300,162, 1.0g,2.67 mmol) in DMSO (15 mL) under nitrogen, DIEA (861 mg,6.68mmol,2.5 eq) was added compound 2 (1.3 g,5.34mmol,2 eq) and the mixture stirred at 60℃for 2 hours. TLC and LCMS detection indicated that the reaction was complete. The mixture was diluted with water (40 mL) and the solid formed was filtered, washed with MeOH and dried to give the desired product C52M (900 mg, 64%) as an off-white solid.

Examples

Example 1: s-triazine derivatives, such as C52, that bind to vimentin can significantly reduce the severity of sepsis and greatly reduce mortality in septic animals.

Materials and methods

Chemical synthesis: all reagents used in the synthesis reached or were above the chemically pure grade. The final product was purified by column chromatography and characterized by ¹H NMR,¹³ C NMR, high resolution MS and HPLC. Purity equal to or higher than 95%.

Animals: SPF male C57BL/6J mice (18-20 g) of 6-8 weeks old were purchased from Shanghai SLAC laboratory animal Co., ltd (Shanghai China) and bred in Nanjing university of Chinese medicine laboratory animal center. The temperature of the animal facility is kept between 20 ℃ and 25 ℃, the relative humidity is kept between 40% and 70%, and the animal facility is regularly light and dark cycled. The mice can eat and drink water freely. All experimental procedures were performed according to the institutional guidelines issued by the ethical committee of the university of chinese medicine in south kyo (ethical approval No. 202207a 066). Animal care is provided according to IACUC approved guidelines.

Model and treatment method: mice were randomized into four groups for mortality studies and four groups for inflammation and tissue injury studies. Cecal Ligation Perforation (CLP) model was used. These four groups were sham + vehicle, CLP +0.2mg/kg of C52 compound and CLP +1mg/kg of C52 compound. Sham surgery refers to surgery performed without ligating and perforating the cecum. The mice were anesthetized with tribromoethanol, a midline incision was made to expose the cecum, the cecum 1cm from its distal end was ligated with 3-0 silk, a 21 gauge needle was used to puncture once, a small amount of stool was gently squeezed out, and the cecum was returned to its normal intra-abdominal position. The abdomen was closed with intermittent suturing and the skin was closed with tissue cement (3M, minnesota mining company). Then, 1mL of physiological saline was subcutaneously injected for resuscitation. In mortality study, each group of mice was given vehicle or C52 compound, respectively, 10min prior to surgery, followed once daily for 6 days and the experiment was ended on day 7. In the inflammation and tissue injury study, each group of mice was given vehicle or C52 compound 10min before surgery and 16 hours after surgery, respectively, and blood and tissue samples were taken 24 hours after surgery.

Disease severity assessment: each mouse was scored for disease severity based on its self-grooming, mobility, body posture, weight loss, wherein self-grooming: 0, (normal); 1, a tarnished/matted (dusty) pelt; 2. the fur becomes upright or scattered. Degree of activity: 0, no stimulatory activity (normal); 1, reduced (decreased) response/activity to stimulus, 2, retarded (motionless) response to stimulus. Body posture: 0, fully extended (normal), 1, bow back, 2, rest position, side lying. Weight loss: 0, minimal weight loss (< 10%), wherein weight loss occurring in sham surgical controls is adjusted to reduce the impact of surgery, 1, mild wasting (10-14.9%); 2. severe wasting (15-19.9%). The disease severity score is calculated as the sum of all class scores. Mice dead received the highest score on the day of death (8), after which they were removed from the score. Score ranges from 0 to 2 are defined as healthy; from 3 to 5, moderate disease; from 6 to 8, severe disease.

Statistical analysis: statistical analysis was performed using graphpatrism 6.0 software. Descriptive results are expressed as mean ± SEM. Survival curves were plotted using the Kaplan-Meier method. Statistical comparison variance (multiparameter analysis for two or more separate groups) tests were performed using a two-tailed student t-test (for two separate groups; mann-WhitneyU test if the variances were not equal), a one-way analysis of variance (for >2 separate groups) or a two-way analysis. p <0.05 is considered statistically significant.

Results and conclusions

To study the therapeutic effect of vimentin-targeted compounds in sepsis, we used representative compound C52 and selected mortality as the most relevant primary assessment index and disease severity as the second assessment index, since mortality is common in human sepsis and is a gold standard without blurred space. Since the compound took about 2 hours to reach the peak systemic exposure (Li et al.A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19and Related Diseases.mBio.2021Oct 12:e0254221), and the proinflammatory cytokine reached the highest level within 6 hours after CLP after oral administration, we treated the mice before surgery (10 minutes), this dosing and prevention regimen was closer to the treatment regimen and provided sufficient time for the drug to act before the whole cytokine storm (fig. 1, a). All mice in the sham group that had undergone surgery but did not undergo Cecal Ligation and Puncture (CLP) survived to the end of the study (mortality rate of 0%) and only developed minimal symptoms for a short period of time after surgery. In contrast, half of the mice with CLP in the vehicle-treated group died rapidly on the first two days post-surgery, with only 20% of the mice surviving on day 7 (80% mortality), and correspondingly, the animals in this group were scored higher for disease severity. Treatment with C52 compound significantly delayed the death time and reduced 7-day mortality to 50% in the 0.2mg/kg C52 compound group and further to 20% in the 1mg/kg C52 compound group (fig. 1, b). The disease severity score was also significantly lower in the C52 compound (1 mg/kg) treated mice than in vehicle treated mice (fig. 1, C). The observed dose-dependent improvement in disease symptoms and survival following treatment with the C52 compound further demonstrates the effectiveness of the compound in treating sepsis.

Example 2: s-triazine derivative representative compound C52 significantly reduces systemic inflammation in septic mice

Materials and methods

Animal, modeling, treatment methods, sample collection and result statistics: as in example 1.

Serum cytokine analysis: to quantify the protein levels of inflammatory cytokines in serum, mice from each group were anesthetized with isoflurane and blood samples were collected from the orbital venous plexus. Blood samples were centrifuged at 3500rpm/min for 20 minutes at 4℃and serum was collected and stored at-80℃for further use. The amounts of proteins of the inflammatory cytokines TNF- α and IL-6 were measured by ELISA kit (Biolegend, USA).

Results and conclusions

In view of the exact efficacy of compound C52 in reducing symptoms and mortality in CLP sepsis mice, we subsequently conducted a separate in vivo study aimed at understanding the effect of this compound on cytokines that play a key role in this model as well as in human sepsis. Mice were treated with vehicle or different doses of compound C52 10 minutes before CLP and 16 hours post-surgery, respectively (fig. 2, a). 24 hours post-surgery, both IL-6 and TNF- α serum protein levels were significantly higher in CLP sepsis mice than in sham surgery control mice (p < 0.01). Serum TNF- α was significantly reduced (p < 0.05) to levels comparable to sham control mice in CLP mice treated with 1mg/kg of compound C52 (fig. 2, b). IL-6 is the most elevated cytokine (up to 1,000 fold) in serum from CLP mice. Compound C52 at 0.2mg/kg and 1mg/kg significantly (p < 0.01) reduced serum IL-6 levels 24 hours after CLP (FIG. 2, C). Compound C52 dose-dependently reduced the levels of cytokines TNF- α and IL-6 in blood. These results indicate that compound C52 significantly reduced systemic inflammation in septic mice.

Example 3: s-triazine derivative representative compound C52 significantly reduces the production of local inflammatory factors in lung organs of septic mice

Materials and methods

Quantitative gene expression by RT-qPCR: RT-qPCR was used to measure mRNA levels of target genes (IL-1. Beta., IL-6 and TNF-. Alpha.) in lung and liver tissues. Briefly, total RNA was extracted from mouse lung and liver tissues using RNA preparation pure tissue kit (tengen, DP 431) and Trizol reagent (Invitrogen), respectively. cDNA was generated using HISCRIPTII one-step RT-PCR kit (Vazyme, P612-01) and β -actin was used as an internal reference. The specific primer set (Pishgam Biotech Company, delaviran, iran) for each gene is IL-1βForward：GAAATGCCACCTTTTGACAGTG(SEQ IDNO：1),Reverse：TGGATGCTCTCATCAGGACAG(SEQ ID NO：2);TNF-αForward：AAGGCCGGGGTGTCCTGGAG(SEQ ID NO：3),Reverse：AGGCCAGGTGGGGACAGCTC(SEQ ID NO：4);IL-6Forward：CCACTTCACAAGTCGGAGGCTTA(SEQ ID NO：5),Reverse：AGTGCATCATCGTTGTTCATAC(SEQ ID NO：6).SYBR Green 5PCR Master Mix(TOYOBO) for quantification of mRNA levels. The Polymerase Chain Reaction (PCR) reaction was set up as follows: a total of 40 cycles of 95 ℃ (30 seconds), 95 ℃ (5 seconds), 60 ℃ (31 seconds). Reactions were performed in triplicate and relative mRNA expression was calculated using the 2 ^-△△Ct method.

Results and conclusions

Although sepsis is characterized by systemic inflammatory response syndrome, lung injury caused by sepsis is one of the leading causes of sepsis death. To assess the major inflammatory mediators produced in the lung, we used RT-qPCR to detect mRNA levels of IL-1β, IL-6 and TNF- α.24 hours post-surgery, IL-1β, IL-6 and TNF- α expression in lung tissue of CLP mice was significantly higher than in sham-operated mice (FIG. 3, A-C). Similar to the trend in systemic cytokine levels, treatment with 0.2 and 1mg/kg of ALD-R491 inhibited gene expression of all three key cytokines in a dose-dependent manner. At 1mg/kg, compound C52 reduced IL-1 beta and TNF-alpha expression in lung tissue of CLP mice to levels indistinguishable from sham-operated controls (FIG. 3, A-C). Compound C52 treatment reduced local cytokine production in tissues and thus reduced cytokine levels in the blood circulation, thereby inhibiting inflammation in specific organs and systemic.

Example 4: s-triazine derivative representative compound C52 significantly reduces pulmonary edema and acute lung injury in septic mice

Materials and methods

Histological examination: CLP sepsis mice were euthanized 24 hours post-surgery. Samples of fresh tissue from the subpulmonary lobes were collected and fixed in 4% (w/v) paraformaldehyde for at least 24 hours. The fixed tissue is embedded in dehydrated paraffin and cut into 4-5 μm thick sections. Sections were stained with hematoxylin and eosin (HE staining) and scanned with a scanner (PannoramicDESK, P-MIDI,3DHISTECH,Hungary). Acute Lung Injury (ALI) scores were calculated based on four parameters, including hemorrhage, alveolar congestion, neutrophil infiltration, and alveolar space size. The score for each parameter was from 0 to 4: a score of 0 indicates very little; score 1 indicates mild; 2 points represent moderate; a score of 3 indicates severe; and 4 points represent extreme weight.

Lung exudation and edema: the extent of pulmonary edema can be manifested by a wet weight/dry weight ratio of the lung tissue. The upper right lung leaf tissue was cut, the surface was wiped dry with filter paper, weighed to give a wet weight, and then dried in an oven at 65 ℃ for 24 hours, and the dry weight was determined. The wet weight/dry weight ratio is calculated by dividing the wet weight by the dry weight.

Results and conclusions

Acute Lung Injury (ALI) is characterized by excessive inflammation resulting in disruption of the pulmonary endothelial and epithelial barrier. It may develop into Acute Respiratory Distress Syndrome (ARDS), a life threatening sepsis complication. To further understand the correlation between compound C52 treatment on reduced mortality and its protective effect on lung tissue, we performed H & E staining and quantified lung tissue damage (fig. 4, a and B). The mice in the sham operation group have normal alveolus structure and no inflammatory cell infiltration. In contrast, CLP-septic mice develop severe lung injury, including alveolar effusion, interstitial edema, hemorrhage, necrosis, and immune cell infiltration, all of which are significantly alleviated by treatment with compound C52. The degree of improvement is dose dependent. Sepsis mice treated with 1mg/kg of compound C52 had significantly reduced Acute Lung Injury (ALI) score and lung wet weight to dry weight ratio (p < 0.01). These results indicate that the efficacy of compound C52 treatment in septic mice is related to its protection of organ tissues from injury.

It will be appreciated that the foregoing describes preferred embodiments of the invention and that modifications may be made thereto without departing from the spirit or scope of the invention as set forth in the claims. The following claims summarize the specification to particularly point out and distinctly claim the subject matter regarded as the invention.

Claims

1. Use of a s-triazine derivative represented by formula a below, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer, or solvate thereof, in the manufacture of a medicament for treating or preventing sepsis or a condition associated with sepsis:

Wherein:

2. The use according to claim 1, wherein the compound of formula a has the structure of formula I:

Wherein:

3. The use according to claim 2, wherein,

R ₁ is hydrogen, halogen or nitro, more preferably H, F, cl or nitro; and/or

R ₂ is-NR ₄R₅,R₄ and R ₅ are independently selected from hydrogen, C ₁-C₆ alkyl and C ₁-C₆ haloalkyl, Or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆, O and S, which heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, Wherein R ₆ is hydrogen, hydroxy or C ₁-C₆ alkyl; Preferably, R ₄ and R ₅ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form an optionally further group selected from NR ₆, A 4-6 membered saturated heterocyclic ring of heteroatoms of O and S, which heterocyclic ring may be substituted with hydroxy, halogen, nitro, amino or C ₁-C₆ alkyl, wherein R ₆ is hydrogen or C ₁-C₆ alkyl; Preferably, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered saturated heterocyclic ring optionally containing a further heteroatom selected from NR ₆ and O, said heterocyclic ring being optionally substituted with a substituent selected from hydroxy and C ₁-C₆ alkyl, Wherein R ₆ is hydrogen or C ₁-C₆ alkyl; Preferably, the 4-6 membered saturated heterocyclic ring is selected from morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl and azetidinyl; and/or

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from hydrogen, C ₁-C₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉R₁₀ and C ₁-C₆ alkyl substituted by 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S optionally substituted by C ₁-C₆ alkyl; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form an optionally further group selected from N, A4 to 6 membered heterocycle of a heteroatom of O, S; preferably, R ₃ is halogen, C ₁-C₆ alkoxy or-COR _a,R_a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O optionally substituted by C ₁-C₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O; preferably, the method comprises the steps of, R ₇ and R ₈ together with the nitrogen atom to which they are attached form a heterocyclic ring and R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a piperidinyl group, piperazinyl, pyrrolidinyl, or morpholinyl; Preferably, when R ₃ is a non-H substituent, it is typically located in the meta or para position of the phenyl group; and/or

X is NH, and is connected with para position or meta position of phenyl; or X is O and is connected with para position of phenyl.

4. The use according to claim 2, wherein in formula I:

R ₁ is hydrogen, halogen or nitro;

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from hydrogen, C ₁-C₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉R₁₀ and C ₁-C₆ alkyl substituted by 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing a further heteroatom selected from N, O and S optionally substituted by C ₁-C₆ alkyl; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form an optionally further group selected from N, A4 to 6 membered heterocycle of a heteroatom of O, S; Or (b)

In the formula I:

R ₁ is hydrogen, halogen or nitro;

X is NH, and is connected with para position or meta position of phenyl; or (b)

In the formula I:

R ₁ is hydrogen, halogen or nitro;

X groups are meta-position and para-position NH or O; or (b)

In the formula I:

R ₁ is hydrogen, halogen or nitro;

R ₃ is hydrogen, halogen or-CONR ₇R₈ wherein R ₇、R₈ is independently selected from hydrogen, optionally C ₁-C₆ substituted alkyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; wherein the C ₁-C₆ alkyl group is optionally substituted with one or more substituents selected from the group consisting of C ₁-C₆ alkylamino and di C ₁-C₆ alkylamino;

X groups are meta-position and para-position NH or O.

5. The use according to claim 2, wherein the compound of formula I has the structure of formula I-1 or formula I-2:

in the method, in the process of the invention,

R ₁ is selected from H, halogen and nitro;

R ₃ is halogen or COR _a; wherein R _a is OH or NR ₇R₈,R₇ and R ₈ are independently selected from C ₁-C₆ alkyl optionally substituted with NR ₉R₁₀ and C ₁-C₆ alkyl substituted with 3- (C ₂-C₆ alkynyl) -3H-bisaziridinyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally substituted with C ₁-C₆ alkyl optionally containing an additional heteroatom selected from N or O; r ₉ and R ₁₀ are independently selected from hydrogen and C ₁-C₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4 to 6 membered saturated heterocyclic ring optionally containing an additional heteroatom selected from N or O;

preferably, in the above formula I-2, R ₃ is halogen;

Preferably, in formula I-1 above, R ₁ is selected from H and halogen, preferably Cl; r ₂ is selected from morpholinyl, preferably morpholino; r ₃ is halogen or COR _a, wherein R _a is OH or NR ₇R₈,R₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocyclic ring optionally substituted by C ₁-C₆ alkyl optionally containing a further heteroatom selected from N or O, preferably piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl, more preferably piperidinyl or piperazinyl substituted by C ₁-C₄ alkyl.

6. The use according to claim 2, wherein the compound of formula I has the structure shown in formula I-3:

in the method, in the process of the invention,

R ₁ is H;

R ₂ is morpholinyl;

7. The use according to claim 1, wherein the compound of formula a has the structure of formula a-1:

Wherein:

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁-C₆ alkyl, hydroxymethyl, aminomethyl or-CONR ₇R₈ wherein R ₇、R₈ is independently selected from hydrogen, C ₁-C₆ optionally substituted alkyl, or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; wherein the C ₁-C₆ alkyl group is optionally substituted with one or more substituents selected from halogen, C ₁-C₆ alkylamino and di C ₁-C₆ alkylamino;

Preferably, in formula A-1, R ₃ is H or halogen.

8. The use according to claim 1, wherein the compound of formula a is selected from the group consisting of the following compounds, and pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers and solvates thereof:

(1) Compounds L1-L22 having the formula:

(2) Compounds L23-L28 having the formula:

(3) A compound L29-L38 having the formula:

(4) A compound L39-L41 having the structural formula:

And (5) compound L42:

9. The use according to any one of claims 1 to 8, wherein the sepsis or sepsis-related condition includes organic and/or functional damage to cells, tissues and organs caused by pathogen infection and/or by an excessive response of the body to pathogen infection;

Preferably, the pathogen is selected from: one or more of bacteria, viruses, fungi, and parasites;

preferably, the injury is an acute fatal systemic pathology, or a sequelae of a specific or non-specific organ parenchymal pathology.

10. The use according to any one of claims 1 to 9, wherein the compound is administered by the following route: oral, topical, parenteral, inhalation or spray or suppository, preferably in oral form, more preferably parenterally in a sterile medium.