WO2024175053A1 - Compound for treating or preventing sepsis or condition associated with sepsis - Google Patents

Abstract

A compound for treating or preventing sepsis or a condition associated with sepsis. The compound of the present invention is a s-triazine derivative represented by the following formula A, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer or solvate thereof. The present invention further comprises corresponding pharmaceutical use and a method for treating and preventing a disease.

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 conditions associated with sepsis.

Background Art

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [Singer et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315: 801-10]. In the United States, there are more than 1.7 million cases of sepsis each year, resulting in 270,000 deaths [www.cdc.gov/sepsis]; globally, there are approximately 50 million cases of sepsis and 11 million deaths each year, with a mortality rate of more than 20% [WHO. Global report on the epidemiology and burden of sepsis: current evidence, identifying gaps and future directions. Geneva: World Health Organization; 2020. License: CC BY-NC-SA 3.0 IGO]. WHO has identified sepsis as a global health priority. Unfortunately, over the past three decades, all drugs tested for sepsis have failed to show clinical efficacy, likely because none of these drugs target the complex pathology of the disease [Cavaillon et al. Sepsis therapies: learning from 30 years 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, and catabolism. All patients with sepsis are routinely treated with broad-spectrum antibiotics after diagnosis. Although bacteria are the most common infectious pathogens that cause sepsis, fungi, parasites, and viruses are also possible causes of sepsis. Medical emergencies leave little time to identify the causative pathogen through blood culture, and patients in the intensive care unit (ICU) often develop multidrug-resistant (MDR) infections, both of which limit the effectiveness of antibiotics in sepsis. Corticosteroids have been used clinically to reduce excessive inflammation in patients with sepsis, but their effectiveness remains uncertain [Lamontagne et al. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ. 2018; 362: k3284]. Because patients with severe sepsis also have Excessive inflammation and immunosuppression. Corticosteroids reduce inflammation by suppressing the immune system, which further aggravates the infection. No other anti-inflammatory drug has shown any efficacy in the treatment of sepsis. Clinically, in addition to antibiotics, the treatment of sepsis is mainly supportive or symptomatic treatment such as fluid supplementation and blood pressure increase. Currently, there is no drug that can simultaneously have anti-inflammatory and anti-immunosuppressive effects, nor can it reverse catabolism to normal metabolism. An effective anti-sepsis drug must have multiple effects on the complex pathogenesis of the disease. Vimentin intermediate filaments are involved in many cellular pathological processes related to the pathogenesis of sepsis [Ridge et al. Roles of vimentin in health and disease. Genes Dev. 2022; 36: 391-407]. We used small molecule compounds targeting vimentin to confirm that targeting vimentin can treat sepsis.

Summary of the invention

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

Where:

_R1 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C12 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _diC1 - _C6 alkylamino, hydroxymethyl or aminomethyl;

_R2 is _-NR4R5 , _R4 and _R5 are independently selected from hydrogen, _C1 - _C6 alkyl and _C1 - _C6 haloalkyl, or R4 and _R5 together with the nitrogen atom to which they _are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing an additional heteroatom selected from _NR6 , O and S, which may be substituted by hydroxy, halogen, nitro, amino or _C1 - _C6 alkyl, wherein _R6 is hydrogen, hydroxy, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

Z is an aryl or heteroaryl group optionally substituted by 1-3 _R3 ; preferably, the aryl group is a 6-14-membered aryl group, such as phenyl or naphthyl; the heteroaryl group is a 5-10-membered heteroaryl group, preferably a nitrogen-containing heteroaryl group, including but not limited to imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazole Preferably, Z is phenyl or pyridyl optionally substituted by 1 or 2 R ₃ ;

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, hydroxymethyl, aminomethyl or -COR _a ;

_Ra is OH or _NR7R8 , _R7 and _{R8 are} independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 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 and S, which is optionally substituted by _C1 - _C6 alkyl;

_R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _R9 and _R10 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; and

X is NH or O, and is connected to the meta-position or para-position of the phenyl group.

In a second aspect, the present invention provides a method for 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 as shown in Formula A herein, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer or solvate thereof, or a pharmaceutical composition containing a therapeutically or prophylactically effective amount of a s-triazine derivative as shown in Formula A herein, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer or solvate thereof.

In a third aspect, the present invention provides a s-triazine derivative represented by Formula A herein, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer or solvate thereof, for treating or preventing sepsis or a condition associated with sepsis, or a pharmaceutical composition containing 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.

The compound of formula A used in any of the above methods and uses is preferably a compound described in any of the embodiments below, especially including compounds described in formula I-1, I-2, I-3 and A-1 and each specific compound listed in the table.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Compound C52 significantly reduced the severity and mortality of CLP-induced sepsis in mice. A: Experimental scheme. C57BL/6J mice were randomly assigned to four groups (n=10 per group), namely: sham hand Surgery + vehicle (procedural control); CLP + vehicle (negative control); CLP + C52 (0.2 mg/kg); CLP + C52 (1 mg/kg). Mice that underwent sham or CLP surgery were given vehicle or C52 compound (0.2 mg/kg or 1 mg/kg) by oral gavage 10 minutes before surgery on the day and on the 1st to 6th day after surgery, respectively. Surviving animals were killed on the 7th day after surgery. B: 7-day survival rate of mice (n=10 per group), **P<0.01Log-Rank test. C: Disease severity was scored every day for 7 days. Data are expressed as mean ± SEM (the initial number of animals in each group was 10, and the number of animals at different time points was reduced due to mortality). **P<0.01, Mann-WhitneyU test.

Figure 2. Compound C52 further reduces mortality and disease severity in CLP-induced sepsis on top of broad-spectrum antibiotics. (A) Experimental scheme: C57BL/6J mice were randomly assigned to five groups (n=11/group), namely: sham surgery + vehicle (procedural control); CLP + vehicle (negative control); CLP + ceftriaxone (positive control); CLP + ceftriaxone + C52 (0.2 mg/kg); CLP + ceftriaxone + C52 (1 mg/kg). On day 0, vehicle or ceftriaxone or ceftriaxone plus C52 were given by oral gavage 2 hours after CLP or sham surgery and once daily from day 1 to day 6. (B) Survival rate by day. (C) Disease severity score by day, with a score of 8 after animal death. Data are presented as mean ± SEM. Significance between treatment groups was analyzed by Mann-Whitney U test. *P < 0.05; **P < 0.01

Figure 3: Compound C52 significantly reduces inflammatory factors in the systemic blood circulation of mice with CLP-induced sepsis. A: Experimental scheme. C57BL/6J mice were subjected to sham or CLP surgery. 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: ELISA was used to determine the concentrations of TNF-α (B) and IL-6 (C) in the serum of mice 24 hours after surgery. Data are expressed as mean ± SEM (n = 6 per group), *P < 0.05, **P < 0.01, Mann-Whitney U test.

Figure 4: Compound C52 significantly reduced the expression of inflammatory factors in specific organs (lungs) of septic mice. AC: The levels of IL-1β (A), IL-6 (B) and TNF-α (C) mRNA in the lungs were evaluated by RT-qPCR. Data are expressed as mean ± SEM (n = 6 per group), *P < 0.05, **P < 0.01, Mann-Whitney U test.

Figure 5: Compound C52 significantly reduces acute damage to lung tissue in septic mice. A: Representative lung tissue pathology 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 μm. B: H&E-stained lung tissue sections were semiquantitatively scored according to hemorrhage, alveolar congestion, neutrophil infiltration, and alveolar cavity size to evaluate lung tissue pathological damage. C: The severity of pulmonary edema was measured by measuring the wet-to-dry weight ratio of lung tissue. Data are expressed as mean ± SEM (n = 6 per group), **P < 0.01, Mann-Whitney U test.

DETAILED DESCRIPTION

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a preferred technical solution.

The inventors have previously developed some compounds that can bind to vimentin with s-triazine as the core structure (U.S. Patent No. US10,611,736). The present invention selects specific representative s-triazine derivatives and uses cecal ligation and puncture (CLP), the most commonly used animal model most relevant to human sepsis, to evaluate the anti-septic effect of small molecule compounds targeting vimentin. The present invention found that oral administration of compound C52 can not only reduce the severity of the disease, but also reduce the mortality rate of animals, regardless of whether broad-spectrum antibiotics are used. Further analysis shows that the compound can reduce the blood content of inflammatory cytokines TNFα and IL-6, which are closely related to sepsis, and reduce the gene expression levels of TNFα, IL-6 and IL1-β in lung tissue, reducing acute lung injury and pulmonary edema. Therefore, this type of s-triazine derivative has a preventive and therapeutic effect on sepsis.

The s-triazine derivative of the present invention preferably has the structural formula shown in the following formula A:

Where:

_R1 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C12 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _diC1 - _C6 alkylamino, hydroxymethyl or aminomethyl;

R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing additional heteroatoms selected from _NR6 , O and S, which may be substituted by hydroxy, halogen, nitro, amino or _C1 - _C6 alkyl, wherein _R6 is hydrogen, hydroxy, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

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

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, hydroxymethyl, aminomethyl or -COR _a ;

_Ra is OH or _NR7R8 , _R7 and _{R8 are} independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 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 and S, which is optionally substituted by _C1 - _C6 alkyl;

_R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _R9 and _R10 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; and

X is NH or O, and is connected to the meta-position or para-position of the phenyl group.

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, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl and tetrazolyl. Preferably, Z is phenyl or pyridyl optionally substituted by 1 or 2 R ₃ .

The s-triazine derivatives of the present invention are preferably the s-triazine derivatives described in US 16/300,162, the entire contents of which are incorporated herein by reference. More specifically, the s-triazine derivatives of the present invention are 2,4,6-trisubstituted s-triazine compounds having the structure shown in the following formula I:

Where:

_R1 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C12 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _diC1 - _C6 alkylamino, hydroxymethyl or aminomethyl;

R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing additional heteroatoms selected from _NR6 , O and S, which may be substituted by hydroxy, halogen, nitro, amino or _C1 - _C6 alkyl, wherein _R6 is hydrogen, hydroxy, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, hydroxymethyl, aminomethyl or -COR _a ;

_Ra is OH or _NR7R8 , _R7 and _{R8 are} independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 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 and S, which is optionally substituted by _C1 - _C6 alkyl;

_R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _R9 and _R10 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; and

X is NH or O, and is connected to the meta-position or para-position of the phenyl group.

The s-triazine derivatives used in the present invention also include pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers or solvates of the compounds represented by formula 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 formula A and formula I, preferably, R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ 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 additional heteroatoms selected from NR ₆ , O and S, and the heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen, hydroxy or C ₁ -C ₆ alkyl. Preferably, R ₄ and R ₅ are independently selected from hydrogen and C ₁ -C ₆ alkyl, or 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 another heteroatom selected from NR ₆ , O and S, the heterocyclic ring may be substituted by hydroxyl, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C ₆ 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 another heteroatom selected from NR ₆ and O, the heterocyclic ring is optionally substituted by a substituent selected from hydroxyl and C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl. The number of substituents on the heterocyclic ring is generally 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 formula A and formula I, preferably, R ₃ is hydrogen, halogen, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, hydroxymethyl, aminomethyl or -COR _a , wherein _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from hydrogen, C 1 -C ₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉ R ₁₀ , and C ₁ -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 additional heteroatoms selected from N, O and S, which is optionally substituted by C ₁ -C 6 alkyl; R ₉ and R 10 are independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ₉ and R _{10 are} independently selected from hydrogen and C ₁ -C ₆ alkyl, R ₁₀ , 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, and S. Preferably, R ₃ is halogen, C ₁ -C ₆ alkoxy or -COR _a , _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C 1 -C 6 alkyl optionally substituted by NR ₉ R ₁₀ and C ₁ -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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, which is optionally substituted by C ₁ -C ₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C _{1 -C 6} 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 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 generally located at the meta or para position of the phenyl group.

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

In a preferred embodiment, in Formula A and Formula I:

_R1 is hydrogen, halogen or nitro;

_R2 is _-NR4R5 , _R4 and _R5 are independently selected from hydrogen, _C1 - _C6 alkyl and _C1 - _C6 haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they _are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing an additional heteroatom selected from _NR6 , O and S, which may be substituted by hydroxy, halogen, nitro, amino or _C1 - _C6 alkyl, wherein _R6 is hydrogen, hydroxy or _C1 - _C6 alkyl; and

_R3 is hydrogen, halogen, nitro, amino, hydroxyl, _C1 - _C6 alkyl, _{hydroxymethyl} , aminomethyl or _-CORa , wherein _Ra is OH or _NR7R8 , _R7 and _R8 are independently selected from hydrogen, C1- _C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by _3- ( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 together with the nitrogen atom to which they are attached form a group optionally containing additional a 4- to 6-membered heterocyclic ring optionally substituted with a C ₁ -C ₆ alkyl group and containing a heteroatom selected from N, O and S; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom selected from N, O and S.

In a preferred embodiment, in Formula A and Formula I:

_R1 is hydrogen, halogen or nitro;

R ₂ is -NR ₄ R ₅ , 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 an additional heteroatom selected from NR ₆ and O, said heterocyclic ring being optionally substituted with a substituent selected from hydroxy and C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl;

R ₃ is halogen or -COR _a , _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C ₁ -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 by C ₁ -C ₆ alkyl which optionally contains an additional heteroatom selected from N or O; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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;

X is NH, connected to the para-position or meta-position of the phenyl group.

In certain embodiments, preferably, in Formula A and Formula I:

_R1 is hydrogen, halogen or nitro;

R ₂ is -NR ₄ R ₅ , R ₄ , R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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 an additional heteroatom selected from NR ₆ , O, S, which may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen, hydroxy, C ₁ -C ₆ alkyl;

_R3 is hydrogen, halogen, nitro, amino, hydroxyl, _C1 - _C6 alkyl, hydroxymethyl, aminomethyl, _-CONR7R8 , wherein _R7 and _R8 are independently selected from _hydrogen , _C1 - _C6 optionally substituted alkyl, or _R7 and _R8 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, and S; wherein the _C1 - _C6 alkyl may be optionally substituted with one or more substituents selected from halogen, _C1 - _C6 alkylamino and _diC1 - _C6 alkylamino;

The X groups are NH or O at the meta and para positions.

In certain embodiments, more preferably, in Formula A and Formula I:

_R1 is hydrogen, halogen or nitro;

R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ 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 an additional heteroatom selected from NR ₆ , O, S, which may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, and R ₆ is hydrogen, C ₁ -C ₆ alkyl;

R ₃ is hydrogen, halogen or -CONR ₇ R ₈ , wherein R ₇ , R ₈ are independently selected from hydrogen, optionally substituted C ₁ -C ₆ 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 -C ₆ alkyl may be optionally substituted with one or more substituents selected from C ₁ -C ₆ alkyl-substituted amino and di-C ₁ -C ₆ alkyl-substituted amino;

The X groups are NH or O at the meta and para positions.

In a preferred embodiment, the compound of formula I herein has a structure shown in the following formula I-1 or the following formula I-2:

In the formula,

_R1 is selected from H, halogen and nitro;

_R2 is selected from morpholinyl, pyrrolidinyl, piperazinyl and azetidinyl, which are optionally substituted with hydroxy or _C1 - _C6 alkyl; and

R ₃ is halogen or COR _a ; wherein _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C 1 -C ₆ alkyl substituted by 3-(C _{2 -C 6} 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 by C ₁ -C ₆ alkyl which optionally contains an additional heteroatom selected from N or O; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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 the above formula I-1, R ₁ is selected from H and halogen (preferably Cl); R ₂ is selected from morpholinyl (preferably R ₃ is halogen or COR _a , wherein _Ra is OH or NR ₇ R ₈ , 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, which is optionally substituted by C ₁ -C ₆ alkyl, preferably piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl, more preferably piperidinyl or piperazinyl substituted by C ₁ -C ₄ alkyl.

In a preferred embodiment, the compound of formula I herein has the structure shown in the following formula I-3:

In the formula,

_R1 is H;

_R2 is morpholinyl;

_Ra is OH or _NR7R8 , _R7 and _R8 are independently selected from _C1 - _C6 alkyl optionally substituted by _NR9R10 and C1- _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 , together with the nitrogen atom to which they are attached, form a 4- to 6-membered saturated _{heterocyclic ring optionally substituted by C1-C6 alkyl which} contains an additional heteroatom selected from N or O; _R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _{R9 and R10 ,} 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 _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C 1 -C ₆ alkyl substituted by 3-(C _{2 -C 6} 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 by C ₁ -C ₆ alkyl which optionally contains an additional heteroatom selected from N or O; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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 at the meta position or para position of the phenyl group. In certain embodiments, in these compounds, when R ₁ is a non-hydrogen substituent, it is located at the meta position of the phenyl group, and R ₃ is located at the para position of the phenyl group. In certain embodiments, in these compounds, the saturated heterocyclic ring includes, but is not limited to, piperazinyl, piperidinyl, pyridinyl, Pyrrolidino and morpholino.

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

Where:

_R3 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C6 alkyl, hydroxymethyl, aminomethyl or _-CONR7R8 , wherein _R7 and _R8 are independently selected from hydrogen, _C1 - _C6 optionally substituted alkyl, or _{R7 and R8} 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 and S; wherein the _C1 - _C6 alkyl may be optionally substituted with one or more substituents selected from halogen, mono- _C1 - _C6 alkyl-substituted amino, di- _C1 - _C6 alkyl-substituted amino.

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

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

And compound L42 (C52M):

The compound of formula A described herein can be prepared by referring to the method disclosed in US 16/300,162.

Herein, "alkyl" refers to _C1 - _C12 alkyl, such as _C1 - _C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and the like.

"Heterocycle" refers to a 4- to 6-membered heterocycle optionally containing a heteroatom 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.

"Carboxyl" refers to -COOH.

In “3-(C ₂ -C ₆ alkynyl)-3H-diaziridinyl”, the alkynyl position of the C ₂ -C ₆ alkynyl is generally at position 1. In certain embodiments, the “3-(C ₂ -C ₆ alkynyl)-3H-diaziridinyl” is “3-(1-butyn-4-yl)-3H-diaziridin-3-yl”.

Herein, NR ₇ R ₈ and NR ₉ R ₁₀ may be a mono-C ₁ -C ₆ alkylamino group or a di-C ₁ -C ₆ alkylamino group. The C ₁ -C ₆ alkyl group may be optionally substituted, for example, by one or more halogens, mono-C ₁ -C ₆ alkylamino or di-C ₁ -C ₆ alkylamino, or by a 4- to 6-membered saturated heterocyclic ring containing N and optionally additional N or O. These heterocyclic rings include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, etc. The heterocyclic ring may also be optionally substituted, for example, by a C ₁ -C ₆ 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, such as 6, 7, 8, 9 or 10 carbon atoms). The aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring. Examples of aryl groups described in various embodiments herein include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazolinone-3 (4H)-one-7-base, etc.

In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered conjugated ring system radical having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, benzindolyl, benzomorpholinyl, benzisodiazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizine, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, and the like.

Herein, when a group is substituted, the number of substituents may vary, for example, from 1, 2, 3 or 4. Generally, unless otherwise specified, the substituents may be selected from halogen, C ₁ -C ₆ alkyl, hydroxy, carboxyl, amino, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, nitro, 3-(C ₂ -C ₆ alkynyl)-3H-bisaziridinyl, heterocyclic groups (such as morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, pyrazolyl, etc.), and C ₆ -C ₁₄ aryl (such as phenyl), etc.

The relevant terms used in this article, such as "isomer", "racemate", "prodrug", and "solvate" are not significantly different from the general meanings of the terms in the relevant field. A person of ordinary skill in the art should know the meaning of these terms. For example, the term "isomer" refers to one of two or more compounds with the same molecular composition but different structures and properties. The term "racemate" refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. The term "prodrug", also known as prodrug, drug precursor, prodrug, etc., refers to a compound that has a pharmacological effect only after transformation in the organism. 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.

As used herein, "pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, 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, naphthalene disulfonate, and the like. These salts may be prepared by methods known in the art.

Herein, "pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the profession.

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 C1-4 alcohols according to methods known in the art); esters of hydroxyl-containing compounds (e.g., esters obtained by condensation with C1-4 carboxylic acids, C3-6 diacids or their anhydrides 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)); acetals or ketal acetals 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 the compounds of formula A described herein (including the compounds of formula I, formula I-1, formula I-2, formula I-3 and formula A-1) or their pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers or solvates in the preparation of drugs for treating or preventing sepsis or conditions associated with sepsis. The present invention also relates to the compounds of formula A described herein (including the compounds of formula I, formula I-1, formula I-2, formula I-3 and formula A-1) or their pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers or solvates for treating or preventing sepsis or conditions associated with sepsis. Also included herein are methods for treating or preventing sepsis or conditions 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, 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 administering a therapeutically or prophylactically effective amount of a pharmaceutical composition described herein.

Herein, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium recognized in the art for delivering biologically active compounds to mammals (eg, humans). Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof.

Herein, "therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic outcome (such as reducing the severity of the disease, increasing the survival rate) at the required dose and for the required period of time. The therapeutically effective amount of a compound may vary according to factors such as the subject's disease state, age, sex and weight, and the ability of the compound to cause the desired response in the subject. The dosing regimen may be adjusted to provide the best therapeutic response. The therapeutically effective amount is also an amount in which any toxic or harmful effects of the compound are exceeded by the therapeutic beneficial effects. "Preventive effective amount" refers to an amount that effectively achieves the desired preventive outcome (such as alleviating the condition, reducing mortality, reducing inflammation and inflammatory factors, reducing complications and sequelae) at the required dose and for the required period of time. Typically, a preventive dose is used in a subject before or in the early stages of the disease, so that the preventive effective amount may be less than the therapeutically effective amount. In a preferred embodiment, the amount of the compound described herein administered is sufficient to play a role in treating and preventing sepsis or conditions associated with sepsis by affecting the structure and function of the vimentin intermediate filaments.

As used herein, "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes:

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

(ii) inhibiting the disease or condition, i.e., arresting its development;

(iii) alleviate the disease or condition, i.e., cause regression of the disease or condition; or

(iv) Alleviation of symptoms caused by the disease or condition, i.e., relief of pain without addressing the underlying disease or condition.

As used herein, the terms "administer", "administer", "administer" and the like refer to the ability to administer a compound or combination Methods for delivering a drug to a desired site for biological action. Any method of administration known in the art can be used in the present invention. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for 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.

Herein, the compounds are used to treat and prevent sepsis or conditions related to sepsis by vimentin. Specifically, the compounds of the present invention can inhibit the cellular pathological process related to the pathogenesis of sepsis in which vimentin intermediate filaments participate by binding to vimentin and/or affecting the structure and function of vimentin intermediate filaments, thereby achieving the effect of treating or preventing sepsis or conditions related to sepsis.

Herein, preferably, the condition associated with sepsis includes, but is not limited to, organ, organ, systemic inflammatory cytokine production and/or organ and/or functional damage to cells, tissues and organs caused by immune disorders caused by pathogen infection. Herein, the effect of the compound of the present invention on tissues, organs and systemic inflammation is measured by detecting the protein amount of inflammatory cytokines in the body fluids of sepsis patients and the mRNA expression level in tissues and organs. The cytokine is a cytokine that plays a key role in sepsis. In certain embodiments, the cytokine is IL-1β, TNF-α and IL-6. The term "body fluid" used herein includes blood, serum, sweat or urine. In certain embodiments, the body fluid is serum. Herein, the organ and/or functional damage to the cells, tissues and organs includes pulmonary edema and/or acute lung injury, such as alveolar exudate, interstitial edema, hemorrhage, necrosis and immune cell infiltration.

Herein, the pathogen may be one or more of bacteria, viruses, fungi and parasites. The pathogen may be clearly identified or difficult to be clearly identified through blood culture.

In a preferred embodiment, the present invention relates to a method for preparing a drug for treating or preventing a pathogen infection or a disease caused by a pathogen infection using 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. The method comprises administering to a subject in need thereof an effective amount of a compound of formula A described herein (including the A compound of formula I, a compound of formula I-1, a compound of formula I-2, a compound of formula I-3, and a 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, the individual or subject is preferably a mammal, more preferably a human.

Herein, therapeutic benefits can be achieved by administering at least 1, 2, 3 or more compounds described herein simultaneously or sequentially. 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 co-administered with other drugs, preferably antibacterial or viral drugs. In some embodiments, the other therapies include administering to the patient a therapeutically effective amount of antibiotics. Antibiotics may be given before, simultaneously or after starting treatment with the compounds of the present invention or their pharmaceutical compositions. The antibiotic may be any type of antibiotic commonly used in the art for treating sepsis or conditions associated with sepsis, including but not limited to penicillins: such as penicillin G, ampicillin, amoxicillin and oxacillin; cephalosporins: such as cephalexin, cefazolin, cefradine, cefuroxime, ceftriaxone, ceftriaxone and cefoperazone; aminoglycosides: such as streptomycin, gentamicin, tobramycin, amikacin, neomycin, ribosomycin, micronomycin and asthmacin; macrolides: such as erythromycin, white mycin, erythromycin without flavor, acetylspiramycin, midecamycin and josamycin; tetracyclines: such as tetracycline, oxytetracycline, doxycycline and chloramphenicol; chloramphenicols: such as chloramphenicol, succinylchloramphenicol and thiamphenicol; lincosamides: such as lincomycin and clindamycin; and polypeptides: such as vancomycin, polymyxin E, fosfomycin and nystatin.

The pharmaceutical compositions provided herein may contain a compound of formula A described in any embodiment 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, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by, for example, the U.S. Food and Drug Administration (FDA) for use in humans or animals. Typically, a pharmaceutically acceptable carrier is an inert diluent.

The pharmaceutical composition of the present invention comprises a compound represented by formula I-1, a pharmaceutically acceptable salt thereof, Drug, enantiomer, diastereomer, tautomer or solvate, wherein R ₁ is selected from H and halogen (preferably Cl), more preferably H; R ₂ is selected from morpholinyl (preferably morpholino); R ₃ is halogen or COR _a , more preferably halogen; _Ra is OH or NR ₇ R ₈ , 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 another heteroatom selected from N or O, optionally substituted by C ₁ -C ₆ alkyl, preferably piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl, more preferably forming a piperidinyl or piperazinyl substituted by C ₁ -C ₄ alkyl. More preferably, the pharmaceutical composition of the present invention contains compound C50 and/or C52.

The pharmaceutical compositions herein can take a variety of forms to accommodate the selected route of administration. Those skilled in the art will recognize various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable compositions of the compounds described herein. Those skilled in the art will recognize that a variety of nontoxic pharmaceutically acceptable solvents can be used to prepare solvates of the compounds of the invention.

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

Pharmaceutical compositions containing the compounds of the 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 contain 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 mixed with non-toxic pharmaceutically acceptable excipients 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 disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin or gum arabic; lubricants, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. ester.

Oral preparations can also be presented in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (for example calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain active substances mixed with excipients suitable for preparing aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and gum arabic. Dispersants or wetting agents, which can be naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxide and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, such as seven eight carbon ethyleneoxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitol monooleate. Aqueous suspensions may also include one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners such as 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 may provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweeteners, flavoring agents and coloring agents, may also be present.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or a mixture of these. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol; 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 flavorings.

Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, and flavoring and coloring agents. Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. The suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable solvents and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injections.

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

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

For administration to non-human animals, the composition containing the therapeutic compound can 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 animal can take in an appropriate amount of the compound in its diet. To further facilitate administration, the compound can be present in the composition in the form of a premix for addition to feed or drinking water. The composition can also be added as a food or beverage supplement for humans.

Useful dosage levels in the treatment of the above conditions include about 1 mg to about 500 mg per day, about 5 mg to about 150 mg per day, and more preferably about 5 mg to about 100 mg per day. The amount of active ingredient that can be combined with a 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 specific disease being treated. However, for the treatment of most diseases, a dosage regimen of 3 times a day or less is preferred. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration and excretion rate, drug combination, and The severity of the specific condition being treated.

Preferred compounds of the present invention will have the desired pharmacological properties, including but not limited to oral bioavailability, low toxicity, low serum protein binding and desired in vitro and in vivo half-life. For compounds used to treat central nervous system diseases, it is necessary to penetrate the blood-brain barrier, while compounds with low exposure levels in brain tissue are generally preferred for the treatment of peripheral diseases. For the treatment of organ-specific diseases, compounds with enriched exposure in the organ and compounds with minimal exposure in other organs or systemic exposure are preferred.

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

The present invention will be described below in the form of specific embodiments. It should be understood that these examples are merely illustrative and are not intended to limit the scope of the present invention. The methods and materials used in the examples, unless otherwise stated, are conventional methods in the art and materials available from commercial sources.

Preparation Example

The compound of formula A can be prepared according to the method disclosed in US 16/300,162.

The preparation method of compound L42 (C52M) is exemplified below.

Step 1

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

Step 2

To a solution of C52 intermediate-C (prepared by the method disclosed in US 16/300,162, 1.0 g, 2.67 mmol) in DMSO (15 mL) was added compound 2 (1.3 g, 5.34 mmol, 2 eq) under nitrogen and DIEA (861 mg, 6.68 mmol, 2.5 eq) and the mixture was stirred at 60 ° C for 2 hours. TLC and LCMS detection indicated that the reaction was complete. The mixture was diluted with water (40 mL), and the formed solid was filtered, washed with MeOH, and dried to give the desired product C52M (900 mg, 64%) as an off-white solid.

Example

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

Materials and methods

Chemical synthesis: All reagents used in the synthesis are of chemical purity or higher. The final product is purified by column chromatography and characterized by ¹ H NMR, ¹³ C NMR, high-resolution MS and HPLC. The purity is equal to or higher than 95%.

Animals: 6-8 week old SPF male C57BL/6J mice (18-20 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China) and housed in the Experimental Animal Center of Nanjing University of Chinese Medicine. The temperature of the animal facility was maintained between 20°C and 25°C, and the relative humidity was maintained between 40% and 70%. The mice had free access to food and water. All experimental procedures were performed in accordance with the institutional guidelines issued by the Ethics Committee of Nanjing University of Chinese Medicine (Ethics Approval No.: 202207A066). Animal care was provided in accordance with the guidelines approved by the IACUC.

Model and treatment methods: Mice were randomly divided into four groups for mortality studies and four groups for inflammation and tissue damage studies. The cecal ligation and puncture (CLP) model was used. The four groups were sham surgery + vehicle, CLP + vehicle, CLP + 0.2 mg/kg of C52 compound, and CLP + 1 mg/kg of C52 compound. Sham surgery refers to surgery without cecal ligation and puncture. The mice were anesthetized with tribromoethanol, and a midline incision was made to expose the cecum. The cecum was ligated 1 cm distal to its distal end with 3-0 silk sutures, punctured once with a 21-gauge needle, and a small amount of feces was gently squeezed out. The cecum was then returned to its normal intra-abdominal position. The abdomen was closed with interrupted sutures, and the skin was closed with tissue glue (3M, Minnesota Mining and Manufacturing Co., Ltd.). Then 1 mL of normal saline was injected subcutaneously for infusion resuscitation. For mortality studies, mice in each group were given vehicle or C52 compound 10 min before surgery and once a day thereafter for 6 days, ending the experiment on the 7th day. In the inflammation and tissue damage studies, mice in each group were given vehicle or C52 compound 10 minutes before surgery and 16 hours after surgery, and blood and tissue samples were collected 24 hours after surgery.

Disease severity assessment: The disease severity of each mouse was scored based on its self-grooming, activity, body posture, and weight loss, where self-grooming: 0, (normal); 1, dull/dull (dusty) fur; 2, fur becomes erect or shaggy. Activity: 0, no activity to stimulation (normal); 1, reduced response to stimulation/activity (reduced), 2, unresponsive to stimulation (immobile). Body posture: 0, fully extended (normal), 1, arched back, 2, side-lying in resting position. Weight loss: 0, minimal weight loss (<10%), where the weight loss that occurred in sham-operated controls was adjusted to reduce the effects of surgery, 1, mild emaciation (10-14.9%); 2, severe emaciation (15-19.9%). The disease severity score was calculated as the sum of all category scores. Dead mice received the highest score (8) on the day of death and were removed from the score thereafter. Scores range from 0 to 2, defined as health; from 3 to 5, moderate disease; and from 6 to 8, severe disease.

Statistical analysis: Statistical analysis was performed using Graphpadprism 6.0 software. Descriptive results are expressed as mean ± SEM. Survival curves were plotted using the Kaplan-Meier method. Statistical comparisons were performed using two-tailed Student's t-test (for two separate groups; if variances were unequal, the Mann-Whitney U test was used), one-way ANOVA (for >2 separate groups), or two-way ANOVA (for two or more separate groups). p<0.05 was considered statistically significant.

Results and Conclusions

To investigate the therapeutic efficacy of vimentin-targeting compounds in sepsis, we used a representative compound C52 and selected mortality as the most relevant primary evaluation indicator and disease severity as the secondary evaluation indicator, because death is common in human sepsis and mortality is a gold standard with no room for ambiguity. Since it takes about 2 hours for the compound to reach peak systemic exposure after oral administration (Li et al. A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases. mBio. 2021 Oct 12: e0254221), and proinflammatory cytokines reach their highest levels within 6 hours after CLP, we treated the mice before surgery (10 minutes), which is closer to a preventive regimen than a therapeutic one and provides enough time for the drug to take effect before the full cytokine storm (Figure 1, A). All mice in the sham group that underwent surgery but without cecal ligation and puncture (CLP) survived to the end of the study (0% mortality) and showed only minimal symptoms shortly after surgery. In contrast, half of the mice with CLP in the vehicle-treated group died rapidly in the first two days after surgery, and only 20% of the mice survived on day 7 (80% mortality), and correspondingly, this group of animals had higher disease severity scores. C52 compound treatment significantly delayed the time to death and reduced the 7-day mortality rate to 50% in the 0.2 mg/kg C52 compound group and further to 20% in the 1 mg/kg C52 compound group (Figure 1, B). Disease severity scores in mice treated with C52 compound (1 mg/kg) were also significantly lower than those in vehicle-treated mice (Figure 1, C). Dose-dependent improvements in disease symptoms and survival were observed after C52 compound treatment, further indicating the effectiveness of this compound in the treatment of sepsis.

Example 2: The representative compound C52 of the s-triazine derivative further reduced the severity and mortality of CLP-induced sepsis on the basis of using broad-spectrum antibiotics.

Materials and methods

Animals, modeling and statistical results: Same as Example 1

The mice were randomly divided into five groups for mortality study. The mice in each group were given solvent two hours after surgery. The mice were given vehicle or ceftriaxone or ceftriaxone plus C52 compound (0.2 or 1 mg/kg) once a day for 6 days, and the experiment was terminated on the 7th day.

Results and Conclusions

Given that sepsis is a life-threatening organ dysfunction caused by host response disorders due to infection, broad-spectrum antibiotics are widely used in clinical treatment. In order to better simulate the actual clinical situation, this experiment used delayed administration of drugs after animal infection to compare the efficacy of antibiotics (cefotaxime) and antibiotics plus C52 compounds (Figure 2, A).

The sepsis caused by CLP in this experiment was very serious. All animals in the vehicle control group died within five days (survival rate 0%), the five-day survival rate of the ceftriaxone group was 18%, and the seven-day survival rate was 9%, while the five-day survival rate of the ceftriaxone plus compound C52 (1 mg/kg) group was 45%, and the seven-day survival rate remained at 45% (Figure 2, B). Accordingly, ceftriaxone plus compound C52 (1 mg/kg) significantly reduced the severity of sepsis (Figure 2, C). This result shows that despite delayed administration, compound C52 can still further reduce the severity and mortality of CLP-induced sepsis on the basis of using broad-spectrum antibiotics.

Example 3: Representative compound C52 of s-triazine derivatives significantly reduced systemic inflammation in septic mice

Materials and methods

Animals, modeling, treatment methods, sample collection and result statistics: the same 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. The blood samples were centrifuged at 3500 rpm/min for 20 min at 4°C, and the serum was collected and stored at -80°C until use. The protein amounts of inflammatory cytokines TNF-α and IL-6 were measured by ELISA kits (Biolegend, USA).

Results and Conclusions

Given the demonstrated efficacy of compound C52 in reducing symptoms and mortality in CLP-induced sepsis mice, we subsequently performed a separate in vivo study aimed at understanding the effects of this compound on cytokines that play a key role in this model as well as in human sepsis. 16 hours after surgery, mice were treated with vehicle or different doses of compound C52 (Figure 3, A). 24 hours after surgery, the serum protein levels of IL-6 and TNF-α in CLP septic mice were significantly higher than those in sham-operated control mice (p < 0.01). The serum TNF-α of CLP mice treated with 1 mg/kg of compound C52 was significantly reduced (p < 0.05) to a level comparable to that of sham-operated control mice (Figure 3, B). IL-6 is the most elevated cytokine in the serum of CLP mice (up to 1,000 times). Both 0.2 mg/kg and 1 mg/kg of compound C52 significantly (p < 0.01) reduced the serum IL-6 levels 24 hours after CLP (Figure 3, C). Compound C52 dose-dependently reduced the levels of cytokines TNF-α and IL-6 in the blood. These results indicate that compound C52 significantly reduced systemic inflammation in septic mice.

Example 4: The representative compound C52 of s-triazine derivatives significantly reduced the production of local inflammatory factors in the lungs of septic mice

Materials and methods

Animals, modeling, treatment methods, sample collection and result statistics: the same as in Example 1.

RT-qPCR quantitative gene expression: RT-qPCR was used to measure the mRNA levels of target genes (IL-1β, IL-6 and TNF-α) in lung and liver tissues. Briefly, total RNA was extracted from mouse lung and liver tissues using RNA preparation pure tissue kit (TIANGEN, DP431) 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 sets for each gene (Pishgam Biotech Company, Tehran, Iran) were IL-1βForward: GAAATGCCACCTTTTGACAGTG (SEQ ID NO: 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 5 PCR Master Mix (TOYOBO) was used to quantify mRNA levels. The polymerase chain reaction (PCR) reaction settings were as follows: 95°C (30 seconds), 95°C (5 seconds), 60°C (31 seconds) for a total of 40 cycles. The reactions were performed in triplicate. line, and use Methods The relative mRNA expression was calculated.

Results and Conclusions

Although sepsis is characterized by a systemic inflammatory response syndrome, sepsis-induced lung injury is one of the leading causes of sepsis mortality. 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. At 24 hours postoperatively, the expression of IL-1β, IL-6, and TNF-α in the lung tissue of CLP mice was significantly higher than that of sham-operated mice (Figure 4, A-C). Similar to the trend of systemic levels of cytokines, treatment with 0.2 and 1 mg/kg of C52 inhibited the gene expression of all three key cytokines in a dose-dependent manner. At 1 mg/kg, compound C52 reduced the expression of IL-1β and TNF-α in the lung tissue of CLP mice to levels indistinguishable from those of sham-operated controls (Figure 4, A-C). Compound C52 treatment reduced local tissue cytokine production and thus reduced the amount of cytokines in the blood circulation, thereby inhibiting specific organ and systemic inflammation.

Example 5: Representative compound C52 of s-triazine derivatives significantly reduced pulmonary edema and acute lung injury in septic mice

Materials and methods

Animals, modeling, treatment methods, sample collection and result statistics: the same as in Example 1.

Histological examination: CLP sepsis mice were euthanized 24 hours after surgery. Fresh tissue samples from the lower lobe of the lung were collected and fixed in 4% (w/v) paraformaldehyde for at least 24 hours. The fixed tissues were dehydrated, paraffin-embedded, and cut into 4-5 μm thick sections. The sections were stained with hematoxylin and eosin (HE staining) and scanned with a scanner (PannoramicDESK, P-MIDI, 3DHISTECH, Hungary). The acute lung injury (ALI) score was calculated based on four parameters, including hemorrhage, alveolar congestion, neutrophil infiltration, and alveolar cavity size. The score for each parameter ranged from 0 to 4: 0 points for minimal; 1 point for mild; 2 points for moderate; 3 points for severe; and 4 points for extremely severe.

Pulmonary exudation and edema: The degree of pulmonary edema can be reflected by the wet weight/dry weight ratio of lung tissue. Cut the right upper lobe tissue, wipe the surface with filter paper, weigh it to get the wet weight, and then dry it in a 65℃ oven for 24 hours. The dry weight was determined. The wet/dry weight ratio was calculated by dividing the wet weight by the dry weight.

Results and Conclusions

Acute lung injury (ALI) is characterized by excessive inflammation leading to the destruction of the lung endothelium and epithelial barrier. It can develop into acute respiratory distress syndrome (ARDS), a life-threatening complication of sepsis. To further understand the correlation between the reduction in mortality caused by compound C52 treatment and its protective effect on lung tissue, we performed H&E staining and quantified the damage of lung tissue (Figure 5, A and B). The alveolar structure of sham-operated mice was normal without inflammatory cell infiltration. In contrast, mice with CLP sepsis developed severe lung injury, including alveolar exudate, interstitial edema, hemorrhage, necrosis, and immune cell infiltration, all of which were significantly alleviated by compound C52 treatment. The degree of improvement was dose-dependent. The acute lung injury (ALI) score and lung wet weight to dry weight ratio of septic mice treated with 1 mg/kg of compound C52 were significantly reduced (p < 0.01). These results indicate that the efficacy of compound C52-treated septic mice is related to its protection of organ tissues from damage.

It should be understood 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.To particularly point out and distinctly claim the subject matter regarded as the invention, the following claims summarize the specification.

Claims (12)

Use of the s-triazine derivative represented by the following formula A, or a pharmaceutically acceptable carrier, prodrug, enantiomer, diastereomer, tautomer or solvate thereof in the preparation of a medicament for treating or preventing sepsis or a condition associated with sepsis in a patient:
Where: _R1 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C12 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _diC1 - _C6 alkylamino, hydroxymethyl or aminomethyl; R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ 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 an additional heteroatom selected from NR ₆ , O and S, which may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen, hydroxy, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; Z is an aryl or heteroaryl group optionally substituted by 1-3 R ₃ ; preferably, the aryl group is a 6-14-membered aryl group, such as phenyl or naphthyl; the heteroaryl group is a 5-10-membered heteroaryl group, preferably a nitrogen-containing heteroaryl group, including but not limited to imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl and tetrazolyl; preferably, Z is a phenyl or pyridyl group optionally substituted by 1 or 2 R ₃ ; R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, hydroxymethyl, aminomethyl or -COR _a ; _Ra is OH or _NR7R8 , _R7 and _{R8 are} independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 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 and S, which is optionally substituted by _C1 - _C6 alkyl; _R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _R9 and _R10 together with the nitrogen atom to which they are attached are selected from Together they form a 4- to 6-membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, S; and X is NH or O, and is connected to the meta-position or para-position of the phenyl group. The use according to claim 1, characterized in that the compound of formula A has a structure shown in the following formula I:
Where: _R1 is hydrogen, halogen, nitro, amino, hydroxy, _C1 - _C12 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _diC1 - _C6 alkylamino, hydroxymethyl or aminomethyl; R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ 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 an additional heteroatom selected from NR ₆ , O and S, which may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen, hydroxy, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, hydroxymethyl, aminomethyl or -COR _a ; _Ra is OH or _NR7R8 , _R7 and _{R8 are} independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from _halogen or _NR9R10 , and _C1 - _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 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 and S, which is optionally substituted by _C1 - _C6 alkyl; _R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _R9 and _R10 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; and X is NH or O, and is connected to the meta-position or para-position of the phenyl group. The use according to claim 2, characterized in that R ₁ is hydrogen, halogen or nitro, more preferably H, F, Cl or nitro; and/or _R2 is _-NR4R5 , _R4 and _R5 are independently selected from hydrogen, _C1 - _C6 alkyl and _C1 - _C6 haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they are attached form a radical _optionally containing another heteroaryl selected from _NR6 , O and S. a 4-6 membered saturated or unsaturated heterocyclic ring of 1-24 atoms, which may be substituted by hydroxyl, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen, hydroxyl or C ₁ -C ₆ alkyl; preferably, R ₄ and R ₅ are independently selected from hydrogen and C ₁ -C ₆ alkyl, or 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 another heteroatom selected from NR ₆ , O and S, which may be substituted by hydroxyl, halogen, nitro, amino or C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C ₆ 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 another heteroatom selected from NR ₆ and O, which is optionally substituted by a substituent selected from hydroxyl and C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C 6 alkyl. ₆ 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, hydroxyl, C ₁ -C ₆ alkyl, hydroxymethyl, aminomethyl or -COR _a , wherein _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from hydrogen, C 1 -C ₆ alkyl optionally substituted by one or more substituents selected from halogen or NR ₉ R ₁₀ , and C ₁ -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 additional heteroatoms selected from N, O and S and optionally substituted by C ₁ -C ₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing additional heteroatoms selected from N, O and S; preferably, R R ₃ is halogen, C ₁ -C ₆ alkoxy or -COR _a , R _a is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C 1 -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 and optionally substituted by C ₁ -C ₆ alkyl; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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 heterocyclic ring formed by R ₇ and R ₈ together with the nitrogen atom to which they are attached and R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl group; preferably, when R ₃ is a non-H substituent, it is usually located at the meta or para position of the phenyl group; and/or X is NH, connected to the para position or meta position of the phenyl group; or X is O, connected to the para position of the phenyl group. The use according to claim 2, characterized in that in the formula I: _R1 is hydrogen, halogen or nitro; _R2 is _-NR4R5 , _R4 and _R5 are independently selected from hydrogen, _C1 - _C6 alkyl and _C1 - _C6 haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they _are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing an additional heteroatom selected from _NR6 , O and S, which may be substituted by hydroxy, halogen, nitro, amino or _C1 - _C6 alkyl, wherein _R6 is hydrogen, hydroxy or _C1 - _C6 alkyl; and R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₆ alkyl, hydroxymethyl, aminomethyl or -COR _a , wherein _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from hydrogen, C ₁ -C 6 alkyl optionally substituted by one or more substituents selected from halogen or NR ₉ R ₁₀ , and C 1 -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 substituted by C ₁ -C ₆ alkyl and optionally containing an additional heteroatom selected from N, O and S; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ alkyl, or R ₉ and R ₁₀ 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; or In the formula I: _R1 is hydrogen, halogen or nitro; R ₂ is -NR ₄ R ₅ , 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 an additional heteroatom selected from NR ₆ and O, said heterocyclic ring being optionally substituted with a substituent selected from hydroxy and C ₁ -C ₆ alkyl, wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl; R ₃ is halogen or -COR _a , _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C ₁ -C ₆ alkyl substituted by 3-(C ₂ -C ₆ 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 by C ₁ -C ₆ alkyl which optionally contains an additional heteroatom selected from N or O; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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; X is NH, connected to the para-position or meta-position of the phenyl group; or In the formula I: _R1 is hydrogen, halogen or nitro; _R2 is _-NR4R5 , _R4 and _R5 are independently selected from hydrogen, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, or _R4 and _R5 together with the nitrogen atom to which they _are attached form a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally containing an additional heteroatom selected from _NR6 , O, S, which heterocyclic ring may be substituted by hydroxy, halogen, nitro, amino or _C1 -C6 haloalkyl. C ₆ alkyl substituted, wherein R ₆ is hydrogen, hydroxyl, C ₁ -C ₆ alkyl; _R3 is hydrogen, halogen, nitro, amino, hydroxyl, _C1 - _C6 alkyl, hydroxymethyl, aminomethyl, _-CONR7R8 , wherein _R7 and _R8 are independently selected from _hydrogen , _C1 - _C6 optionally substituted alkyl, or _R7 and _R8 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, and S; wherein the _C1 - _C6 alkyl may be optionally substituted with one or more substituents selected from halogen, _C1 - _C6 alkylamino and _diC1 - _C6 alkylamino; The X group is NH or O at the meta and para positions; or In the formula I: _R1 is hydrogen, halogen or nitro; R ₂ is -NR ₄ R ₅ , R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ 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 an additional heteroatom selected from NR ₆ , O, S, which may be substituted by hydroxy, halogen, nitro, amino or C ₁ -C ₆ alkyl, and R ₆ is hydrogen, C ₁ -C ₆ alkyl; R ₃ is hydrogen, halogen or -CONR ₇ R ₈ , wherein R ₇ and R ₈ are independently selected from hydrogen, optionally C ₁ -C ₆ 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 -C ₆ alkyl may be optionally substituted with one or more substituents selected from C ₁ -C ₆ alkylamino and di-C ₁ -C ₆ alkylamino; The X groups are NH or O at the meta and para positions. The use according to claim 2, characterized in that the compound of formula I has a structure shown in the following formula I-1 or the following formula I-2:
In the formula, _R1 is selected from H, halogen and nitro; _R2 is selected from morpholinyl, pyrrolidinyl, piperazinyl and azetidinyl, which are optionally substituted with hydroxy or _C1 - _C6 alkyl; and R ₃ is halogen or COR _a ; wherein _Ra is OH or NR ₇ R ₈ , R ₇ and R ₈ are independently selected from C ₁ -C ₆ alkyl optionally substituted by NR ₉ R ₁₀ and C 1 -C ₆ alkyl substituted by 3-(C _{2 -C 6} 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 by C ₁ -C ₆ alkyl and optionally containing an additional heteroatom selected from N or O; R ₉ and R ₁₀ are independently selected from hydrogen and C ₁ -C ₆ 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 the above formula I-1, 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 _Ra is OH or NR ₇ R ₈ , and 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 another heteroatom selected from N or O, which is optionally substituted by a C ₁ -C ₆ alkyl group, preferably a piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl group, more preferably a piperidinyl or piperazinyl group substituted by a C ₁ -C ₄ alkyl group. The use according to claim 2, characterized in that the compound of formula I has a structure shown in the following formula I-3:
In the formula, _R1 is H; _R2 is morpholinyl; _Ra is OH or _NR7R8 , _R7 and _R8 are independently selected from _C1 - _C6 alkyl optionally substituted by _NR9R10 and C1- _C6 alkyl substituted by 3-( _C2 - _C6 alkynyl)-3H-bisaziridinyl, or _R7 and _R8 , together with the nitrogen atom to which they are attached, form a 4- to 6-membered saturated _{heterocyclic ring optionally substituted by C1-C6 alkyl which} contains an additional heteroatom selected from N or O; _R9 and _R10 are independently selected from hydrogen and _C1 - _C6 alkyl, or _{R9 and R10 ,} 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. The use according to claim 1, characterized in that the compound of formula A has the following formula A- The structure shown in 1:
Where: R ₃ is hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₆ alkyl, hydroxymethyl, aminomethyl or -CONR ₇ R ₈ , wherein R ₇ and R ₈ are independently selected from hydrogen, C ₁ -C ₆ 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 -C ₆ alkyl may be optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkylamino and di-C ₁ -C ₆ alkylamino; Preferably, in formula A-1, R ₃ is H or halogen. The use according to claim 1, characterized in that the compound of formula A is selected from the following compounds and pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, tautomers and solvates: (1) Compounds L1-L22 having the following structural formula:


(2) Compounds L23-L28 having the following structural formula:

(3) Compounds L29-L38 having the following structural formula:


(4) Compounds L39-L41 having the following structural formula:

and (5) compound L42:
The use according to any one of claims 1 to 8, characterized in that the sepsis or sepsis-related condition includes organic and/or functional damage to cells, tissues and organs caused by pathogen infection and/or 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 disease, or a sequelae caused by a specific or non-specific organ parenchymal disease. The use according to any one of claims 1 to 9, characterized in that the compound is administered by the following routes: oral, topical, parenteral, inhalation or spray or suppository, preferably in oral form, more preferably parenteral in a sterile medium. The use according to any one of claims 1 to 10, characterized in that the patient also receives antibiotics. The use according to claim 11, characterized in that the antibiotic is selected from: Penicillins: such as penicillin G, ampicillin, amoxicillin and oxacillin; Cephalosporins: such as cephalexin, cefazolin, cephradine, cefuroxime, ceftriaxone, cefotaxime, and cefoperazone; Aminoglycosides: such as streptomycin, gentamicin, tobramycin, amikacin, neomycin, ribosomycin, metronidazole, and azoxystrobin; Macrolides: such as erythromycin, leucomycin, erythromycin without flavor, acetylspiramycin, midecamycin and josamycin; Tetracyclines: such as tetracycline, oxytetracycline, doxycycline and chlortetracycline; Chloramphenicol: such as chloramphenicol, succinylchloramphenicol and thiamphenicol; Lincosamides: such as lincomycin and clindamycin; and Peptides: such as vancomycin, polymyxin E, fosfomycin and nystatin.