Antioxidant drug conjugate FPR1 modulators, compositions comprising same, and methods of use thereof

Abstract

The present disclosure provides compounds of Formula (I), compositions comprising the compounds, and methods of use thereof, including in the treatment of diseases, disorders, or conditions mediated by formyl peptide receptor 1 (FPR1) signaling. (I).

Description

Technical Field

[0001] This disclosure provides a compound of formula I, its tautomers, a deuterated derivative of the compound or the tautomer, and a pharmaceutically acceptable salt of the foregoing substances; a pharmaceutical composition comprising a compound of formula I, its tautomers, the deuterated derivative of the compound or the tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances; and a method of using the above substances to treat, for example, diseases, symptoms, or conditions mediated by formylpeptide receptor 1 (FPR1) protein regulation. Background Technology

[0002] Antioxidants are drugs that neutralize free radicals by accepting or donating electrons to eliminate their unpaired state. Antioxidant drugs can directly react with and scavenge certain reactive free radicals, while the free radicals generated by antioxidants may become new free radicals with lower activity, longer lifespan, and less harmful than the original reactive free radicals. Generally, antioxidants exert these effects through a variety of mechanisms, including scavenging substances that trigger peroxidation, quenching singlet oxygen molecules, chelating metal ions, disrupting chain reactions of free radicals, or reducing superoxide. Some antioxidants can also modulate reactive oxygen species (ROS)-related enzymes and provide an important defense against free radicals by inhibiting the activity and expression of free radical-generating enzymes (such as NAD(P)H oxidase and xanthine oxidase (XO)) or by enhancing the activity and expression of antioxidant enzymes (such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX)). It has been reported that imbalances in antioxidant enzymes are associated with many other specific pathologies, such as chronic granulomatous disease, Down syndrome, diabetic complications, hepatitis, rheumatoid arthritis, influenza virus, ulcers, pneumonia, HIV infection, cataracts, and glaucoma. Therefore, the primary characteristic of antioxidants is the prevention of intracellular oxidation, a chemical reaction that produces free radicals and reactive oxygen species, thereby protecting healthy cells in the body from oxidative damage. Representative antioxidants include vitamins A, C, and E, uric acid, glutathione, phenolic compounds (such as phenol and polyphenols), flavonoids, carotenoids, steroids, thiols, edaravone, borneol, T-0080, nordihydroguaiac acid (NDGA), vanillin, and quercetin.

[0003] In recent years, formyl peptide receptors (FPR1, FPR2, FPR3) have become increasingly important as therapeutic targets due to their beneficial biological properties. FPRs are G protein-coupled receptors that are activated by recognizing formyl peptides, then transmit chemotactic signals in phagocytes and mediate host defense and inflammatory responses, including cell adhesion, directed migration, particle release, and superoxide production. Restoring homeostasis after injury or pathogen infection is crucial for the survival of an organism. Physiological wound healing and innate immune responses are triggered by soluble mediators released from invading pathogens or damaged lesions. This time-regulated, interactive repair process involves, for example, numerous chemokines, cytokines, acute-phase proteins, infiltrating and resident cells, fibroblasts, nerve cells, and the vascular system. If the injury persists or is severe, physiological wound repair or anti-infective responses can become pathological, leading to excessive inflammation, edema, unnecessary fibrotic repair, organ dysfunction, acute respiratory distress syndrome (ARDS), sepsis, and ultimately organ failure and / or death. Therefore, effective regulation of the intensity and duration of inflammation and resolution responses is essential for injury repair. Following tissue damage or pathogen infection (by bacteria, viruses, fungi, and / or microorganisms), invading pathogens, damaged cells, and diseased tissues release a series of formylates, damage-associated molecular pattern molecules (DMAPs), inflammatory lipid mediators (such as leukotrienes and lipoxygenin), and acute-phase proteins (such as annexin). Three FPR receptors serve as key sensors for these chemotactic and activating molecules in the human body, and they are highly expressed on neutrophils, macrophages, T lymphocytes, dendritic cells, epithelial cells, fibroblasts, microglia, and astrocytes. These chemically active molecules and acute proteins bind to FPR receptors, recruiting leukocytes, stimulating the production of superoxide dismutase and cytokines, and activating microglia, astrocytes, and other inflammatory and remission responses to repair damage and enhance host defenses.

[0004] On the other hand, pathological inflammatory responses caused by FPR receptor-mediated signal transduction imbalances are the cause of various disease states following injury or infection, including, for example, cerebral edema, functional impairment, and organ failure after stroke or traumatic brain injury. Furthermore, chronic activation of FPR receptor-mediated signal transduction induced by invading pathogens, tissue stress, tissue damage, and peripheral and central nervous system diseases is associated with the pathogenesis of brain cancer, gastric cancer, colorectal cancer, hematological disorders, Alzheimer's disease, and Parkinson's syndrome.

[0005] ARDS is a clinical syndrome of non-cardiogenic pulmonary edema, accompanied by bilateral pulmonary infiltration, lung stiffness, and refractory hypoxemia. ARDS is characterized by a fulminant acute inflammatory response in the lung parenchyma, leading to alveolar edema, decreased lung compliance, and ultimately hypoxemia, with a mortality rate between 30-50%. Significant progress has not been made in drug treatment. Mechanical ventilation is the primary medical intervention for treating ARDS. Currently, the only proven method to reduce inflammation and mortality is the use of lung-protective ventilation strategies, namely low tidal volume and high positive end-expiratory pressure. Therefore, there is an urgent need to develop more effective ARDS treatment compositions and methods. FPR1 modulators, by antagonizing FPR1, can reduce vascular inflammation and limit pulmonary infiltration, thereby improving the condition of ARDS patients.

[0006] Stroke is a leading cause of death worldwide, and treatment options are limited. The FPR receptor is highly expressed in microglia, astrocytes, and the cerebrovascular system. Following intracerebral hemorrhage (ICH), infiltrating leukocytes, activated platelets, microglia, and astrocytes release a series of pro-inflammatory mediators, acute-phase proteins, and DMAP from dying cells. FPR1 activation-induced leukocyte infiltration, reactive oxygen species (ROS) production, and cytokine release may be the initial inflammatory response after injury, leading to perihemorrhagic cerebral edema and exacerbated mass effects.

[0007] Traumatic brain injury (TBI) is a leading cause of disability worldwide. The global annual incidence of TBI is estimated at 200 cases per 100,000 people. Severe injuries often lead to behavioral disorders, brain atrophy, dementia, permanent damage, and ultimately death. Treatment options for TBI are limited, and FPR1 activation is involved in mediating the initial inflammatory process of TBI.

[0008] Glioblastoma and malignant glioma are the most common primary brain tumors. The annual incidence of malignant glioma is approximately 6 cases per 100,000 people, and there is currently no effective treatment. The FPR1 receptor is highly expressed in glial cells, astrocytes, and the cerebrovascular system. The interaction of the FPR receptor with chemokines produced by injury, stress, and pathogens is closely related to the pathophysiology of brain cancer.

[0009] Atherosclerosis is a leading and increasingly prevalent cause of death and disability worldwide, and inflammation is involved throughout its development and progression to complications. Therefore, targeting inflammatory pathways may offer promising new avenues for the prevention and treatment of atherosclerosis. Indeed, clinical studies have clearly demonstrated that modulating inflammation can prevent clinical complications of atherosclerosis. This advance underscores the necessity of conducting preclinical research to refine strategies for combating inflammation in human diseases. FPR1 is a potential therapeutic target for atherosclerotic diseases. FPR1 participates in vascular inflammation, directly acting on immune cells in arterial plaques in patients with atherosclerosis, and plays a crucial role in plaque formation and stability.

[0010] Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, glial proliferation, axonal damage, and inflammation. The disease is thought to be caused by an autoimmune response to CNS autoantigens in genetically susceptible individuals, with autoreactive T cells presumed to be the disease-inducing immune cells. While there are currently no therapies that can directly induce and enhance a repertoire of regulatory immune cells, numerous studies have identified potential net effects on these cell types. Recently, FPR1 was found to play a crucial role in host defense during demyelination. FPR1 deficiency leads to reduced demyelination of the corpus callosum and decreased expression of cellular markers and cytokines in microglia or astrocytes of the corpus callosum and / or cortex after cuprizone feeding. This contributes to a better understanding of the disease and may serve as a starting point for new approaches to its treatment.

[0011] Inflammatory bowel disease (IBD) is characterized by complex interactions between immune cells and tissue cells, and these interactions can become dysregulated. FPR1 is expressed in both immune cells and stromal cells (including epithelial cells), and it plays a central role in the recruitment of neutrophils to IBD and contributes to the development of colitis.

[0012] Given the above, FPR1-antioxidant drug conjugates, formed by combining the structure of FPR1 regulators with antioxidant drugs through various linking groups, may have better therapeutic effects than the original FPR1 regulators. Simultaneously, FPR1-antioxidant drug conjugates possess the properties of antioxidant drugs and can prevent or delay certain types of cell damage caused by oxidative stress. Therefore, the development of FPR1-antioxidant drug conjugates remains necessary to effectively address the current limited effective treatment options for various diseases, such as ARDS, stroke, TBI, glioblastoma, glioma, atherosclerosis, IBD, and multiple sclerosis. Invention Overview One aspect of this disclosure provides compounds selected from formulas I, II, II-i, III, and III-i, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, for the treatment of diseases mediated by FPR1 protein signaling. For example, compounds having the following structural formula I are disclosed herein: (I), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) X and Y are independently selected from: O, S, N, NR 4 C(R) 4 )2 and CR 4 And at least one of X and Y is O, S, N or NR. 4 ; (ii) Further, where R 4 Selected from: hydrogen, CH3, CHF2, and CF3; (iii) Z is C or N; Y 1 Not present or selected from: O, S, and NR 5 ; Furthermore, where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (iv) R a Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R a Y, together with the atoms they are attached to, forms cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; (v) R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vi) Each R c Each is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vii) Each Y 2 and Y 3 Each of the following groups is either independent or selected from: , Furthermore, each R 6 and R 7 It is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or it is not present; (viii) L 1Not present or selected from: straight-chain alkyl, branched alkyl, cycloalkyl and PEG groups; (ix) Further, where each R 6 R 7 and L 1 Each is independently and optionally substituted by at least one group selected from the group consisting of: straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl.

[0014] (x) D is selected from the following antioxidant compounds: .

[0015] In one aspect of this disclosure, the compounds of formula I are selected from compounds 1-4 shown below, their tautomers, deuterated derivatives of the compounds or their tautomers, and pharmaceutically acceptable salts of the aforementioned substances.

[0016] In some embodiments, this disclosure provides pharmaceutical compositions comprising compounds of formulas I, II, II-i, III, and III-i, their tautomers, deuterated derivatives of the compounds or the tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions may include compounds selected from the group consisting of compounds 1-4 shown below, their tautomers, deuterated derivatives of the compounds or the tautomers, and / or pharmaceutically acceptable salts of the foregoing substances. These compositions may further comprise additional active pharmaceutical agents.

[0017] Another aspect of this disclosure provides a method for treating a disease, symptom, or condition mediated by the regulation of the FPR1 protein in a subject, comprising administering a therapeutically effective amount of a compound of formula I, II, II-i, III, and III-i, its tautomers, a deuterated derivative of said compound or said tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances. In some embodiments, the treatment method comprises administering to a subject a therapeutically effective amount of a compound selected from the group consisting of compounds 1-4 shown below, their tautomers, said compound or a deuterated derivative of said tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances.

[0018] In some embodiments disclosed herein, the treatment method includes administering an additional active agent to a subject in need, the active agent being administered in the same composition or in a separate composition with compounds of formulas I, II, II-i, III, and III-i, their tautomers, deuterated derivatives of the compounds or their tautomers, and / or pharmaceutically acceptable salts of the foregoing substances. In some embodiments disclosed herein, the treatment method includes administering a compound selected from the group consisting of compounds 1-4 shown below, their tautomers, deuterated derivatives of the compounds or their tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, and an additional active agent, these components being administered in the same composition or in a separate composition.

[0019] This document also discloses a method for reducing the activity of the FPR1 protein, comprising administering to a subject a therapeutically effective amount of a compound of formula I, II, II-i, III, and III-i, its tautomers, a deuterated derivative of said compound or said tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances. In some embodiments disclosed herein, the method of modulating the FPR1 protein comprises administering to a subject a compound selected from the group consisting of: compounds 1-4 shown below, their tautomers, said compound or a deuterated derivative of said tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing substances. Invention Details I. Definition As used in this article, when “a” (“a” or “an”) refers to a noun, it includes the expression “at least one”, and therefore includes both the singular and plural units of the noun. For example, “additional medicine” refers to one or two or more additional medicines.

[0021] As used herein, the term "FPR1" or "formylpeptide receptor 1" refers to the cell surface receptor protein encoded by the human FPR1 gene. FPR1 regulates various neutrophil functional responses and plays an important role in the pathogenesis of many diseases, including those mentioned above.

[0022] As used herein, the term "FPR1 modulator" refers to a small organic chemical molecule (≤10 kDa) capable of altering any or more FPR1-mediated immune responses or signal transduction events, and can be an FPR1 agonist or an FPR1 antagonist. If the FPR1 modulator is an agonist, the compound has the ability to increase any or more FPR1-mediated immune responses or signal transduction events from its native state, for example, by binding to a receptor to activate the receptor. If the FPR1 modulator is an antagonist, the compound has the ability to decrease or inhibit any or more FPR1-mediated immune responses or signal transduction events from its native state, for example, by blocking agonist-binding sites or allosteric-binding sites on the receptor to achieve a decreasing or inhibiting effect.

[0023] The term "isotopic isotope" refers to substances whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise stated, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those that differ only in the substitution of hydrogen with deuterium or tritium, or those that differ in the presence of deuterium or tritium. 13 C or 14 Compounds having the structure of this application other than carbon substitution (C) are within the scope of this disclosure.

[0024] When referring to the compounds of this disclosure, the term "compound" means a collection of molecules having the same chemical structure, unless otherwise specified as a collection of stereoisomers (e.g., a collection of racemic mixtures, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), the difference being that isotopic variations may exist between the constituent atoms of the molecules. Therefore, those skilled in the art will appreciate that a compound represented by a specific chemical structure containing a designated deuterium atom will also contain a smaller amount of isotopic aberrations having hydrogen atoms at one or more designated deuterium positions in that structure. The relative amount of such isotopic aberrations in the compounds of this disclosure will depend on a number of factors, including, for example, the isotopic purity of the reagents used to prepare the compound, and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compound. However, as stated above, the total relative amount of such isotopic aberrations will be less than 49.9% of the compound. In other embodiments, the total relative amount of such isotopic isotopes in the compound will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%.

[0025] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” Generally, the term “substituted” means that a hydrogen group in a given structure is replaced by a group of a particular substituent. Unless otherwise stated, an “optionally substituted” group may have a substituent at each substituted position of that group, and when more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituent may be the same or different at each position. The combinations of substituents contemplated in this disclosure are those that result in the formation of stable or chemically viable compounds.

[0026] Unless otherwise stated, the structures described herein are also intended to include all isomers of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of this application are within the scope of this disclosure. Unless otherwise stated, all tautomers of the compounds of this application are within the scope of this application.

[0027] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the migration of intramolecular atoms (e.g., hydrogen atoms) or groups.

[0028] As used in this article, “stereoisomer” refers to enantiomers and diastereomers.

[0029] As used herein, "deuterated derivative" refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or "Deuterated"). 2Compounds with H” substitution. It should be recognized that, depending on the source of the chemical materials used in the synthesis, some variation in the natural isotope abundance will occur in the synthesized compounds. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotope substitution of the deuterated derivatives disclosed herein. Therefore, unless otherwise stated, when referring to the compounds of this disclosure as “deuterated derivatives,” at least one hydrogen atom is substituted with deuterium, and the deuterium level is much higher than its natural isotope abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotope enrichment factor per deuterium atom of: at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4500 (67.5% deuterium doping at each specified deuterium atom), at least 5000 (75% deuterium doping at each specified deuterium atom), at least 5500 (82.5% deuterium doping at each specified deuterium atom), at least 6000 (90% deuterium doping at each specified deuterium), at least 6333.3 (95% deuterium doping at each specified deuterium), at least 6466.7 (97% deuterium doping at each specified deuterium), or at least 6600 (99% deuterium doping at each specified deuterium).

[0030] As used in this article, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0031] As used herein, the term "alkyl" refers to a fully saturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise stated, an alkyl group contains 1-30 alkyl carbon atoms. In some embodiments, the alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1-4 alkyl carbon atoms. In other embodiments, the alkyl group contains 1-3 alkyl carbon atoms. In still other embodiments, the alkyl group contains 1-2 alkyl carbon atoms. In some embodiments, the alkyl group is substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is linear or straight-chain or unbranched. In some embodiments, the alkyl group is branched.

[0032] The term "cycloalkyl" refers to a fully saturated monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons, wherein any single ring in the bicyclic system has 3-7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is C3-C6. 12Cycloalkyl. In some embodiments, the cycloalkyl group is a C3-C8 cycloalkyl group. In some embodiments, the cycloalkyl group is a C3-C6 cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] The term "carbocycloyl" encompasses the term "cycloalkyl" and refers to a fully saturated or partially saturated monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons are partially saturated because they contain one or more unsaturated but non-aromatic units, wherein any single ring in the bicyclic system has 3-7 members. The bicyclic carbocyclic group includes combinations of monocyclic carbocyclic rings fused to, for example, a phenyl group. In some embodiments, the carbocyclic group is substituted. In some embodiments, the carbocyclic group is unsubstituted. In some embodiments, the carbocyclic group is C3-C. 12 Carbocyclic group. In some embodiments, the carbocyclic group is C3-C. 10 Carbocyclic group. In some embodiments, the carbocyclic group is a C3-C8 carbocyclic group. Non-limiting examples of monocyclic carbocyclic groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc.

[0034] As used herein, the term "alkylene" refers to a divalent alkyl radical. 1-10 Representative examples of alkylene groups include, but are not limited to: methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0035] As used herein, the term "alkenyl" refers to a straight-chain or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear, straight-chain, or unbranched. In some embodiments, the alkenyl group is branched.

[0036] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight-chain or branched group with 2-8 carbon atoms, also referred to herein as C... 2-8 Alkyne group. Exemplary alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, penynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0037] As used herein, the term "heterocyclic group" refers to a non-aromatic (i.e., fully saturated or partially saturated, partially saturated being due to the inclusion of one or more unsaturated but non-aromatic units), monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system, wherein one or more ring members are independently selected heteroatoms. Bicyclic heterocyclic groups include, for example, combinations of the following monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclic group; a monocyclic heterocyclic group fused to another monocyclic heterocyclic group; a monocyclic heterocyclic group fused to a phenyl group; a monocyclic heterocyclic group fused to a monocyclic carbocyclic / cycloalkyl group; and a monocyclic heteroaryl group fused to a monocyclic carbocyclic / cycloalkyl group. In some embodiments, the "heterocyclic group" contains 3-14 ring members, wherein one or more ring members are independently selected heteroatoms, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in the bicyclic or tricyclic ring system contains 3-7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one nitrogen atom. In some embodiments, the heterocycle has one oxygen atom. In some embodiments, the heterocycle has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocyclic group is a 3-12 membered heterocyclic group. In some embodiments, the heterocyclic group is a 4-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a 3-8 membered heterocyclic group. In some embodiments, the heterocyclic group is a 5-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a 5-8 membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- or 6-membered heterocyclic group. In some embodiments, the heterocyclic group is a 6-membered heterocyclic group. Non-limiting examples of monocyclic heterocyclic groups include: piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azahexacyclic butyl, oxacyclobutyl, tetrahydrothiophenyl, dihydropyranyl, and tetrahydropyridinyl.

[0038] The term "heteroatom" refers to one or more of oxygen, sulfur, and nitrogen, including any oxidized form of nitrogen or sulfur or silicon; any quaternized form of basic nitrogen, or a heterocyclic substituted nitrogen, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0039] As used herein, the term "unsaturated" refers to a portion having one or more unsaturated units or degrees of unsaturation. Unsaturation is a state in which not all available valence bonds in a compound are satisfied by substituents, and therefore the compound contains double or triple bonds.

[0040] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is attached between two carbon atoms.

[0041] The term "halogen" includes F, Cl, Br, and I, which are fluorine, chlorine, bromine, and iodine, respectively.

[0042] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0043] As used herein, an "aromatic ring" refers to a carbon ring or heterocycle containing a conjugated planar ring system, having delocalized π-electron orbitals consisting of [4n+2] p-orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbon ring or heterocycle that does not meet the above requirements for an aromatic ring, and may be fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined below.

[0044] The term "aryl," used alone or as part of a larger portion (such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl"), refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5-14 ring members, wherein each ring in the system is an aromatic ring containing only a carbon atom, and wherein each ring in a bicyclic or tricyclic system contains 3-7 ring members. Non-limiting examples of aryl include phenyl (C6) and naphthyl (C5). 10 The aryl group is substituted in some embodiments. In some embodiments, the aryl group is unsubstituted.

[0045] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic system having a total of 5-14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic system contains 3-7 ring members. Bicyclic heteroaryls include combinations of monocyclic rings, such as: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl group. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl group is a 3-12 membered heteroaryl group. In some embodiments, the heteroaryl group is a 3-10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3-8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group. Non-limiting examples of monocyclic heteroaryl groups are pyridyl, pyrimidinyl, thiophene, thiazolyl, isoxazolyl, etc.

[0046] A "spirocyclic system" refers to a ring system with two or more rings, where each pair of rings shares only one common atom.

[0047] The term "prodrug group" refers to a group covalently linked to a compound to produce a compound with improved oral bioavailability and / or tumor targeting and / or higher activity in vivo. Some compounds of Formula I may contain a prodrug group, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (see Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes chemical change under physiological conditions to produce the active compound. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent drug. For example, they may become bioavailable through oral administration, while the parent drug may not be bioavailable. Various prodrug derivatives are known in the art, such as those that depend on the hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrug groups (but not limited to) are parts of a compound (such as an ester group) that are subsequently metabolized and hydrolyzed to a carboxylic acid to release the active entity. Other examples of prodrug groups include peptide derivatives of compounds.

[0048] Non-limiting examples of suitable solvents that can be used in this disclosure include: water, methanol (MeOH), ethanol (EtOH), dichloromethane or “dichloromethane” (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0049] Non-limiting examples of suitable bases that can be used in this disclosure include: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0050] This document discloses pharmaceutically acceptable salts of the disclosed compounds. The salts of the compounds are formed between an acid and a basic group of the compound (such as an amino functional group), or between a base and an acidic group of the compound (such as a carboxyl functional group).

[0051] As used herein, the term "pharmaceutically acceptable" means a component that, to a reasonable extent of medical judgment, is suitable for contact with tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that can directly or indirectly provide the compounds of this disclosure when administered to a recipient. Suitable pharmaceutically acceptable salts are, for example, SM Berge. et al.J. Pharmaceutical Sciences , 1977, 66 Those published, pp. 1-19.

[0052] Acids commonly used to form pharmaceutically acceptable salts include: inorganic acids such as hydrosulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartrate, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butynedi-1,4-butynediate. -Diosidates, hexyn-1,6-diosidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0053] Pharmaceutically acceptable salts derived from suitable bases include: alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4Alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group in the disclosed compounds. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0054] The term "subject" refers to animals, including but not limited to humans.

[0055] The term "therapeutic effective amount" refers to the amount of a compound that produces the desired effect of its administration (e.g., improving symptoms of a disease, condition, or disease mediated by FPR1 regulation, reducing the severity or symptoms of a disease, condition, or disease mediated by FPR1 regulation, and / or reducing the progression or symptoms of a disease, condition, or disease mediated by FPR1 regulation). The exact amount of the therapeutic effective amount will depend on the purpose of treatment and will be determined by a person skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0056] As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein include, but are not limited to, complete or partial remission, disease, symptoms and conditions mediated by FPR1 regulation, and a reduction in the risk of disease-related complications. Any improvement in these symptoms or a reduction in their severity can be readily assessed using methods and techniques known in or subsequently developed in the art.

[0057] The terms “about” and “approximately”, when used in conjunction with a dose, amount, or weight percentage of an ingredient in a composition or dosage form, include a specified value of a dose, amount, or weight percentage, or a range of said dose, amount, or weight percentage, which, as can be discerned by one of ordinary skill in the art, would provide a pharmacological effect equivalent to that obtained from said specified dose, amount, or weight percentage.

[0058] The compounds and compositions of this application may be administered in combination with one or more therapeutic agents (drug combinations) or modes of treatment at therapeutically effective doses, such as conventional chemotherapy agents or any other antiproliferative, anticancer, and / or non-pharmacological therapies. For example, additive or synergistic effects may occur when used with antiproliferative or anticancer substances. If the compounds of this application are administered in combination with other therapies, the dosage of the compound administered in combination will naturally vary depending on factors such as the type of combination drug used, the specific drug used, and the condition being treated. Combination therapy includes further use of the target compound with one or more other bioactive ingredients (e.g., but not limited to: conventional chemotherapy agents, kinase inhibitors, a second different antitumor agent) and non-pharmacological therapies (e.g., but not limited to surgery or radiation therapy). For example, the compounds of this application may be used in combination with other pharmaceutically active compounds, preferably with compounds that can enhance the effect of the compounds of this application. The compounds of this application may be administered simultaneously (as a single formulation or a separate formulation) or sequentially with other drug therapies or modes of treatment. Generally, combination therapy considers the administration of two or more drugs within a course or cycle of treatment.

[0059] II. Compounds and Compositions In the first embodiment, the compound disclosed herein is a compound having the following structural formula I: (I), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) X and Y are independently selected from: O, S, N, NR 4 C(R) 4 )2 and CR 4 And at least one of X and Y is O, S, N or NR. 4 ; (ii) Further, where R 4 Selected from: hydrogen, CH3, CHF2, and CF3; (iii) Z is C or N; Y 1 Not present or selected from: O, S, and NR 5 ; Furthermore, where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (iv) R a Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R a Y, together with the atoms they are attached to, forms cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; (v) R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vi) Each R c Each is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vii) Each Y 2 and Y 3 Each of the following groups is either independent or selected from: , Furthermore, each R 6 and R 7 It is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or it is not present; (viii) L 1 It is either absent or selected from: straight-chain alkyl, branched alkyl, cycloalkyl and PEG groups.

[0060] (ix) Further, where each R 6 R 7 and L 1 Each is independently and optionally substituted by at least one group selected from the group consisting of: straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl.

[0061] (x) D is selected from the following antioxidant compounds: .

[0062] In the second embodiment, X is O in the compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0063] In the third embodiment, X is S in the compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0064] In the fourth embodiment, X is N in the compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0065] In the fifth embodiment, X is NR in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I. 4 ; and all other variables not specifically defined herein are identical to those defined in the first implementation scheme; where R 4Selected from: hydrogen, CH3, CHF2, CF3; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0066] In the sixth embodiment, X is NR in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I. 4 , where R 4 Selected from: hydrogen, CH3, CHF2, CF3; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0067] In the seventh embodiment, X is NR in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I. 4 , where R 4 It is hydrogen; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0068] In the eighth embodiment, X is NR in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I. 4 , where R 4 CH3; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0069] In the ninth embodiment, X is NR in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I. 4 , where R 4 CHF2; and all other variables not specifically defined herein are the same as those defined in the first implementation scheme.

[0070] In the tenth embodiment, X is NR in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt. 4 , where R 4 CF3; and all other variables not specifically defined here are the same as those defined in the first implementation.

[0071] In the eleventh embodiment, X is a CR among compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 , where R 4 It is hydrogen; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0072] In the twelfth embodiment, X is a CR in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt. 4 , where R 4CH3; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0073] In the thirteenth embodiment, X is a CR among compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 , where R 4 CHF2; and all other variables not specifically defined herein are the same as those defined in the first implementation scheme.

[0074] In the fourteenth embodiment, X is a CR among compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 , where R 4 CF3; and all other variables not specifically defined here are the same as those defined in the first implementation.

[0075] In the fifteenth embodiment, Z is C in the compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0076] In the sixteenth embodiment, Z is 0 in compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0077] In the seventeenth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It does not exist; and all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0078] In the eighteenth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For chemical bonds; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0079] In the eighteenth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The value is 0; and all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0080] In the nineteenth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 Let S be the variable; and all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0081] In the twentieth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For NR 5 , where R 5 The variables are selected from: hydrogen, straight-chain alkyl, branched alkyl and cycloalkyl, heterocyclic, aryl and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0082] In the twenty-first embodiment, for compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, Y 1 For NR 5 , where R 5 It is hydrogen; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0083] In the twenty-first embodiment, for compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, Y 1 For NR 5 , where R 5 It is hydrogen; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0084] In the twenty-second embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For NR 5 , where R 5 It is a straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0085] In the twenty-third embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For NR 5 , where R 5 Selected from: heterocyclic, aryl, and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0086] In the twenty-fourth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For NR 5 , where R 5 Selected from heterocyclic groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0087] In the twenty-fifth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt.1 For NR 5 , where R 5 Selected from aryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0088] In the twenty-sixth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For NR 5 , where R 5 Selected from heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0089] In the twenty-seventh embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a The variables are selected from: straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0090] In the twenty-eighth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0091] In the twenty-ninth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Selected from heterocyclic groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0092] In the thirtieth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Selected from aryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0093] In the thirty-first embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Selected from heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0094] In the thirty-second embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. aY, together with the atoms to which they are attached, forms a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0095] In the thirty-third embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Y, together with the atoms to which they are attached, forms a cycloalkyl group; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0096] In the thirty-fourth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Y, together with the atoms to which they are attached, forms a heterocyclic alkyl group; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0097] In the thirty-fifth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Y, together with the atoms to which they are attached, forms an aryl group; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0098] In the thirty-sixth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a Y and the atoms to which they are attached form heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0099] In the thirty-seventh embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b The variables are selected from: hydrogen, straight-chain alkyl, branched alkyl and cycloalkyl, heterocyclic, aryl and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0100] In the thirty-eighth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is hydrogen; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0101] In the thirty-ninth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b Selected from: straight-chain alkyl, branched alkyl, and cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0102] In the fortieth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b Selected from heterocyclic groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0103] In the forty-first embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b Selected from aryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0104] In the forty-second embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b Selected from heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0105] In the forty-third embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R c All of these are independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0106] In the forty-fourth embodiment, among the compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, one R c For hydrogen, another R c The variables are selected from: straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0107] In the forty-fifth embodiment, among the compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, one R c For hydrogen, another R c Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0108] In the forty-sixth embodiment, among the compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, one R c For hydrogen, another R c Selected from: heterocyclic, aryl, and heteroaryl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0109] In the forty-seventh embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R c All variables are independently selected from: straight-chain alkyl, branched alkyl, cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0110] In the forty-eighth embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R c All variables are independently selected from heterocyclic, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0111] In the forty-ninth embodiment, in each Y compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, 2 and Y 3 Each of the following groups is either independent or selected from: ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0112] In the fiftieth embodiment, each Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 and Y 3 Each of the following groups is either independent or selected from: ; Each R 6 and R 7 All variables are independently selected from: hydrogen, straight-chain alkyl, branched alkyl and cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or are not present; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0113] In the fifty-first embodiment, in each Y compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, 2 and Y 3 Each of the following groups is either independent or selected from: ; Each R 6 and R 7 All variables are independently selected from: hydrogen, straight-chain alkyl, branched alkyl and cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or are not present; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0114] In the fifty-second embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The following are not present or are selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl and PEG groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0115] In the fifty-third embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The following variables are not present or are selected from: straight-chain alkyl, branched alkyl, cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0116] In the fifty-fourth embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The PEG group is absent or selected; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0117] In the fifty-fifth embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R 6 R 7 and L 1 Each is independently and optionally substituted with one or more straight-chain alkyl, branched-chain alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0118] In the fifty-sixth embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R 6 Optionally substituted with one or more straight-chain alkyl, branched-chain alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0119] In the fifty-seventh embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R 7 Each is independently and optionally substituted with one or more straight-chain alkyl, branched-chain alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0120] In the fifty-eighth embodiment, in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each L 1Each is independently and optionally substituted with one or more straight-chain alkyl, branched-chain alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first embodiment.

[0121] In the fifty-ninth embodiment, D is selected from the following antioxidant compounds: compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0122] In the sixtieth embodiment, D is: (The provided text appears to be incomplete and contains several errors. A more accurate translation would require the full context.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0123] In the sixty-first embodiment, D is: (The provided text appears to be incomplete and contains several errors. A more accurate translation would require the full context.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0124] In the sixty-second embodiment, D is: (The provided text appears to be incomplete and contains errors. A more accurate translation would require the full context.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0125] In the sixty-third embodiment, D is: (The following is a list of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0126] In the sixty-fourth embodiment, D is: (The provided text appears to be incomplete and contains several errors. A more accurate translation would require the full context.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0127] In the sixty-fifth embodiment, D is: (The following is a list of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of formula I.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0128] In the sixty-sixth embodiment, D is: (The following is a list of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of formula I.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0129] In the sixty-seventh embodiment, D is: (The following is a list of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of formula I.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0130] In the sixty-eighth embodiment, D is: (The provided text appears to be incomplete and contains errors. A more accurate translation would require the full context.) ; Furthermore, all other variables not specifically defined here are the same as those defined in the first implementation scheme.

[0131] In the sixty-ninth embodiment, the compound of formula I has formula II: (II), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; or two R groups. 2Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: .

[0132] In the seventieth embodiment, XYZ is –N(CH3)–N=C in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0133] In the seventy-first embodiment, XYZ is –C(CH3)=N–N– in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0134] In the seventy-second embodiment, in the compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0135] In the seventy-third embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted cycloalkyl groups; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0136] In the seventy-fourth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted heterocyclic alkyl groups; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0137] In the seventy-fifth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted aryl groups; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0138] In the seventy-sixth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0139] In the seventy-seventh embodiment, R' is independently selected from: hydrogen, halogen groups, and alkoxy groups in the compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0140] In the seventy-eighth embodiment, R' is hydrogen in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0141] In the 80th embodiment, R' is independently selected from halogen groups in the compounds of Formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 69th embodiment.

[0142] In the eighty-first embodiment, R' is independently selected from alkoxy groups in the compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the sixty-ninth embodiment.

[0143] In the 82nd embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The variables are independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; and all other variables not specifically defined herein are the same as those defined in the seventy-ninth embodiment.

[0144] In the 83rd embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For hydrogen; and all other variables not specifically defined herein are the same as those defined in the 79th embodiment.

[0145] In the 84th embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The variables are independently selected from halogen groups; and all other variables not specifically defined herein are the same as those defined in the seventy-ninth embodiment.

[0146] In the 85th embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The variables are independently selected from: straight-chain alkyl, branched alkyl, and cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the seventy-ninth embodiment.

[0147] In the 86th embodiment, in the compound of formula II, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R 2 The variables are independently selected from: hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are the same as those defined in the seventy-ninth embodiment.

[0148] In the 87th embodiment, in a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, the two Rs 2 Groups are linked together to form heterocyclic groups; and all other variables not specifically defined herein are the same as those defined in the seventy-ninth embodiment.

[0149] In the 88th embodiment, D is selected from the following antioxidant compounds: compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. ; Furthermore, all other variables not specifically defined here are the same as those defined in the 79th implementation scheme.

[0150] According to the compound of the first embodiment, said compound has formula II-i: (II-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (vii) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (i) Cycloalkyl A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (ii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iii) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (iv) D is selected from the following antioxidant compounds: ; In the 90th embodiment, XYZ is –N(CH3)–N=C in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0151] In the ninety-first embodiment, XYZ is –C(CH3)=N–N– in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the eighty-ninth embodiment.

[0152] In the 92nd embodiment, in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted cycloalkyl groups; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0153] In the 93rd embodiment, in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted heterocyclic alkyl groups; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0154] In the 94th embodiment, in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted aryl groups; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0155] In the 95th embodiment, in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0156] In the 96th embodiment, R' is hydrogen in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0157] In the 97th embodiment, R' is a halogen in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0158] In the 98th embodiment, R' is selected from alkoxy groups in compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0159] In the ninety-ninth embodiment, R is a compound of formula II-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1For hydrogen; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0160] In the first hundredth embodiment, R is a compound of formula II-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a halogen; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0161] In the 101st embodiment, R is a compound of formula II-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The variables are selected from straight-chain alkyl, branched alkyl, and cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0162] In the first 102nd embodiment, in the compound of formula II-i, tautomer, deuterated derivative, or pharmaceutically acceptable salt, each R 1 It is cyano; and all other variables not specifically defined herein are the same as those defined in the 89th embodiment.

[0163] In the first 103rd embodiment, D is selected from the following antioxidant compounds among compounds of formula II-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts: ; Furthermore, all other variables not specifically defined herein are identical to those defined in the 79th embodiment; and all other variables not specifically defined herein are identical to those defined in the 89th embodiment.

[0164] In the 104th embodiment, the compound according to the first embodiment has Formula III: (III), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; or two R groups. 2 Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: .

[0165] In the first 105th embodiment, XYZ is –N(CH3)–N=C in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0166] In the 106th embodiment, XYZ is –C(CH3)=N–N– in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0167] In the first 107th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted cycloalkyl groups; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0168] In the first 108th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted heterocyclic alkyl groups; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0169] In the first 109th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted aryl groups; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0170] In the first 110th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is selected from optionally substituted heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0171] In the 111th embodiment, R' is hydrogen in the compounds of Formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0172] In the 112th embodiment, R' is a halogen in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0173] In the 113th embodiment, R' is selected from alkoxy groups in the compounds of Formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0174] In the 142nd embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For hydrogen; and all other variables not specifically defined herein are the same as those defined in the first 104th implementation.

[0175] In the 143rd embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For halogens; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment. (The same applies to the 104th embodiment.)

[0176] In the 144th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyano; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0177] In the 145th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 Selected from: straight-chain alkyl, branched alkyl, and cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the 104th embodiment.

[0178] In the 146th embodiment, each R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from: hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0179] In the 147th embodiment, in a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, an R 2 It is hydrogen, and an R 2The variables are independently selected from: hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0180] In the 148th embodiment, in a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, the two Rs 2 The groups together form a heterocyclic group; and all other variables not specifically defined herein are the same as those defined in the first 104th embodiment.

[0181] In the 149th embodiment, D is selected from the following antioxidant compounds: compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. ; Furthermore, all other variables not specifically defined here are the same as those defined in the 104th implementation scheme.

[0182] In the 150th embodiment, the compound according to the first embodiment has formula III-i: (III-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (vii) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (viii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (ix) R' is independently selected from: hydrogen, halogen groups, and alkoxy groups; (x) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (xi) D is selected from the following antioxidant compounds: .

[0183] In the first 151st embodiment, XYZ is –N(CH3)–N=C in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the first 150th embodiment.

[0184] In the 152nd embodiment, XYZ is –C(CH3)=N–N– in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0185] In the first 153rd embodiment, in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted cycloalkyl groups; and all other variables not specifically defined herein are the same as those defined in the first 150th embodiment.

[0186] In the first 154th embodiment, in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted heterocyclic alkyl groups; and all other variables not specifically defined herein are the same as those defined in the first 150th embodiment.

[0187] In the 155th embodiment, in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted aryl groups; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0188] In the 156th embodiment, in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is selected from optionally substituted heteroaryl groups; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0189] In the 157th embodiment, R' is hydrogen in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0190] In the 158th embodiment, R' is a halogen in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0191] In the 159th embodiment, R' is selected from alkoxy groups in compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0192] In the first 160th embodiment, R is a compound of formula III-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For hydrogen; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0193] In the 161st embodiment, R is a compound of formula III-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 For halogens; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment. (The same applies to the 150th embodiment.)

[0194] In the 162nd embodiment, R is a compound of formula III-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyano; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0195] In the 163rd embodiment, R is a compound of formula III-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 Selected from: straight-chain alkyl, branched alkyl, and cycloalkyl; and all other variables not specifically defined herein are the same as those defined in the 150th embodiment.

[0196] In the first 162nd embodiment, D is selected from the following antioxidant compounds: compounds of formula III-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. ; Furthermore, all other variables not specifically defined here are the same as those defined in the 141st implementation scheme.

[0197] In some embodiments, each straight-chain alkyl, branched-chain alkyl, cycloalkyl and fused bicycloalkyl, heterocyclic, aryl and heteroaryl group is optionally substituted with at least one group selected from the following: Halogen groups, hydroxyl group Thiols amino, Cyano, -OC(O)C1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, -C(O)OC1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, -NHC1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, -N(C1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl)2, -NHC(O)C1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, -C(O)NHC1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, -C(O)N(C1-C6)2 straight-chain alkyl, branched alkyl, and cycloalkyl, -NH aryl, -N(aryl)2, -NHC(O)aryl, -C(O)NH aryl, -NH heteroaryl, -N(heteroaryl)2, -NHC(O) heteroaryl, -C(O)NH heteroaryl, -S(O)2C1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, C1-C6 straight-chain alkyl, branched alkyl, and cycloalkyl, C2-C6 straight-chain alkenyl, branched alkenyl, and cycloalkenyl C1-C6 straight-chain hydroxyalkyl, branched hydroxyalkyl, and cyclohydroxyalkyl C1-C6 straight-chain aminoalkyl, branched aminoalkyl, and cycloaminoalkyl C1-C6 straight-chain alkoxy, branched-chain alkoxy, and cycloalkoxy C1-C6 straight-chain thioalkyl, branched thioalkyl, and cyclothioalkyl C1-C6 straight-chain haloalkyl, branched haloalkyl, and cyclohaloalkyl C1-C6 straight-chain haloaminoalkyl, branched haloaminoalkyl, and cyclohaloaminoalkyl C1-C6 straight-chain halothioalkyl, branched halothioalkyl, and cyclohalothioalkyl C1-C6 straight-chain haloalkoxy, branched haloalkoxy, and cyclohaloalkoxy benzyloxy, benzylamino, and benzylthio 3-6 membered heterocyclic alkenyl groups, 3-6 membered heterocyclic groups, and 3-6 membered heteroaryl.

[0198] In some embodiments, at least one compound of this disclosure is selected from compounds 1-4 shown in Table 1 below, their tautomers, deuterated derivatives of the compound or the tautomers, or pharmaceutically acceptable salts of the aforementioned substances.

[0199] Table 1 .

[0201] Another aspect of this disclosure provides a pharmaceutical composition comprising at least one compound selected from the group consisting of: compounds of formulas I, II, II-i, III and III-i, compounds 1-4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions comprising any of the aforementioned substances; and at least one pharmaceutically acceptable carrier.

[0202] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable solvents and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0203] It should also be recognized that the pharmaceutical compositions disclosed herein can be used in combination therapies; that is, the pharmaceutical compositions disclosed herein may also contain additional active pharmaceutical agents. Alternatively, pharmaceutical compositions comprising compounds selected from the group consisting of: compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutical compositions comprising pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any of the foregoing substances, may be administered as a separate composition simultaneously, before, or after a composition containing additional active pharmaceutical agents.

[0204] As described above, the pharmaceutical compositions disclosed herein comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be selected from excipients and solvents. The pharmaceutically acceptable carrier used herein may, for example, be selected from any and all solvents, diluents, other liquid solvents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, provided they are suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy , 21st edition, 2005, ed. DB Troy, LippincottWilliams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical TechnologyJ. Swarbrick and JC Boylan, eds., 1988 to 1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, produces any adverse biological effects, or interacts harmfully with any other component of the pharmaceutical composition, its use should be within the scope of this disclosure. Non-limiting examples of pharmaceutically acceptable carriers include: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) and buffers (such as phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as...). Sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solutions, non-toxic and compatible lubricants (such as sodium dodecyl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, aroma agents, preservatives, and antioxidants.

[0205] III. Treatment methods and applications In another aspect, the use of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, in the treatment of diseases, symptoms, or conditions mediated by FPR1 protein regulation. In another aspect, the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof disclosed herein, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, and pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases, symptoms, or conditions mediated by FPR1 protein regulation. In another aspect, this document discloses a method for treating diseases, symptoms, or conditions mediated by the regulation of the FPR1 protein in a subject, the method comprising administering a therapeutically effective amount of compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts as disclosed herein, comprising: compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, deuterated derivatives of said compounds or said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof.

[0206] In some implementations, the disease, symptom, or condition is related to the central nervous system (CNS).

[0207] In some implementations, the disease, symptom, or condition is selected from: ARDS, stroke, TBI, glioblastoma, glioma, atherosclerosis, IBD, and multiple sclerosis.

[0208] In some implementations, the disease, symptom, or condition is stroke, including thrombotic stroke, embolic stroke, thromboembolic stroke, hemorrhagic stroke, venous vasoconstrictive stroke, and venous stroke.

[0209] In some implementations, the disease, symptom, or condition is traumatic brain injury.

[0210] In one implementation, the disease, symptom, or condition is a malignant glioma.

[0211] In some embodiments, the malignant glioma is selected from: glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglioglioma. In one embodiment, the malignant glioma is glioblastoma.

[0212] In some implementations, the disease, symptom, or condition is selected from: chronic granulomatous disease, Down syndrome, diabetic complications, hepatitis, rheumatoid arthritis, influenza virus, ulcer, pneumonia, HIV infection, cataracts, and glaucoma.

[0213] In another aspect of this disclosure, the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, for modulating FPR1 activity is disclosed herein. In another aspect, the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, is disclosed herein in the preparation of medicaments for modulating FPR1 activity. In another aspect, this document discloses a method for modulating FPR1 activity, the method comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as disclosed herein, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof. In yet another aspect, this document discloses a method for modulating FPR1 activity, the method comprising contacting a subject with said compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, including compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, said compounds or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof.

[0214] Compounds of formulas I, II, II-i, III and III-i, compounds 1-4, their tautomers, deuterated derivatives of the compounds or the tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, may be administered once daily, twice daily or three times daily, for example, to treat diseases, symptoms or conditions mediated by FPR1 regulation.

[0215] In some embodiments, compounds of formula I, II, II-i, III, and III-i, compounds 1-4, their tautomers, deuterated derivatives of said compounds or said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, are administered once daily, twice daily, or three times daily, for example, to treat diseases, symptoms, or conditions mediated by FPR1 regulation.

[0216] Compounds of formulas I, II, II-i, III, and III-i, compounds 1-4, their tautomers, deuterated derivatives of said compounds or said tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, orally, vaginally, transdermally, via a patch, via a pump, or via an implanted receptacle, and said pharmaceutical compositions will be formulated accordingly. Parenterally administration routes include, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration. For example, parenterally administration may be achieved by continuous infusion over a selected period of time. Other forms of application considered in this disclosure are described in international patent applications WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142 and WO 2015 / 023915.

[0217] The effective dose or therapeutically effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro and in vivo activities in animal models. Methods for extrapolating effective doses from mice and other animals to humans are known in the art; see, for example, U.S. Patent 4,938,949.

[0218] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of that compound is an amount equivalent to the concentration of the free base of that compound. The amounts of compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives disclosed herein are all based on the free base form of a reference compound. For example, “1000 mg of at least one compound selected from compounds of formula I and their pharmaceutically acceptable salts” includes 1000 mg of a compound of formula I and pharmaceutically acceptable salts of a compound of formula I with a concentration equivalent to 1000 mg of a compound of formula I. In another aspect of this disclosure, the compounds and compositions disclosed herein can be used in combination with one or more therapeutic agents (drug combinations) or modes of treatment (e.g., anti-inflammatory agents, antioxidants, and / or non-pharmacological therapies, etc.) at therapeutically effective doses. For example, synergistic effects can occur with antioxidants or anti-inflammatory substances. When the compounds disclosed herein are used in combination with other therapies, the dose of the co-administered compounds will naturally vary depending on the type of combination drug used, the specific drug used, the condition being treated, etc. Combination therapy involves further administration of the test compound in combination with one or more other bioactive ingredients or non-pharmacological therapies (such as surgery or radiation therapy). For example, the compounds disclosed herein can be used in combination with other pharmaceutically active compounds, preferably with compounds that enhance the effects of the compounds disclosed herein. The compounds disclosed herein can be administered simultaneously (as a single formulation or alone) or sequentially with other drug therapies or modes of treatment. Generally, combination therapy refers to the administration of two or more drugs within a single course or cycle of treatment.

[0219] Non-limiting exemplary implementation 1. Compounds of Formula I: (I), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) X and Y are independently selected from: O, S, N, NR 4 C(R) 4 )2 and CR 4 And at least one of X and Y is O, S, N or NR. 4 ; (ii) Further, where R 4 Selected from: hydrogen, CH3, CHF2, and CF3; (iii) Z is C or N; Y 1 Not present or selected from: O, S, and NR 5 ; Furthermore, where R 5Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (iv) R a Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R a Y, together with the atoms they are attached to, forms cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; (v) R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vi) Each R c Each is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vii) Each Y 2 and Y 3 Each of the following groups is either independent or selected from: , Furthermore, each R 6 and R 7 It is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or it is not present; (viii) L 1 It is either absent or selected from: straight-chain alkyl, branched alkyl, cycloalkyl and PEG groups.

[0220] (ix) Further, where each R 6 R 7 and L 1 Each is independently and optionally substituted by at least one group selected from the group consisting of: straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl.

[0221] (x) D is selected from the following antioxidant compounds: .

[0222] 2. The compound of embodiment 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound has the structure of formula II: (II), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; or two R groups. 2 Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: .

[0223] 3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 2, wherein the compound has the structure of formula III: (III), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups; (iii) R' is independently selected from hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched-chain alkyl, and cycloalkyl groups; (v) R 2 Independently selected from hydrogen, methyl, and cyclopropyl; or two R groups. 2 Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: .

[0224] 4. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiments 1, 2, or 3, wherein the compound has the structure of formula II-i: (II-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) D is selected from the following antioxidant compounds: .

[0225] 5. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 2, wherein the compound has the structure of formula III-i: (III-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (xii) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (xiii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (xi) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (xii) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (xiii) D is selected from the following antioxidant compounds: .

[0226] 6. The compound according to any one of the exemplary embodiments 1-5, wherein Z is C.

[0227] 7. The compound according to any one of the exemplary embodiments 1-5, wherein Z is N.

[0228] 8. The compound according to any one of the exemplary embodiments 1-7, wherein D is edaravone.

[0229] 9. The compound according to any one of the exemplary embodiments 1-7, wherein D is borneol.

[0230] 10. The compound according to any one of the exemplary embodiments 1-7, wherein D is T-0080.

[0231] 11. The compound according to any one of the exemplary embodiments 1-7, wherein D is NDGA.

[0232] 12. The compound according to any one of the exemplary embodiments 1-7, wherein D is vanillin.

[0233] 13. The compound according to any one of the exemplary embodiments 1-7, wherein D is quercetin.

[0234] 14. The compound according to any one of the exemplary embodiments 1-7, wherein D is vitamin A.

[0235] 15. The compound according to any one of the exemplary embodiments 1-7, wherein D is vitamin C.

[0236] 16. The compound according to any one of the exemplary embodiments 1-7, wherein D is vitamin E.

[0237] 17. The compound according to exemplary embodiment 1, wherein R a It is an aryl group.

[0238] 18. The compound according to exemplary embodiment 1, wherein R a It is a phenyl group.

[0239] 19. The compound according to exemplary embodiment 1, wherein R b It is an aryl group.

[0240] 20. The compound according to exemplary embodiment 1, wherein R b It is a phenyl group.

[0241] 21. The compound according to exemplary embodiment 1, wherein R 4 It is CH3.

[0242] 22. The compound according to exemplary embodiment 1, wherein R 4 It is CHF2.

[0243] 23. The compound according to exemplary embodiment 1, wherein R 4 It is CF3.

[0244] 24. The compound according to exemplary embodiment 1, wherein Y 1It does not exist.

[0245] 25. The compound according to any one of exemplary embodiments 2-5, wherein R 1 It is a cyano group.

[0246] 26. The compound according to any one of exemplary embodiments 2-5, wherein R' is a halogen group.

[0247] 27. The compound according to any one of exemplary embodiments 2-5, wherein R' is a fluorine group.

[0248] 28. The compound according to any one of exemplary embodiments 2-5, wherein ring A is aryl.

[0249] 29. The compound according to any one of exemplary embodiments 2-5, wherein ring A is phenyl.

[0250] 30. The compound according to exemplary embodiment 2 or 3, wherein each R 2 All are CH3.

[0251] 31. The compound according to exemplary embodiment 2 or 4, wherein each R 2 Both are hydrogen.

[0252] 32. The compound according to exemplary embodiment 2 or 3, wherein at least one R 2 It is cyclopropyl.

[0253] 33. The compound according to exemplary embodiment 2 or 3, wherein at least one R 2 It is CH3.

[0254] 34. Selected from the following compounds:

[0255] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substance.

[0256] 35. A pharmaceutical composition comprising a compound, a tautomer, a deuterated derivative and / or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier, as described in any one of exemplary embodiments 1-34.

[0257] 36. A method for treating or alleviating a disease, symptom, or condition mediated by the regulation of the FPR1 protein, comprising administering to a subject in need a therapeutically effective amount of any one of the exemplary embodiments 1-34, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt, or the pharmaceutical composition of exemplary embodiment 35.

[0258] 37. A method for reducing the activity of FPR1 protein in a disease, symptom, or condition, comprising administering to a subject in need a therapeutically effective amount of any one of the exemplary embodiments 1-34, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt, or the pharmaceutical composition of exemplary embodiment 35.

[0259] 38. The method according to exemplary embodiment 36 or 37, wherein the disease, symptom or condition relates to the central nervous system (CNS), circulatory system, respiratory system and / or digestive system.

[0260] 39. The method according to exemplary embodiment 36 or 37, wherein the disease, symptom or condition is selected from: ARDS, stroke, TBI, glioblastoma, glioma, atherosclerosis, IBD and multiple sclerosis.

[0261] 40. The method according to exemplary embodiment 36 or 37, wherein the disease, symptom or condition is selected from: chronic granulomatous disease, Down syndrome, diabetic complications, hepatitis, rheumatoid arthritis, influenza virus, ulcer, pneumonia, HIV infection, cataract and glaucoma.

[0262] 41. The method according to any one of exemplary embodiments 36-40 further includes administering an existing standard therapy or an FDA-approved therapy to the subject.

[0263] 42. The method according to any one of exemplary embodiments 36-41, further comprising administering at least one additional agent to the subject.

[0264] 43. The method according to exemplary embodiment 41 or 42, wherein the at least one additional agent is selected from: anti-inflammatory agents, antioxidants, anti-allergic agents, anticancer agents, antithrombotic agents, antidiabetic agents, anti-infective agents, anti-neurodegenerative drugs, and adjuvant therapeutic agents.

[0265] Example Synthetic compounds To provide a full understanding of this disclosure, the following embodiments are provided. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the scope of this disclosure in any way.

[0266] All specific and general compounds, as well as intermediates disclosed for the preparation of these compounds, are considered part of this disclosure.

[0267] The compounds disclosed herein can be prepared according to standard chemical methods or the methods disclosed herein. In the following synthetic schemes and in the description of compounds of formula I, compounds 1-4, any pharmaceutically acceptable salts of these compounds, solvates of the aforementioned substances, and deuterated derivatives of any of the aforementioned substances, the following abbreviations are used: abbreviation Å = angstrom Ac = Acetyl group Ac₂O = Acetic anhydride Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-prop-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = Ethyl acetate EtOH = ethanol HOAc = Acetic acid KOAc = Potassium acetate LiHMDS = Lithium bis(trimethylsilyl)amide MeMgBr = Methylmagnesium bromide MeOH = methanol NaOAc = Sodium acetate NBS = N-bromosuccinimide Pd(dppf)₂Cl₂=[1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloro PTSA = p-Toluenesulfonic acid monohydrate rt = room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide TEA = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran TsCl = p-Toluenesulfonyl chloride UV = Ultraviolet light X-Phos=2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Synthesizing exemplary compounds: Compound 1: (S)-((4-cyano-N-(5-(((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-yl)phenyl)sulfonamido)methyl(3-methyl-1-phenyl-1H-pyrazole-5-yl)carbonate Option 1 Step 1. Preparation of chloromethyl (3-methyl-1-phenyl-1H-pyrazole-5-yl) carbonate: At 0 °C, chloromethyl chloroformate (296 mg, 2.30 mmol) was added to a THF solution (3 mL) of 5-methyl-2-phenylpyrazole-3-ol (200 mg, 1.15 mmol) and TEA (232 mg, 2.30 mmol). The reaction mixture was stirred under N2 for 1 hour at room temperature. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH / DCM = 1:10) to give the target product as a white solid (200 mg, yield 62.1%). Mass spectrometry (m / z): 267.0 [M+H] + .

[0268] Step 2. Preparation of iodomethyl (3-methyl-1-phenyl-1H-pyrazole-5-yl) carbonate: NaI (225 mg, 1.50 mmol) was added to a Me₂CO₃ solution (5 mL) of chloromethyl (3-methyl-1-phenyl-1H-pyrazole-5-yl) carbonate (200 mg, 0.749 mmol). The mixture was stirred at 40 °C for 18 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give a yellow oily target product (200 mg, yield 74.6%).

[0269] Step 3. Preparation of (S)-((4-cyano-N-(5-(((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-yl)phenyl)sulfonamide)methyl(3-methyl-1-phenyl-1H-pyrazole-5-yl) carbonate: Add potassium tert-butoxide (t-BuOK) (62.6 mg, 0.559 mmol) to a THF solution (5 mL) of iodomethyl(3-methyl-1-phenyl-1H-pyrazole-5-yl) carbonate (200 mg, 0.559 mmol) and (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbut-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (135 mg, 0.280 mmol). The mixture was stirred under N2 for 16 hours at room temperature. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC [Gemini-C18 150 x 21.2 mm, 5 μm; ACN-H2O (0.1% FA), 50-70] to give the desired product as a white solid (1.5 mg, yield: 3.8%). Mass spectrometry (m / z): 736.1 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 - 7.90 (m, 1H), 7.81 - 7.61 (m, 3H), 7.60 - 7.35 (m, 5H), 7.30 -7.25 (m, 1H), 7.25 - 6.62 (m, 3H), 6.60 - 6.25 (m, 1H), 6.25 – 5.20 (m, 2H), 4.23 – 3.81 (m, 3H), 3.75 – 3.60 (m, 1H), 2.48 – 2.35 (m, 3H), 1.39 – 1.15 (m, 3H), 1.10 – 0.76 (m, 9H).

[0270] Compound 2: [N-(5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-fluorophenyl)-1-methylpyrazol-4-yl)(4-cyanobenzene)sulfonamido]methyl{1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} carbonate Option 2 Step 1. Preparation of chloromethyl (1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate: NaH (60%, 77.8 mg, 1.94 mmol) was added to a DMSO solution (5 mL) of 1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol (200 mg, 1.30 mmol) at 0 °C under N2 conditions. Then, a DMSO solution (1 mL) of chloro(chloromethoxy) methyl ketone (184 mg, 1.43 mmol) was added dropwise. The resulting solution was stirred at room temperature for 16 hours. The mixture was quenched with a saturated aqueous NH4Cl solution (20 mL) and extracted with EA (20 mL x 2). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oily target product (133 mg, yield 41.6%). 1 H NMR (400MHz, CDCl3) δ 5.73 (s, 2H), 4.03 – 4.02 (m, 1H), 2.30 (dd, J = 7.3, 2.6 Hz, 1H),1.91 - 1.89 (s, 1H), 1.73 - 1.72 (m, 1H), 1.64 - 1.63 (m, 1H), 1.22 (d, J = 2.1Hz, 2H), 0.97 - 0.95 (m, 1H), 0.85 (s, 9H).

[0271] Step 2. Preparation of iodomethyl (1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate: NaI (118 mg, 0.786 mmol) was added to a Me₂CO₃ solution (5 mL) of chloromethyl (1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate (133 mg, 0.541 mmol). The mixture was stirred at 60 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily target product (181 mg, yield 98.9%). Mass spectrometry (m / z): 339.1 [M+H] + .

[0272] Step 3. Preparation of [N-(5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-fluorophenyl)-1-methylpyrazol-4-yl)(4-cyanophenyl)sulfonamido]methyl{1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl} carbonate: Add Cs2CO3 (351 mg, 1.08 mmol) to a DMF solution (5 mL) of iodomethyl(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate (181 mg, 0.536 mmol) and (S)-4-((4-cyanophenyl)sulfonamido)-N-(3,3-dimethylbut-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-carboxamide (130 mg, 0.269 mmol). The mixture was stirred under N2 at 50 °C for 16 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by pre-TLC (PE / EA = 1 / 2) to give the desired product as a white solid (17.5 mg, yield 4.67%). Mass spectrometry (m / z): 694.3 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 7.65 - 7.61 (m, 1H), 7.58 (d, J = 5.3 Hz, 1H), 7.42 (dd, J =26.3, 8.3 Hz, 2H), 7.07 (dd, J = 8.3, 5.3 Hz, 2H), 6.76 (t, J = 8.4 Hz, 2H), 5.74 (dd, J = 40.9, 10.6 Hz, 2H), 4.83 - 4.77 (m, 1H), 4.15 - 4.07 (m, 1H), 4.04 (d, J = 5.0 Hz, 3H), 2.40 – 2.32 (m, 1H), 1.88 (dd, J = 10.2, 5.9 Hz, 1H), 1.77 (d, J = 3.7 Hz, 1H), 1.62 (t, J= 5.0 Hz, 1H), 1.32 (s, 1H), 1.23 - 1.20 (m, 2H), 1.04 (s, 3H), 1.00 (s, 6H), 0.89 (d, J = 4.3 Hz, 6H), 0.86 – 0.83 (m, 6H).

[0273] Compound 3: [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-fluorophenyl)-1-methylpyrazol-4-yl)carbamoyl}propionate Option 3 Step 1. Preparation of 1-benzyl 4-chloromethyl succinate: NaHCO3 (3228 mg, 38.42 mmol) and Bu4NHSO4 (326 mg, 0.96 mmol) were added to a DCM / H2O (1:1, -40 mL) solution of 4-(benzyloxy)-4-oxobutyric acid (2000 mg, 9.61 mmol). The reaction mixture was stirred under N2 at -10 °C for 15 min, followed by the addition of chloro[(chlorosulfonyl)oxy]methane (2060 mg, 12.49 mmol). The reaction mixture was stirred under N2 at room temperature for 16 h. After the reaction was complete, H2O (200 mL) was added to the reaction mixture, followed by extraction with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified using Combiflash (PE / EA = 0–20%) to give a colorless oily product, 4-1-benzyl-4-chloromethylsuccinate (1940 mg, 78%). Mass spectrometry (m / z): 278.9 [M + Na] + .

[0274] Step 2. Preparation of benzyl (iodomethyl)succinate: NaI (2273 mg, 15.15 mmol) was added to an acetone solution (40 mL) of 1940 mg (7.56 mmol) of 4,1-benzyl-4-chloromethylsuccinate. The reaction mixture was stirred under N2 at 60 °C for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure to give a brown solid product, benzyl (iodomethyl)succinate (2000 mg, yield 62%). Mass spectrometry (m / z): 370.9 [M + Na] + .

[0275] Step 3. Preparation of 1-benzyl 4-[(5-methyl-2-phenylpyrazole-3-yl)oxy]methyl succinate: 5-methyl-2-phenylpyrazole-3-ol (1357 mg, 5.79 mmol) and K₂CO₃ (2154 mg, 11.58 mmol) were added to a DMF solution (40 mL) of benzyl (iodomethyl) succinate (2000 mg, 5.79 mmol). The reaction mixture was stirred under N₂ at 50 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified using Combiflash (PE / EA = 0–50%) to give a yellow oily product, 1-benzyl 4-[(5-methyl-2-phenylpyrazole-3-yl)oxy]methyl succinate (500 mg, 16%). Mass spectrometry (m / z): 395.0 [M+H] + .

[0276] Step 4. Preparation of 4-{[(5-methyl-2-phenylpyrazole-3-yl)oxy]methoxy}-4-oxobutyric acid: 10% Pd / C (50 mg) was added to a methanol solution (10 mL) of 1-benzyl 4-[(5-methyl-2-phenylpyrazole-3-yl)oxy]methylsuccinate (500 mg, 1.27 mmol). The reaction mixture was stirred under H2 at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a yellow solid product, 4-{[(5-methyl-2-phenylpyrazole-3-yl)oxy]methoxy}-4-oxobutyric acid (309 mg, 80%). Mass spectrometry (m / z): 304.9 [M+H] + .

[0277] Step 5. Preparation of [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-fluorophenyl)-1-methylpyrazol-4-yl)carbamoyl}propionate: Add 4-[(4-cyanobenzene)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-fluorophenyl)-2-methylpyrazol-3-carboxamide (79 mg, 0.16 mmol) and DCC (102 mg, 0.49 mmol) to a DMF solution (5 mL) of 4-{[(5-methyl-2-phenylpyrazol-3-yl)oxy]methoxy}-4-oxobutyric acid (50 mg, 0.16 mmol) and DCC (102 mg, 0.49 mmol). The reaction mixture was stirred under N2 at 50 °C for 2 hours. After the reaction was complete, H2O (100 mL) was added to the reaction mixture, followed by extraction with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified with Combiflash (PE / EA = 0–50%) to give a white solid product [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-fluorophenyl)-1-methylpyrazol-4-yl)carbamoyl}propionate (2 mg, 1%). Mass spectrometry (m / z): 770.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.85 (s, 2H), 7.73 (s,1H), 7.67 – 7.57 (m, 2H), 7.52 (s, 2H), 7.43 (s, 3H), 7.32 (t, J = 7.8 Hz, 1H), 7.02 (dt, J = 24.4, 8.8 Hz, 2H), 5.86 (s, 1H), 5.73 (s, 2H), 4.09 (d, J = 20.6Hz, 3H), 2.75 – 2.46 (m, 4H), 2.27 (s, 3H), 1.19 (dd, J = 20.8, 6.8 Hz, 3H), 1.00 (d, J = 4.4 Hz, 9H).

[0278] Compound 4: [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-methoxycyclohexyl)-1-methylpyrazol-4-yl)carbamoyl}propionate Option 4 Step 1. Preparation of [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-methoxycyclohexyl)-1-methylpyrazol-4-yl)carbamoyl}propionate: Add 4-[(4-cyanobenzene)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-methoxycyclohexyl)-2-methylpyrazol-3-carboxamide (49 mg, 0.1 mmol) and DCC (41 mg, 0.20 mmol) to a DMF solution (5 mL) of 4-{[(5-methyl-2-phenylpyrazol-3-yl)oxy]methoxy}-4-oxobutyric acid (30 mg, 0.1 mmol) and DCC (41 mg, 0.20 mmol). The reaction mixture was stirred under N2 at 40 °C for 2 hours. After the reaction was complete, H2O (100 mL) was added to the reaction mixture, followed by extraction with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified with Combiflash (PE / EA = 0–50%) to give a white solid product [(5-methyl-2-phenylpyrazol-3-yl)oxy]methyl 3-{[(4-cyanobenzene)sulfonyl](5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-methoxycyclohexyl)-1-methylpyrazol-4-yl)carbamoyl}propionate (1.5 mg, 1%). Mass spectrometry (m / z): 788.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.16 (dd, J = 19.2, 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 6.2 Hz, 2H), 7.44 (dd, J= 9.6, 6.0 Hz, 2H), 7.32 (s, 1H), 5.83 (s, 1H), 5.73 – 5.66(m, 2H), 3.98 (d, J = 17.2 Hz, 3H), 3.48 (s, 1H), 2.66 (s, 3H), 2.56 (s, 2H), 2.46 (s, 2H), 2.26 (s, 3H), 1.95 (s, 5H), 1.75 – 1.56 (m, 3H), 1.49 – 1.41(m, 2H), 1.12(dd, J = 34.6, 6.8 Hz, 3H), 0.95 (s, 9H).

[0279] General measurement procedure: Biochemical antioxidant assay DPPH reagent (SolaRbio, D9370-250 mg) stock solution (20 mM) and compound stock solution were both prepared with DMSO. Then, 10 μL / well of the compound (final concentration 100 μM) and 190 μL / well of DPPH reagent (DPPH stock solution diluted 1:100 with 70% ethanol, pH 4.0) were added to each well of a 96-well plate (Costar, 3590), and the plates were incubated for another 5 h at room temperature. The OD value at 515 nm was recorded, and the antioxidant effect of the test compound (compared to the solvent control group) was calculated using the following formula: Antioxidant effect (%) = {(A0-A1) / A0} x 100 Where A0 is the absorbance of the solvent control group and A1 is the absorbance of the test compound.

[0280] The results of the antioxidant assay are shown in Table 2 below.

[0281] Table 2. Results of antioxidant assays for the compounds

[0282] The above results indicate that the reference compound has no antioxidant activity. Compound 1 of this disclosure exhibits better antioxidant activity than the reference compound.

[0283] Cellular antioxidant activity assay IMR-32 cells were seeded in 96-well plates (Corning, 3603), and the test compound was prepared from the stock solution using the appropriate culture medium. Cells were incubated with the test compound (final concentration: 10 μM) at 37°C for 1 hour, followed by the addition of 0.5 μM fMLP (except for control wells) to the 96-well plates, and incubation at 37°C for another hour. Then, 10 μM DCFH-DA was added to the wells at 37°C, and incubation was continued for 30 minutes. Fluorescence intensity was measured using a fluorescence microplate reader at an emission wavelength of 538 nm and an excitation wavelength of 485 nm. The antioxidant effect of the test compound (compared to the solvent control group) was calculated using the following formula: Antioxidant effect (%) = {(F0-F1) / F0} x 100, where F0 is the fluorescence intensity of the solvent control group, and F1 is the fluorescence intensity of the test compound. The results of the cellular antioxidant assay are shown in Table 3 below.

[0284] Table 3. Results of the compounds in cellular antioxidant assays

[0285] The above results indicate that the coupling compounds disclosed herein have better antioxidant activity than the reference compounds alone and edaravone.

[0286] Other implementation plans This disclosure provides only exemplary embodiments. Those skilled in the art will readily recognize from this disclosure and the claims that various changes, modifications, and variations can be made without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

1. Compounds of Formula I: (I)， Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) X and Y are independently selected from: O, S, N, NR 4 C(R) 4 )2 and CR 4 And at least one of X and Y is O, S, N or NR. 4 ; (ii) Further, where R 4 Selected from: hydrogen, CH3, CHF2, and CF3; (iii) Z is C or N; Y 1 Not present or selected from: O, S, and NR 5 ; Furthermore, where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (iv) R a Selected from: straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R a Y, together with the atoms they are attached to, forms cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; (v) R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vi) Each R c Each is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; (vii) Each Y 2 and Y 3 Each of the following groups is either independent or selected from: ， Furthermore, each R 6 and R 7 It is independently selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, or it is not present; (viii) L 1 Not present or selected from: straight-chain alkyl, branched alkyl, cycloalkyl and PEG groups; (ix) Further, where each R 6 R 7 and L 1 Each is independently and optionally substituted by at least one group selected from the group consisting of: straight-chain alkyl, branched alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl. (x) D is selected from the following antioxidant compounds: 。 2. The compound according to claim 1, wherein the compound is of formula II: (II), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; or two R groups. 2 Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: 。 3. The compound according to claim 1, wherein the compound is of formula II-i: (II-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) D is selected from the following antioxidant compounds: 。 4. The compound according to claim 1, wherein the compound is of formula III: (III), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; or two R groups. 2 Groups link together to form heterocyclic groups; (vi) D is selected from the following antioxidant compounds: 。 5. The compound according to claim 1, wherein the compound is of formula III-i: (III-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) XYZ is selected from: –N(CH3)–N=C– and –C(CH3)=N–N–; (ii) Ring A is selected from: optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from: hydrogen, halogen groups and alkoxy groups; (iv) R 1 Independently selected from: hydrogen, halogen groups, cyano groups, and straight-chain alkyl, branched alkyl, and cycloalkyl groups; (v) D is selected from the following antioxidant compounds: 。 6. The compound according to any one of claims 1-5, wherein Z is C.

7. The compound according to any one of claims 1-5, wherein Z is N.

8. The compound according to any one of claims 1-7, wherein D is edaravone.

9. The compound according to any one of claims 1-7, wherein D is borneol.

10. The compound according to any one of claims 1-7, wherein D is T-0080.

11. The compound according to any one of claims 1-7, wherein D is NDGA.

12. The compound according to any one of claims 1-7, wherein D is vanillin.

13. The compound according to any one of claims 1-7, wherein D is quercetin.

14. The compound according to any one of claims 1-7, wherein D is vitamin A.

15. The compound according to any one of claims 1-7, wherein D is vitamin C.

16. The compound according to any one of claims 1-7, wherein D is vitamin E.

17. The compound according to claim 1, wherein R a It is an aryl group.

18. The compound according to claim 1, wherein R a It is a phenyl group.

19. The compound according to claim 1, wherein R b It is an aryl group.

20. The compound according to claim 1, wherein R b It is a phenyl group.

21. The compound according to claim 1, wherein R 4 It is CH3.

22. The compound according to claim 1, wherein R 4 It is CHF2.

23. The compound according to claim 1, wherein R 4 It is CF3.

24. The compound according to claim 1, wherein Y 1 It does not exist.

25. The compound according to any one of claims 2-5, wherein R 1 It is a cyano group.

26. The compound according to any one of claims 2-5, wherein R' is a halogen group.

27. The compound according to any one of claims 2-5, wherein R' is a fluorine group.

28. The compound according to any one of claims 2-5, wherein ring A is aryl.

29. The compound according to any one of claims 2-5, wherein ring A is phenyl.

30. The compound according to claim 2 or 4, wherein each R 2 All are CH3.

31. The compound according to claim 2 or 4, wherein each R 2 Both are hydrogen.

32. The compound according to claim 2 or 4, wherein at least one R 2 It is cyclopropyl.

33. The compound according to claim 2 or 4, wherein at least one R 2 It is CH3.

34. Selected from the following compounds: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substance.

35. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative and / or pharmaceutically acceptable salt of any one of claims 1-34, and at least one pharmaceutically acceptable carrier.

36. A method for treating or alleviating a disease, symptom, or condition mediated by the regulation of the FPR1 protein, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-34, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt, or a pharmaceutical composition of claim 35.

37. A method for reducing the activity of FPR1 protein in a disease, symptom, or condition, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-34, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt, or a pharmaceutical composition of claim 35.

38. The method of claim 36 or 37, wherein the disease, symptom, or condition relates to the central nervous system (CNS), circulatory system, respiratory system, and / or digestive system.

39. The method of claim 36 or 37, wherein the disease, symptom, or condition is selected from: ARDS, stroke, TBI, glioblastoma, glioma, atherosclerosis, IBD, and multiple sclerosis.

40. The method according to claim 36 or 37, wherein the disease, symptom or condition is selected from: chronic granulomatous disease, Down syndrome, diabetic complications, hepatitis, rheumatoid arthritis, influenza virus, ulcer, pneumonia, HIV infection, cataract and glaucoma.

41. The method according to any one of claims 36-40, further comprising administering to the subject an existing standard therapy or an FDA-approved therapy.

42. The method according to any one of claims 36-41, further comprising administering at least one additional agent to the subject.

43. The method of claim 42, wherein the at least one additional agent is selected from: anti-inflammatory agents, antioxidants, anti-allergic agents, anticancer agents, antithrombotic agents, antidiabetic agents, anti-infective agents, anti-neurodegenerative drugs, and adjuvant therapeutic agents.

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