FPR1 modulators, compositions comprising same, and methods of use thereof

Abstract

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

Description

[0001] Invention Field 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 composition comprising a compound of formula I, its tautomers, the compound or the deuterated derivative of the tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances; and a method of treating, for example, diseases, symptoms, or conditions mediated by the regulation of the formylpeptide receptor 1 (FPR1) protein using the aforementioned substances. Background of the Invention Nitric oxide (NO) donors are prodrugs that release NO in vivo. They refer to drugs that can produce NO independently or through interaction with other substances without the catalysis of nitric oxide enzyme (NOS). They can serve as a form of NO transport or storage in vivo, extending the half-life of NO and overcoming the inconvenience of inhaled NO. NO donor drugs are primarily prodrugs formed by linking the structure of a known drug or active compound with a NO donor through various linking groups. They can release the parent drug and NO in vivo through related enzymatic or non-enzymatic reactions. Studies have shown that due to the release of NO, NO donor drugs are generally more effective than the parent drug, and their adverse reactions are significantly lower. Currently, the research trend for NO donor drugs is to utilize the prodrug principle to combine NO donors with effective drugs to form more effective conjugated new drugs. This drug design method can improve drug bioavailability, enhance drug stability, reduce drug side effects, and / or promote long-term drug efficacy. Simultaneously, it possesses the characteristics of a NO donor and can exert NO-dependent biological activity. In recent years, research on NO donors has become one of the cutting-edge directions in the biomedical and pharmaceutical fields.

[0003] 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 the release of soluble mediators from invading pathogens or damaged lesions. This time-regulated, interactive repair process involves various 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-infection responses can transform into pathological responses, leading to excessive inflammation, edema, unnecessary fibrotic repair, organ dysfunction, acute respiratory distress syndrome (ARDS), sepsis, and ultimately organ failure and / or death. Therefore, effectively regulating the degree and duration of inflammation and resolution responses is essential for injury repair. Following tissue injury or pathogen infection (via bacteria, viruses, fungi, and / or microorganisms), a group of formyl peptides, damage-associated molecular pattern molecules (DMAPs), inflammatory lipid mediators (such as leukotrienes and lipoxygenin), and acute-phase proteins (such as annexin) can be released from invading pathogens, damaged cells, and diseased tissues. Three formyl peptide receptors (FPR1, FPR2, and FPR3) are key sensors for these chemotactic and activating molecules in the human body. These FPR receptors are highly expressed in neutrophils, macrophages, T lymphocytes, dendritic cells, epithelial cells, fibroblasts, microglia, and astrocytes. The binding of these chemically active molecules and acute proteins to FPR receptors can recruit leukocytes, stimulate the production of superoxide and cytokines, and activate microglia, astrocytes, and other inflammatory and remission responses, thereby repairing damage and defending the host.

[0004] On the other hand, pathological inflammatory responses resulting from imbalanced FPR receptor-mediated signal transduction can lead to various disease states following injury or infection, including, for example, cerebral edema, dysfunction, and organ failure after stroke or traumatic brain injury. Furthermore, chronic activation of FPR receptor-mediated signal transduction caused 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, characterized 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 remaining in the 30-50% range. Currently, there has been no significant progress in drug treatment. Mechanical ventilation is the primary interventional treatment for ARDS. The only proven method to reduce inflammation and mortality is the use of a lung-protective ventilation strategy with low tidal volume and high positive end-expiratory pressure. Therefore, there is an urgent need to develop more effective therapeutic compositions and methods for treating ARDS. FPR1 modulators can reduce vascular inflammation and limit pulmonary infiltration, thereby improving the condition of patients with ARDS.

[0006] Inflammatory bowel disease (IBD) is characterized by complex interactions between immune cells and tissue cells, and these interactions can be dysregulated. FPR1 is expressed in both immune cells and stromal cells (including epithelial cells), plays a central role in the recruitment of neutrophils to IBD, and contributes to the development of colitis.

[0007] Stroke is one of the leading causes of death worldwide, with limited treatment options. The FPR receptor is highly expressed in microglia, astrocytes, and the cerebrovascular system. Following induced intracerebral hemorrhage (ICH), infiltrating leukocytes, activated platelets, microglia, and astrocytes release a series of pro-inflammatory mediators, acute-phase proteins, and DMAPs from dying cells. FPR1 activation-induced leukocyte infiltration, reactive oxygen species (ROS) production, and cytokine release may be the initial wave of the post-injury inflammatory response, promoting the development of perihematoma edema and exacerbating the mass effects of stroke.

[0008] Traumatic brain injury (TBI) is a leading cause of disability worldwide. The global incidence of TBI is estimated at 200 cases per 100,000 people per year. Severe injury often leads 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.

[0009] 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 from injury, stress, and pathogens is involved in the pathophysiology of brain cancer.

[0010] Atherosclerosis is a leading and ever-growing cause of death and disability worldwide, and inflammation is involved in its development and the emergence of complications. Therefore, targeting inflammatory pathways offers a promising new approach for the prevention and treatment of atherosclerosis. Indeed, clinical studies have clearly demonstrated that the modulation of inflammation can prevent the clinical complications of atherosclerosis. This advance underscores the need to conduct 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 plaque stability.

[0011] Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, glial proliferation, axonal damage, and inflammation. It 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. Although there are no therapies that directly induce an enhanced repertoire of regulatory immune cells, numerous studies have shown the potential net effect of these cell types. Recently, FPR1 has been found to be important for host defense in demyelination. FPR1 deficiency can lead to reduced demyelination of the corpus callosum, as well as decreased expression of markers and cytokines of microglia or astrocytes in the corpus callosum and / or cortex after dicyclohexanone oxalyl dihydrazone feeding.

[0012] Given the foregoing, FPR1-NO bifunctional drugs, which combine the structure of FPR1 modulators with NO donors through various linking groups, may exhibit better therapeutic effects than the original FPR1 modulators. Furthermore, FPR1-NO bifunctional drugs possess the characteristics of NO donors and can provide NO-dependent biological activity. Therefore, there is still a need to develop FPR1-NO bifunctional drugs to effectively address the limited effective treatment options currently available for various diseases, such as ARDS, stroke, TBI, glioblastoma, glioma, atherosclerosis, and multiple sclerosis. Invention Overview One aspect of this disclosure provides a compound selected from formulas I, II, III, IV-i, IV-ii, and IV-iii, its tautomers, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, which can be used to treat diseases mediated by FPR1 protein signaling. For example, a compound having the following structural formula I is disclosed herein: (I), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: X and Y are independently selected from: O, S, N, NR4 C(R) 4 )2 and CR 4 And at least one of X and Y is O, S, N or NR. 4 ; Where R 4 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is either C or N; Y 1 Not present or selected from: bond, O, S and NR 5 ; Where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; 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; R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Each R c Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 2 Selected from: C(R) 6 2. O, S, and P, or they do not exist; Among them, each R 6 Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 3 Selected from: ester bonds, amide bonds, sulfonamide bonds, sulfate ester bonds, phosphoramide bonds, phosphate ester bonds, ketone bonds, aryl groups, C(O)-(CH2)2-C(O)-, -OC(O)-(CH2)2-C(O)-, -OC(O)-CH=CH-C(O)-, -C(O)-CH=CH-C(O)- and the following groups: , L 1It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by at least one group selected from the following groups: 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 5-membered heteroaryl and 6-membered heteroaryl.

[0014] In one aspect of this disclosure, the compound of formula I is selected from compounds 1-10 as shown below, their tautomers, deuterated derivatives of the compound or the tautomers, and pharmaceutically acceptable salts of the aforementioned substances.

[0015] In some embodiments, this disclosure provides pharmaceutical compositions comprising: compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, their tautomers, deuterated derivatives of said compounds or said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise: compounds selected from compounds 1-10 as shown below, their tautomers, said compounds or said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances. These compositions may also contain additional active pharmaceutical agents.

[0016] Another aspect of this disclosure provides a method for treating diseases, symptoms, or conditions mediated by the regulation of the FPR1 protein in a subject, comprising administering a therapeutically effective amount of a compound of formulas I, II, III, IV-i, IV-ii, and IV-iii, 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 compounds 1-10 as shown below, its tautomers, 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.

[0017] In some embodiments disclosed herein, the treatment method includes administering an additional active pharmaceutical agent to a subject in need, the active pharmaceutical agent being in the same pharmaceutical composition or in a separate composition with compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, their tautomers, deuterated derivatives of said compounds or said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances. In some embodiments disclosed herein, the treatment method includes administering a compound selected from compounds 1-10 as shown below, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, along with an additional active pharmaceutical agent, either in the same composition or in a separate composition.

[0018] This document also discloses methods for reducing FPR1 protein activity, comprising administering to a subject a therapeutically effective amount of a compound of formulas I, II, III, IV-i, IV-ii, and IV-iii, 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 FPR1 protein comprises administering to a subject a compound selected from compounds 1-10 below, its tautomers, 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. Invention Details I. Definition When the term "a / an" refers to a noun, as used herein, it encompasses the expression "at least one / an," thus covering both the singular and plural units of the noun. For example, "additional agents" refers to one, two, or more additional agents.

[0020] As used herein, the term "FPR1" or "formylpeptide receptor 1" refers to the receptor derived from human cells. FPR1 FPR1 is a gene-encoded cell surface receptor protein. It regulates various neutrophil functional responses and plays an important role in the pathogenesis of many diseases, including those mentioned above.

[0021] 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 either 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 their native state, for example, by binding to a receptor to activate that 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 their native state, for example, by blocking agonist-binding sites or allosteric-binding sites on the receptor to achieve a decreasing or inhibiting effect.

[0022] 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 relative amount of such isotopic aberrations in total will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic isotopes in total 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% of the compound.

[0023] 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.

[0024] 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 also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those that, in addition to replacing hydrogen with deuterium or tritium, or those that, use... 13 C or 14 Compounds having the structure of this application other than carbon substitution (C) are within the scope of this disclosure.

[0025] Unless otherwise stated, the structures described herein are also intended to include all isomers of the structures, 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.

[0026] 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.

[0027] As used in this article, “stereoisomer” refers to enantiomers and diastereomers.

[0028] 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"). 2 Compounds with H” substitution. It should be recognized that some variation in the natural isotope abundance can occur in the synthesized compounds, depending on the source of the chemical materials used in the synthesis. Despite such variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotope substitution in the deuterated derivatives described 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 at a level much higher than its natural isotope abundance (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).

[0029] 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.

[0030] 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.

[0031] 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 a 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. 12 Cycloalkyl. 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.

[0032] 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 a 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.

[0033] 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.

[0034] 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.

[0035] 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, 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.

[0036] As used herein, the term "heterocyclic group" refers to a non-aromatic (i.e., fully saturated or partially saturated, partially saturated because it contains 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 from heteroatoms such as 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, azacyclic butyl, oxacyclic butyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, etc.

[0037] 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 substituted nitrogen in a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0038] 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, thus the compound contains double or triple bonds.

[0039] 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.

[0040] The term "halogen" includes F, Cl, Br, and I, which are fluorine, chlorine, bromine, and iodine, respectively.

[0041] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0042] 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.

[0043] 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 the 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.

[0044] 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 heteroaryl includes 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 is substituted. In some embodiments, the heteroaryl has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl has one heteroatom. In some embodiments, the heteroaryl has two heteroatoms. In some embodiments, the heteroaryl is a monocyclic system having 5 ring members. In some embodiments, the heteroaryl is a monocyclic system having 6 ring members. In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is a 3-12 membered heteroaryl. 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.

[0045] A "spirocyclic system" refers to a ring system with two or more rings, where each pair of rings shares only one common atom.

[0046] 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 greater activity in vivo. Certain compounds of Formula I may include a prodrug group, as described in... Hydrolysis in Drug and Product Metabolism: Chemistry, Biochemistry, and Enzymology (See Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in certain circumstances, they can be more readily administered than the parent drug. For example, they may have bioavailability via oral administration, which the parent drug may not. Various prodrug derivatives are known in the art, such as those that depend on the hydrolytic cleavage or oxidative activation of the prodrug. One example (but not limited to) of a prodrug group may be part of a compound (such as an ester group) but subsequently hydrolyzed by metabolism to a carboxylic acid to release the active entity. Other examples of prodrug groups include peptide derivatives of the compound.

[0047] Non-limiting examples of suitable solvents that may be used in this disclosure include: water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (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).

[0048] 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).

[0049] 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).

[0050] 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.

[0051] 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, butynedi-1,4- Diasterates, hexyn-1,6-diasterates, 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.

[0052] Pharmaceutically acceptable salts derived from suitable bases include: alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4 Alkyl)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 halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0053] The term "subject" refers to animals, including but not limited to humans.

[0054] 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).

[0055] 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.

[0056] 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 such dose, amount, or weight percentage, which, as can be discerned by one of ordinary skill in the art, provides a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage.

[0057] The compounds and compositions of this application may be administered in combination therapy with one or more therapeutic agents (drug combinations) or modes of treatment, 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. When the compounds of this application are administered in combination with other therapies, the dosage of the co-administered compounds will naturally vary based on the type of combined drugs used, the specific drugs used, the condition being treated, etc. Combination therapy includes further administration 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 compounds capable of enhancing the effects 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 envisions the administration of two or more drugs in a single treatment cycle or course.

[0058] 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: 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 ; Where R 4 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is either C or N; Y 1 Not present or selected from: bond, O, S and NR 5 ; Where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; 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; R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Each R c Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 2 Selected from: C(R) 6 2. O, S, and P, or they do not exist; Among them, each R 6 Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 3 Selected from: ester bonds, amide bonds, sulfonamide bonds, sulfate ester bonds, phosphoramide bonds, phosphate ester bonds, ketone bonds, aryl groups, C(O)-(CH2)2-C(O)-, -OC(O)-(CH2)2-C(O)-, -OC(O)-CH=CH-C(O)-, -C(O)-CH=CH-C(O)- and the following groups: , L 1It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0059] In the second embodiment, X is NR among compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 Furthermore, all other variables not specifically defined herein are as defined in the first implementation scheme.

[0060] In the third embodiment, X is NR in the compounds of Formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 , where R 4 The methyl group is methyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0061] In the fourth embodiment, X is a CR in the compound of formula I, tautomer, deuterated derivative, or pharmaceutically acceptable salt. 4 Furthermore, all other variables not specifically defined herein are as defined in the first implementation scheme.

[0062] In the fifth embodiment, X is CR among compounds of formula I, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. 4 , where R 4 The methyl group is methyl; and all other variables not specifically defined herein are as defined in the first embodiment.

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

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

[0065] In the eighth 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 as defined in the first embodiment.

[0066] In the ninth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The key is defined here; and all other variables not specifically defined here are defined as in the first implementation scheme.

[0067] In the tenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is aryl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0068] In the eleventh embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is aryl, optionally substituted with halogen; and all other variables not specifically defined herein are as defined in the first embodiment.

[0069] In the twelfth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is aryl, optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0070] In the thirteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is a cycloalkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0071] In the fourteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy, branched-chain alkoxy, or cycloalkoxy; and all other variables not specifically defined herein are as defined in the first embodiment.

[0072] In the fifteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0073] In the sixteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is a cycloalkyl group, optionally substituted with a methoxy group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0074] In the seventeenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is a heterocyclic group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0075] In the eighteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. a It is tetrahydropyranyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0076] In the eighteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is aryl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0077] In the nineteenth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b The phenyl group is optionally substituted; and all other variables not specifically defined herein are as defined in the first embodiment.

[0078] In the twentieth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b The phenyl group is chlorinated; and all other variables not specifically defined herein are as defined in the first embodiment.

[0079] In the twenty-first embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is 4-chlorophenyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0080] In the twenty-second embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is a cyano-substituted phenyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0081] In the twenty-third embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. bIt is 4-cyanophenyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0082] In the twenty-fourth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b The phenyl group is a C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl substituted phenyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0083] In the twenty-fifth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is 4-cyclopropylphenyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0084] In the twenty-sixth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. b It is 4-methylphenyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0085] In the twenty-seventh embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. c The components are selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0086] In the twenty-eighth embodiment, R is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. c Selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl, wherein at least one R c The group is hydrogen; and all other variables not specifically defined herein are as defined in the first embodiment.

[0087] In the twenty-ninth embodiment, in a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, an R c The group is hydrogen, and the other R c The group is a branched C6 alkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0088] In the thirtieth embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The methylene group is used; and all other variables not specifically defined herein are defined as in the first embodiment.

[0089] In the thirty-first embodiment, Y is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 The ester bond is -OC(O)-; and all other variables not specifically defined herein are as defined in the first embodiment.

[0090] In the thirty-second embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 Selected from C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -CH2-ONO 2, -(CH2)2-ONO2, -(CH2)3-ONO2 or -CH2-CH(CH3)-ONO2 containing nitrate ester group.

[0091] In the thirty-third embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 =-C(CH3)2-CH2-ONO2; and all other variables not specifically defined herein are as defined in the first embodiment.

[0092] In the thirty-fourth embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The value is -C(CH3)-(CH2-ONO2)2; and all other variables not specifically defined herein are defined as in the first embodiment.

[0093] In the thirty-fifth embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The nitrate-containing ester ethers are selected from -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -O-(CH2)3-ONO2, -O-(CH2)2-ONO2 and isosorbide mononitrate; and all other variables not specifically defined herein are as defined in the first embodiment.

[0094] In the thirty-sixth embodiment, L is a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 Isosorbide mononitrate; and all other variables not specifically defined herein are as defined in the first embodiment.

[0095] In the thirty-seventh embodiment, in a compound of formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, L 1For ONO2; and all other variables not specifically defined herein are defined as in the first implementation scheme.

[0096] In the thirty-eighth embodiment, the compound disclosed herein is a compound having the following structural formula II: (II), 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; (vi) R 3 Not present or selected from: –OR” and –C(R”)3; (vii) R” is independently selected from: methylene, alkoxy, straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocycloalkyl, fused heterocycloalkyl, aryl and heteroaryl; (viii) R a It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0097] In the thirty-ninth 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 as defined in the thirty-eighth embodiment.

[0098] In the fortieth 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 as defined in the thirty-eighth embodiment.

[0099] In the forty-first embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted cycloalkyl group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0100] In the forty-second embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted heterocyclic group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0101] In the forty-third embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0102] In the forty-fourth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted heteroaryl group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0103] In the forty-fifth embodiment, ring A is aryl in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0104] In the forty-sixth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with a halogen; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0105] In the forty-seventh embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0106] In the forty-eighth embodiment, ring A is cycloalkyl in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0107] In the forty-ninth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with C1-C6 straight-chain alkoxy, branched-chain alkoxy or cycloalkoxy; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0108] In the fiftieth embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0109] In the fifty-first embodiment, in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with methoxy; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0110] In the fifty-second embodiment, ring A is a heterocyclic group in the compound of formula II, tautomer, deuterated derivative, or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0111] In the fifty-third embodiment, ring A is tetrahydropyranyl in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts. All other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0112] In the 54th embodiment, R' is a halogen in the compound of formula II, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the 38th embodiment.

[0113] In the 55th embodiment, R' is fluorine in the compounds of Formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 38th embodiment.

[0114] In the fifty-sixth embodiment, R' is a C1-C6 alkoxy group in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0115] In the fifty-seventh embodiment, R' is a methoxy group in compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0116] In the fifty-eighth embodiment, R' is a C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl in the compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0117] In the fifty-ninth embodiment, R' is hydrogen in the compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0118] In the sixtieth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a halogen; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0119] In the sixty-first embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is chlorine; and all other variables not specifically defined herein are defined as in the thirty-eighth implementation scheme.

[0120] In the sixty-second embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyano; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0121] In the sixty-third embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a C1-C6 cycloalkyl group; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0122] In the sixty-fourth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyclopropyl; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0123] In the sixty-fifth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1The methyl group is methyl; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0124] In the sixty-sixth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0125] In the sixty-seventh embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl groups, wherein at least one R 2 The group is hydrogen; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0126] In the sixty-eighth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0127] In the sixty-ninth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is hydrogen; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0128] In the seventieth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The methyl group is methyl; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0129] In the seventy-first embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is tert-butyl; and all other variables not specifically defined herein are defined as in the thirty-eighth implementation scheme.

[0130] In the seventy-second embodiment, for compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, R 2 Each instance is independently selected from hydrogen, methyl, and tert-butyl; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0131] In the seventy-third embodiment, for compounds of formula II, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, R 2 Each instance is independently selected from hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0132] In the seventy-fourth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 "-OR"; and all other variables not specifically defined here are defined as in the thirty-eighth implementation scheme.

[0133] In the seventy-fifth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 "-OR", where "R" is isosorbide monohydrate; and all other variables not specifically defined herein are defined as in the thirty-eighth embodiment.

[0134] In the seventy-sixth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 =-C(R”)3, wherein each instance of R” is independently selected from methyl and -C(CH3)2-CH2-ONO2; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0135] In the seventy-seventh embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 The form is -C(R”)3, where one instance of R” is methyl and both instances of R” are -C(CH3)2-CH2-ONO2; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0136] In the seventy-eighth embodiment, R is a compound of formula II, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 3 The value is -C(R”)3, where two instances of R’’ are methyl groups and one instance of R’’ is -C(CH3)2-CH2-ONO2; and all other variables not specifically defined herein are as defined in the thirty-eighth embodiment.

[0137] In the seventy-ninth embodiment, the compound disclosed herein is a compound having the following structural formula III: (III), 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; (vi) R” is selected from: hydrogen and optionally substituted straight-chain alkyl and branched-chain alkyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0138] In the 80th 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 as defined in the 79th embodiment.

[0139] In the 81st 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 as defined in the 79th embodiment.

[0140] In the 82nd embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted cycloalkyl group; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0141] In the 83rd embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted heterocyclic group; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0142] In the 84th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0143] In the 85th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted heteroaryl group; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0144] In the 86th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with a halogen; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0145] In the 87th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0146] In the 88th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with C1-C6 straight-chain alkoxy, branched-chain alkoxy or cycloalkoxy; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0147] In the 89th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0148] In the 90th embodiment, in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with methoxy; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0149] In the ninety-first embodiment, ring A is tetrahydropyranyl in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the seventy-ninth embodiment.

[0150] In the 92nd 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 as defined in the 79th embodiment.

[0151] In the 93rd embodiment, R' is fluorine in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0152] In the 94th embodiment, R' is a C1-C6 alkoxy group in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0153] In the 95th embodiment, R' is methoxy in compounds of formula III, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0154] In the 96th embodiment, R' is a C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl in the compound of formula III, tautomer, deuterated derivative, or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0155] In the 97th embodiment, R' is hydrogen in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0156] In the 98th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a halogen; and all other variables not specifically defined herein are defined as in the 79th implementation scheme.

[0157] In the ninety-ninth embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is chlorine; and all other variables not specifically defined herein are defined as in the 79th implementation scheme.

[0158] In the first hundredth 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 as defined in the 79th embodiment.

[0159] In the 101st embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1It is a C1-C6 cycloalkyl group; and all other variables not specifically defined herein are as defined in the seventy-ninth embodiment.

[0160] In the first 102nd embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyclopropyl; and all other variables not specifically defined herein are defined as in the 79th embodiment.

[0161] In the first 103rd embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 79th embodiment.

[0162] In the first 104th embodiment, 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 and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the seventy-ninth embodiment.

[0163] In the first 105th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl, wherein at least one R 2 The group is hydrogen; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0164] In the first 106th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the seventy-ninth embodiment.

[0165] In the 107th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is hydrogen; and all other variables not specifically defined herein are defined as in the 79th implementation scheme.

[0166] In the first 108th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 79th embodiment.

[0167] In the first 109th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is tert-butyl; and all other variables not specifically defined herein are defined as in the 79th implementation scheme.

[0168] In the first 110th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and tert-butyl; and all other variables not specifically defined herein are defined as in the seventy-ninth embodiment.

[0169] In the 111th embodiment, R is a compound of formula III, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are defined as in the seventy-ninth embodiment.

[0170] In the 112th embodiment, R'' is methyl in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0171] In the 113th embodiment, R'' is -CH2-ONO2 in the compound of formula III, tautomer, deuterated derivative or pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in the 79th embodiment.

[0172] In the 114th embodiment, the compound disclosed herein is a compound having the following structural formula IV-i: (IV-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) Ring A is selected from: optionally substituted 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (iv) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0173] In the 115th embodiment, XYZ is –N(CH3)–N=C– in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0174] In the 116th embodiment, XYZ is –C(CH3)=N–N– in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0175] In the 117th embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0176] In the 118th embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with a halogen; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0177] In the 119th embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl, optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0178] In the first 120th embodiment, in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is cycloalkyl; and all other variables not specifically defined herein are as defined in the first 114th embodiment.

[0179] In the first 121 embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with C1-C6 straight-chain alkoxy, branched-chain alkoxy or cycloalkoxy; and all other variables not specifically defined herein are as defined in the first 114 embodiment.

[0180] In the 122nd embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0181] In the first 123rd embodiment, in the compound of formula IV-i, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with methoxy; and all other variables not specifically defined herein are as defined in the first 114th embodiment.

[0182] In the 124th embodiment, R' is a halogen in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0183] In the first 125th embodiment, R' is fluorine in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 114th embodiment.

[0184] In the first 126th embodiment, R' is a C1-C6 alkoxy group in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 114th embodiment.

[0185] In the 127th embodiment, R' is methoxy in compounds of formula IV-i, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0186] In the 128th embodiment, R is a compound of formula IV-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 defined as in the 114th implementation scheme.

[0187] In the 129th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is chlorine; and all other variables not specifically defined herein are defined as in the 114th implementation scheme.

[0188] In the first 130th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt.1 It is cyano; and all other variables not specifically defined herein are defined as in the 114th embodiment.

[0189] In the 131st embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a C1-C6 cycloalkyl group; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0190] In the 132nd embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 114th implementation scheme.

[0191] In the 133rd embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0192] In the 134th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl, wherein at least one R 2 The group is hydrogen; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0193] In the 135th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0194] In the 136th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 For hydrogen; and all other variables not specifically defined herein are defined as in the 114th implementation scheme.

[0195] In the 137th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 114th implementation scheme.

[0196] In the 138th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is tert-butyl; and all other variables not specifically defined herein are defined as in the 114th implementation scheme.

[0197] In the 139th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and tert-butyl; and all other variables not specifically defined herein are defined as in the 114th embodiment.

[0198] In the first 140th embodiment, R is a compound of formula IV-i, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are as defined in the 114th embodiment.

[0199] In the 141st embodiment, the compound disclosed herein is a compound having the following structural formula IV-ii: (IV-ii), 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 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0200] In the first 142 embodiment, XYZ is –N(CH3)–N=C– in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 141 embodiment.

[0201] In the first 143 embodiment, XYZ is –C(CH3)=N–N– in compounds of formula IV-ii, tautomers, deuterated derivatives or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 141 embodiment.

[0202] In the 144th embodiment, in the compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted cycloalkyl group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0203] In the first 145th embodiment, in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted heterocyclic group; and all other variables not specifically defined herein are as defined in the first 141th embodiment.

[0204] In the 146th embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0205] In the 147th embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is an optionally substituted heteroaryl group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0206] In the 148th embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with a halogen; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0207] In the 149th embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is aryl and optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0208] In the first 150th embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is cycloalkyl, optionally substituted with C1-C6 straight-chain alkoxy, branched-chain alkoxy or cycloalkoxy; and all other variables not specifically defined herein are as defined in the first 141 embodiment.

[0209] In the 151st embodiment, in the compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0210] In the 152nd embodiment, in the compound of formula IV-ii, tautomer, deuterated derivative or pharmaceutically acceptable salt, ring A is a cycloalkyl group, optionally substituted with a methoxy group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0211] In the first 153 embodiment, ring A is tetrahydropyranyl in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 141 embodiment.

[0212] In the 154th embodiment, R' is a halogen in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0213] In the 155th embodiment, R' is fluorine in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0214] In the 156th embodiment, R' is a C1-C6 alkoxy group in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0215] In the 157th embodiment, R' is methoxy in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0216] In the 158th embodiment, R' is a C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0217] In the 159th embodiment, R' is hydrogen in compounds of formula IV-ii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0218] In the first 160th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a halogen; and all other variables not specifically defined herein are defined as in the 141st implementation scheme.

[0219] In the 161st embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is chlorine; and all other variables not specifically defined herein are defined as in implementation 141.

[0220] In the 162nd embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyano; and all other variables not specifically defined herein are defined as in the 141st implementation scheme.

[0221] In the first 163rd embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a C1-C6 cycloalkyl group; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0222] In the 162nd embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyclopropyl; and all other variables not specifically defined herein are defined as in the 141st embodiment.

[0223] In the first 163rd embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 141st implementation scheme.

[0224] In the first 164th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0225] In the first 165th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl, wherein at least one R 2 The group is hydrogen; and all other variables not specifically defined herein are as defined in embodiment 141.

[0226] In the 166th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0227] In the 167th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 For hydrogen; and all other variables not specifically defined herein are defined as in implementation 141.

[0228] In the 168th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 141st implementation scheme.

[0229] In the 169th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is tert-butyl; and all other variables not specifically defined herein are defined as in the 141st implementation scheme.

[0230] In the 170th embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and tert-butyl; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0231] In the 171st embodiment, R is a compound of formula IV-ii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are as defined in the 141st embodiment.

[0232] In the 172nd embodiment, the compound disclosed herein is a compound having the following structural formula IV-iii: (IV-iii), 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 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0233] In the first seventy-third embodiment, XYZ is –N(CH3)–N=C– in compounds of formula IV-iii, tautomers, deuterated derivatives or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first seventy-second embodiment.

[0234] In the first seventy-fourth embodiment, XYZ is –C(CH3)=N–N– in compounds of formula IV-iii, tautomers, deuterated derivatives or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first seventy-twoth embodiment.

[0235] In the first 175th embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted cycloalkyl group; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0236] In the first seventy-fourth embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted heterocyclic group; and all other variables not specifically defined herein are as defined in the first seventy-twoth embodiment.

[0237] In the first 175th embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0238] In the first seventy-sixth embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is an optionally substituted heteroaryl group; and all other variables not specifically defined herein are as defined in the first seventy-twoth embodiment.

[0239] In the first seventy-seventh embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is aryl and optionally substituted with a halogen; and all other variables not specifically defined herein are as defined in the first seventy-two embodiment.

[0240] In the first seventy-eighth embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is aryl and optionally substituted with fluorine; and all other variables not specifically defined herein are as defined in the first seventy-second embodiment.

[0241] In the 179th embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy, branched-chain alkoxy, or cycloalkoxy group; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0242] In the first 180th embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is a cycloalkyl group, optionally substituted with a C1-C6 straight-chain alkoxy group; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0243] In the first 181 embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is a cycloalkyl group, optionally substituted with a methoxy group; and all other variables not specifically defined herein are as defined in the first 172 embodiment.

[0244] In the first 182nd embodiment, in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, ring A is tetrahydropyranyl; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0245] In the first 183rd embodiment, R' is a halogen in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0246] In the first 184th embodiment, R' is fluorine in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0247] In the first 185th embodiment, R' is a C1-C6 alkoxy group in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0248] In the first 186th embodiment, R' is methoxy in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first 172nd embodiment.

[0249] In the 187th embodiment, R' is a C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0250] In the first eighty-eighth embodiment, R' is hydrogen in compounds of formula IV-iii, tautomers, deuterated derivatives, or pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in the first seventy-second embodiment.

[0251] In the 189th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a halogen; and all other variables not specifically defined herein are defined as in the 172nd implementation scheme.

[0252] In the first 190th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt.1 It is chlorine; and all other variables not specifically defined herein are defined as in implementation 172.

[0253] In the 191st embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyano; and all other variables not specifically defined herein are as defined in implementation 172.

[0254] In the 192nd embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is a C1-C6 cycloalkyl group; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0255] In the 193rd embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 It is cyclopropyl; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0256] In the 194th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 1 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 172nd embodiment.

[0257] In the 195th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The variables are independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0258] In the 196th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Independently selected from hydrogen and C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl, wherein at least one R 2 The group is hydrogen; and all other variables not specifically defined herein are as defined in embodiment 172.

[0259] In the 197th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2The variables are independently selected from C1-C6 straight-chain alkyl, branched alkyl, or cycloalkyl; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0260] In the 198th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 For hydrogen; and all other variables not specifically defined herein are defined as in implementation 172.

[0261] In the 199th embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 The methyl group is defined as methyl; and all other variables not specifically defined herein are defined as in the 172nd embodiment.

[0262] In the second hundredth embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 It is tert-butyl; and all other variables not specifically defined herein are defined as in implementation 172.

[0263] In the second 101st embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and tert-butyl; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0264] In the second 202nd embodiment, R is a compound of formula IV-iii, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt. 2 Each instance is independently selected from hydrogen, methyl, and cyclopropyl; and all other variables not specifically defined herein are as defined in the 172nd embodiment.

[0265] In some embodiments, at least one compound of this disclosure is selected from compounds 1-10 shown in Table 1 below, their tautomers, deuterated derivatives of the compound or the tautomers, or pharmaceutically acceptable salts of the aforementioned substances.

[0266] Table 1

[0267] 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, III, IV-i, IV-ii and IV-iii, compounds 1-5, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances; or a pharmaceutical composition comprising any of the foregoing substances and at least one pharmaceutically acceptable carrier.

[0268] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable excipients and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0269] It will also be understood that the pharmaceutical compositions disclosed herein can be used in combination therapies; that is, the pharmaceutical compositions disclosed herein may further comprise additional active pharmaceutical agents. Alternatively, a pharmaceutical composition comprising compounds selected from formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or any of the foregoing substances, may be administered as a standalone composition, concurrently with, before, or after a composition comprising additional active pharmaceutical agents.

[0270] As described above, the pharmaceutical compositions disclosed herein include pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may be selected from adjuvants and excipients. As used herein, pharmaceutically acceptable carriers may be selected from, for example, any and all solvents, diluents, other liquid carriers, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, which are suitable for the desired specific dosage form. Various carriers for formulating pharmaceutical compositions and known techniques for their preparation are disclosed in Remington. The Science and Practice of Pharmacy ,21st edition, 2005, ed. DB Troy, Lippincott Williams&Wilkins, Philadelphia,and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988 to 1999, Marcel Dekker, New York. Unless any conventional carrier is incompatible with the compounds of this disclosure, for example, producing any undesirable biological effects or interacting harmfully with any other component of the pharmaceutical composition, its use should be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of partial glycerides of saturated vegetable fatty acids, water, salts and electrolytes (such as proteinamine sulfate, disodium hydrogen phosphate, potassium 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 carboxylic acid...). Sodium methylcellulose, ethylcellulose, and cellulose acetate), astragalus gum 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 solution, non-toxic and compatible lubricants (such as sodium dodecyl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants.

[0271] III. Treatment methods and applications In another aspect of this disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, said compounds or deuterated derivatives of said tautomers, pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, are disclosed for the treatment of diseases, symptoms, or conditions mediated by FPR1 protein regulation. In another aspect, the use of said compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, is disclosed for the preparation of medicaments for treating diseases, symptoms, or conditions mediated by FPR1 protein regulation. On the other hand, this document also discloses a method for treating a disease, condition, or illness mediated by the FPR1 protein in a subject, comprising administering a therapeutically effective amount of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, the compounds or deuterated derivatives of the tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof.

[0272] In some implementations, the disease, condition, or ailment is related to the central nervous system (CNS). In some implementations, the disease, condition, or ailment is selected from: stroke, multiple sclerosis, dementia, Alzheimer's disease, Parkinson's disease, Pix's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizures, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sach's disease, Sandhoff's disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedrich's ataxia, Wilson's disease, Menke's syndrome, autosomal dominant cerebral arteriosclerosis with subcortical infarction (CADASIL), spinal muscular atrophy, muscular dystrophy, and Charcot-Marie Tooth disease. Diseases, neurofibromatosis, von Hippel-Lindau disease, Fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waldenberg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Hidege syndrome, olivopontocerebellar degeneration, striatum substantia nigra degeneration, Guillain-Barré syndrome, burning pain, type I and II complex regional pain syndromes, diabetic neuropathy and alcoholic neuropathy, trigeminal neuralgia, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, spinal cord disease, traumatic brain injury, trauma Spinal cord injury, radiation-induced brain injury, multiple sclerosis, postmeningitis syndrome, prions, myelitis, radiculitis, diabetes mellitus associated with abnormal proteinemia, thyroxine-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy-related neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, polyneuritis of the skull, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0273] In some implementations, the disease, condition, or illness is associated with the following: brain cancers, such as meningioma, meningeal sarcoma, glioma, astrocytoma, medulloblastoma, neuroblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, sarcoma; respiratory and / or lung cancers, including pulmonary nodules, non-small cell lung cancer, small cell lung cancer, and mesothelioma; gastrointestinal cancers, such as esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, and liver cancer; bone cancer, malignant lymphoma, multiple myeloma, and hematologic disorders. In some implementations, the disease, condition, or illness is coronary artery disease or peripheral artery disease, specifically atherosclerosis or multiple sclerosis. In some implementations, the disease, condition, or illness is a respiratory system lung disease (acute respiratory distress syndrome, acute lung injury, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis). In some implementations, the disease, symptom, or condition is inflammatory bowel disease (Crohn's disease and ulcerative colitis).

[0274] In one embodiment, the disease, condition, or illness is stroke (thrombotic stroke, embolic stroke, thromboembolic stroke, hemorrhagic stroke, venous constrictive stroke, and venous stroke). In one embodiment, the disease, condition, or illness is traumatic brain injury. In one embodiment, the disease, condition, or illness is malignant glioma. In one embodiment, 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.

[0275] In another aspect of this disclosure, the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, are used for modulating FPR1 activity. In another aspect, the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, said compounds or deuterated derivatives of said tautomers, and / or pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof, are used in the preparation of a medicament for modulating FPR1 activity. In another aspect, this document discloses a method for modulating FPR1 activity, comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, 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, comprising contacting FPR1 with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein (including compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, their tautomers, said compounds or deuterated derivatives of said tautomers, pharmaceutically acceptable salts of the aforementioned substances, or pharmaceutical compositions thereof).

[0276] Compounds of formulas I, II, III, IV-i, IV-ii and IV-iii, compounds 1-5, 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.

[0277] In some embodiments, 2-1500 mg or 5-1000 mg of compounds of formulas I, II, III, IV-i, IV-ii and IV-iii, compounds 1-5, their tautomers, deuterated derivatives of the compounds or the tautomers and / or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, are administered once daily, twice daily or three times daily.

[0278] Compounds of formulas I, II, III, IV-i, IV-ii, and IV-iii, compounds 1-5, 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, or by oral, parenteral, sublingual, topical, rectal, nasal, buccal, vaginal, transdermal, patch, pump, or via implanted reservoir, and the pharmaceutical composition will be formulated accordingly. Parenteral administration includes, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration. Parenteral administration may be performed, for example, by continuous infusion over a selected time period. Other forms of application considered in this disclosure are described in international patent applications WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142 and WO2015 / 023915.

[0279] The useful 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 in mice and other animals to humans are known in the art; see, for example, U.S. Patent 4,938,949.

[0280] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of the pharmaceutically acceptable salt form of that compound is equal to the amount of the free base concentration of that compound. The amounts of compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives disclosed herein are 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 a concentration of a pharmaceutically acceptable salt of a compound of formula I equivalent to 1000 mg of a compound of formula I. In another aspect of this disclosure, the compounds and compositions disclosed herein can be administered in combination therapy 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 amounts. For example, a synergistic effect may be produced with antioxidants or anti-inflammatory substances. When the compounds disclosed herein are administered in combination with other therapies, the dosage of the co-administered compounds will naturally vary depending on the type of co-medication used, the specific drug used, the condition being treated, etc. Combination therapy includes the further administration of a target compound in combination with one or more other bioactive ingredients or non-pharmacological therapies (e.g., surgery or radiation therapy). For example, the compounds disclosed herein may be used in combination with other pharmaceutically active compounds, preferably compounds that enhance the effects of the compounds disclosed herein. The compounds disclosed herein may be administered simultaneously (as a single formulation or alone) or sequentially with other pharmaceutical therapies or modes of treatment. Typically, combination therapy envisions the administration of two or more drugs during a single treatment cycle or course.

[0281] Non-limiting exemplary implementation 1. Compound 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: 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 ; Where R 4 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is either C or N; Y 1 Not present or selected from: bond, O, S and NR 5 ; Where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; 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; R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Each R c Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 2 Selected from: C(R) 4 2. O, S, and P, or they do not exist; Y 3 Selected from: ester bonds, amide bonds, sulfonamide bonds, sulfate ester bonds, phosphoramide bonds, phosphate ester bonds, ketone bonds, aryl groups, C(O)-(CH2)2-C(O)-, -OC(O)-(CH2)2-C(O)-, -OC(O)-CH=CH-C(O)-, -C(O)-CH=CH-C(O)- and the following groups: , L 1 It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

[0282] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein X is NR. 4 , where R 4 It is a methyl group.

[0283] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein Y is N.

[0284] 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein Z is C.

[0285] 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein Y 1 For key.

[0286] 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R a It is 4-fluorophenyl.

[0287] 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R a It is 4-methoxycyclohexyl.

[0288] 8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R a It is a tetrahydropyranyl group.

[0289] 9. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R b It is 4-chlorophenyl.

[0290] 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R b It is 4-cyanophenyl.

[0291] 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R b It is 4-cyclopropylphenyl.

[0292] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R b It is 4-methylphenyl.

[0293] 13. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R c At least one instance is hydrogen.

[0294] 14. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein R c One example is hydrogen, R c Another example is .

[0295] 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein L 1It is isosorbide monohydrate.

[0296] 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein L 1 It is C(CH3)-(CH2-ONO2)2.

[0297] 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein L 1 It is isosorbide monohydrate.

[0298] 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein L 1 It is C(CH3)2-(CH2-ONO2).

[0299] 19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein the structure of the compound is of formula (II).

[0300] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 19, wherein the compound has the structure of formula (III).

[0301] 21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, 19 or 20, wherein the structure of the compound is of formula (IV-i).

[0302] 22. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiments 1, 19, 20, or 21, wherein the compound has the structure of formula (IV-ii).

[0303] 23. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 19, wherein the structure of the compound is of formula (IV-iii).

[0304] 24. Selected from the following compounds:

[0305] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substance.

[0306] 25. 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 embodiments 1-24.

[0307] 26. 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 compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts of embodiments 1-24, or the pharmaceutical composition of embodiment 25.

[0308] 27. 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 a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt of any one of embodiments 1-24, or a pharmaceutical composition of embodiment 25.

[0309] 28. A method for treating or alleviating a disease, symptom, or condition mediated by FPR1 protein regulation, comprising administering to a subject in need a therapeutically effective amount of a compound selected from:

[0310] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substance.

[0311] 29. 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 a compound selected from:

[0312] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substance.

[0313] 30. Any of the methods in embodiments 26-29, wherein the disease, condition, or symptom is related to the central nervous system (CNS), circulatory system, respiratory system, and digestive system. In some embodiments, the disease, condition, or symptom is selected from: stroke, dementia, Alzheimer's disease, Parkinson's disease, Pix's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizures, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tey-Sachs disease, Sandhof's disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedrich's ataxia, Wilson's disease, Menkes syndrome, and subcortical infarction. Death-related autosomal dominant cerebral arteriosclerosis (CADASIL); spinal muscular atrophy, muscular dystrophy, peroneal muscular atrophy, neurofibromatosis, von Hippel-Lindau disease, fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waddenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Hildegerd syndrome, olivopontocerebellar degeneration, striatum. Degeneration, Guillain-Barré syndrome, burning pain, type I and II complex regional pain syndromes, diabetic neuropathy and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation-induced brain injury, multiple sclerosis, postmeningitis syndrome, prions, myelitis, radiculitis, diabetes mellitus associated with abnormal proteinemia, thyroxine-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, cranial polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma. In some implementations, the disease, condition, or illness is respiratory and / or lung cancer, including pulmonary nodules, non-small cell lung cancer, small cell lung cancer, and mesothelioma; gastrointestinal cancers, such as esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, and liver cancer; bone cancer, malignant lymphoma, multiple myeloma, and hematologic disorders. In some implementations, the disease, condition, or illness is coronary artery disease or peripheral artery disease, specifically atherosclerosis or multiple sclerosis. In some implementations, the disease, condition, or illness is a respiratory lung disease (acute respiratory distress syndrome, acute lung injury, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis). In some implementations, the disease, condition, or illness is an inflammatory bowel disease (Crohn's disease and ulcerative colitis).

[0314] 31. The method of embodiment 30, wherein the disease, condition, or illness is stroke (thrombotic stroke, embolic stroke, thromboembolic stroke, hemorrhagic stroke, venous constrictive stroke, and venous stroke). In one embodiment, the disease, condition, or illness is traumatic brain injury. In one embodiment, the disease, condition, or illness is malignant glioma. In one embodiment, the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglioglioma.

[0315] 32. The method of implementation scheme 31, wherein the malignant glioma is glioblastoma.

[0316] 33. Any of the methods in Implementation Scheme 26-32, further comprising administering existing standard treatment or FDA-approved therapy to the subject.

[0317] 34. Any of the methods in Implementation Schemes 26-33, further comprising administering at least one additional agent to the subject.

[0318] 35. The method of embodiment 34, wherein the at least one additional agent is selected from: anti-inflammatory agents, antioxidants, and adjuvant therapeutic agents.

[0319] Example Compound Synthesis To fully understand 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 this disclosure in any way.

[0320] All specific and general compounds, as well as the disclosed intermediates for the preparation of these compounds, are considered part of this disclosure.

[0321] The compounds disclosed herein can be prepared according to standard chemical practice or as described herein. Throughout the following synthetic schemes and descriptions of the preparation of compounds of formula I, compounds 1-5, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing substances, and deuterated derivatives of any of the foregoing substances, the following abbreviations are used: abbreviation Å = angstrom Ac = Acetyl group Ac₂O = Acetic anhydride Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-2-amino 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)amino 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 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 X-Phos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Synthesis of intermediates: Intermediate 1: Iodomethyl ((3S,3aR,6R,6aS)-6-(nitoxy)hexahydrofurano[3,2-b]furan-3-yl) carbonate Option 1 Step 1. (3S,3aR,6R,6aS) Preparation of 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-ylchloromethyl carbonate: (3R,3aS,6S,6aR)6-Hydroxy-hexahydrofurano[3,2-b]furan-3-yl nitrate (5.0 g, 0.0262 mol) was dissolved in DCM (50 mL), and pyridine (6.22 g, 0.786 mol) and methyl chloroformate (3.72 g, 0.0288 mol) were added. The reaction was stirred at 20 °C for 2 hours. The residue was diluted with water and then extracted with DCM (150 mL × 3), washed successively with NH4Cl solution and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE: EA = 0 ~ 5%) to give a white solid product (3.7 g, yield 47.3%). 1 H NMR (400 MHz, CDCl3) δ 5.72 (q, J = 6.4 Hz, 2H), 5.36 (td, J = 5.6, 2.8 Hz, 1H), 5.17 (d, J = 3.0 Hz, 1H), 5.00(t, J = 5.2 Hz, 1H), 4.55 (d, J = 5.0 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.99-4.05(m, 2H), 3.90 (dd, J = 11.4, 5.6 Hz, 1H).

[0322] Step 2. 3S, 3aR, 6R, 6aS Preparation of 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yliodomethyl carbonate: ( 3S, 3aR, 6R, 6aS 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-ylchloromethyl carbonate (100 mg, 0.353 mmol) was dissolved in acetone (3 mL), and NaI (106 mg, 0.705 mmol) was added. The reaction mixture was stirred at 55 °C for 2 hours. The residue was diluted with water, then extracted with EtOAc (50 mL × 3), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a yellow oily crude product (70 mg, yield 47.7%). Mass spectrometry (m / z): 375.9 [M+H] + .

[0323] Synthesis of exemplary compounds: (3R,3aS,6S,6aR)-6-({[(1-{4-[(4-chlorobenzene)sulfonamido]-5-(4-fluorophenyl)-2-methylpyrazol-3-yl}-N-[(2S)-3,3-dimethylbut-2-yl]formamido]methoxy]carbonyl}oxy)-hexahydrofurano[3,2-b]furan-3-yl nitrate Option 2 (3R,3aS,6S,6aR) Preparation of -6-({[(1-{4-[(4-chlorobenzene)sulfonamido]-5-(4-fluorophenyl)-2-methylpyrazol-3-yl}-N-[(2S)-3,3-dimethylbut-2-yl]carbamate)methoxy]carbonyl}oxy)-hexahydrofurano[3,2-b]furan-3-yl nitrate: 4-[(4-chlorobenzene)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-fluorophenyl)-2-methylpyrazol-3-carbamate (200 mg, 0.406 mmol) was dissolved in THF (4 mL), and tBuOK (91 mg, 0.811 mmol) and (3S,3aR,6R,6aS) 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yliodomethyl carbonate (228 mg, 0.609 mmol). The reaction mixture was stirred at 20 °C for 16 h. The residue was diluted with water, extracted with EtOAc (50 mL × 3), washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE / EA = 0 ~ 100%) to give the desired product as a white solid (110 mg, 34% yield). Mass spectrometry (m / z): 739.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 9.6 Hz, 1H), 7.46 (d, J =8.6 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.18 (d, J = 8.6 Hz, 1H), 7.09 – 7.06 (m,2H), 7.01 – 6.96 (m, 2H), 6.81 – 6.75 (m, 2H), 5.94 – 5.83 (m, 1H), 5.60 (dd, J = 10.6, 4.4 Hz, 1H), 5.40 – 5.35 (m, 2H), 5.13 – 5.08 (m, 2H), 4.97 (dt, J=20.0, 5.2 Hz, 1H), 4.63 (d, J = 4.8 Hz, 1H), 4.11 (dd, J = 11.2, 5.2 Hz, 2H), 4.06 – 4.04 (m, 6H), 3.94 – 3.88 (m, 2H), 1.25 (dd, J = 22.4, 6.8 Hz, 3H), 1.02– 0.97 (m, 9H).

[0324] (3S,3aR,6R,6aS) -6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yl[N-(5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-methoxycyclohexyl)-1-methylpyrazol-4-yl)(4-methylbenzene)sulfonamide]methyl carbonate Option 3 (3S,3aR,6R,6aS) Preparation of 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yl[N-(5-{[(2S)-3,3-dimethylbut-2-yl]carbamoyl}-3-(4-methoxycyclohexyl)-1-methylpyrazol-4-yl)(4-methylbenzene)sulfonamido]methyl carbonate: N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-methoxycyclohexyl)-2-methyl-4-[(4-methylbenzene)sulfonamido]pyrazol-3-carboxamide (30 mg, 0.0611 mmol) was dissolved in DMF (2 mL), and Cs2CO3 (39.8 mg, 0.122 mmol) was added. (3S,3aR,6R,6aS) 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yliodomethyl carbonate (45.8 mg, 0.122 mmol). The reaction was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE / EA = 3:1) to give the desired product as a white solid (3 mg, yield 6.1%). Mass spectrometry (m / z): 737.8 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.73 – 7.68 (m, 2H), 7.34 (t, J= 7.2 Hz, 2H), 5.38 – 5.35 (m, 1H), 5.13 – 4.91 (m, 2H), 4.05 – 3.89 (m, 7H), 3.29 (s, 1H), 3.23 (s, 1H), 2.47 – 2.45 (m, 3H), 1.84 – 1.71 (m, 3H), 1.23 –1.20 (m, 3H), 0.99 (s, 3H).

[0325] ((4-cyano-N-(5-((((S)-3,3-dimethylbut-2-yl)carbamoyl)-3-((1s,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-4-yl)phenyl)sulfonamide)methyl(( 3S, 3aR, 6R, 6aS 6-(nitoxy)hexahydrofurano[3,2-b]furan-3-yl)carbonate Option 4 Preparation of ((4-cyano-N-(5-((((S)-3,3-dimethylbut-2-yl)carbamoyl)-3-((1s,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-4-yl)phenyl)sulfonamide)methyl(( 3S, 3aR, 6R, 6aS 6-(nitoxy)hexahydrofurano[3,2-b]furan-3-yl)carbonate: 4-[(4-cyanobenzene)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-methoxycyclohexyl)-2-methylpyrazol-3-carboxamide (100 mg, 0.199 mmol) was dissolved in THF (4 mL), and potassium tert-butoxide (0.2 mL, 0.398 mmol) was added at 50 °C and reacted for 1 hour. (3S,3aR,6R,6aS 6-(nitoxy)-hexahydrofurano[3,2-b]furan-3-yliodomethyl carbonate (224 mg, 0.597 mmol). The reaction mixture was stirred at 50 °C for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 3:1) to give a white solid product (34 mg, yield 57.3%). Mass spectrometry (m / z): 519.8 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.12-8.10 (d, J = 8 Hz, 2H), 7.96-7.92 (d, J= 16 Hz, 2H), 5.73-5.52 (m,2H), 5.51-5.48 (m, 1H), 4.94-4.88 (m, 2H), 4.49-4.39 (m, 1H), 3.86-3.83 (m,2H), 3.81-3.76 (m, 1H), 3.73-3.63 (m, 5H), 3.13 (s, 3H), 2.04 (s, 1H), 1.53-1.45 (m, 5H), 1.44-1.22 (m, 1H), 1.10-1.09 (m, 1H), 0.98-0.87 (m, 2H),0.85(s, 9H), 0.98-0.87 (m, 2H), 0.73-0.65 (m, 2H).

[0326] Compound 4: (S)-((4-cyano-N-(5-(((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)phenyl)sulfonamido)methyl 2,2-dimethyl-3-(nitrooxy)propionate Option 5 Step 1.2, Preparation of 2-dimethyl-3-(nitro)propionic acid: Fuming nitric acid (4.02 g, 63.8 mmol) was added to Ac₂O (10 mL) at 0 °C, and the solution was stirred for 10 min. Then, a solution of 3-hydroxy-2,2-dimethylpropionic acid (1.00 g, 8.50 mmol) in EA (10 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 20 min. The mixture was extracted with 3N HCl (35 mL) and EA (35 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow oily target compound (1.05 g, yield 75.3%). 1 HNMR (400 MHz, CDCl3) δ 4.52 (s, 2H), 1.36 (s, 6H).

[0327] Step 2. Preparation of chloromethyl 2,2-dimethyl-3-(nitoxy)propionate: To a solution of 2,2-dimethyl-3-(nitoxy)propionic acid (1.05 g, 6.4 mmol) in DCM (20 mL), NaHCO3 (2.15 g, 25.6 mmol) and tetrabutylammonium hydrogen sulfate (0.22 g, 0.64 mmol) were added, followed by water (20 mL). The mixture was stirred at room temperature for 10 minutes and then cooled to 0 °C. A solution of chloro[(chlorosulfonyl)oxy]methane (1.37 g, 8.32 mmol) in DCM (4 mL) was added dropwise. The reaction was stirred at 0 °C for 1 hour and then at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL × 2). The organic phases were combined, washed with brine (20 mL), dried with Na2SO4, and concentrated under reduced pressure to give a yellow oily target product (1.13 g, yield 82.8%). 1 H NMR (400 MHz, CDCl3) δ 5.74 (s, 2H), 4.53 (s, 2H), 1.33 (s, 6H).

[0328] Step 3. Preparation of (S)-((4-cyano-N-(5-(((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)phenyl)sulfonamide)methyl 2,2-dimethyl-3-(nitrooxy)propionate: NaI (142 mg, 0.945 mmol) was added to a solution of chloromethyl 2,2-dimethyl-3-(nitrooxy)propionate (100 mg, 0.473 mmol) in acetone (5 mL). The mixture was stirred at 60 °C for 16 hours under nitrogen protection. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Then 4-[(4-cyanophenyl)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-fluorophenyl)-2-methylpyrazole-3-carboxamide (114 mg, 0.236 mmol) was added, followed by t-BuOK (106 mg, 0.945 mmol). The resulting solution was stirred at 60 °C for 16 hours under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with EA (20 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative-grade thin-layer chromatography (Pre-TLC) (PE / EA = 1:1) to give the target product as a white solid (19.6 mg, yield 6.3%). Mass spectrometry (m / z): 658.8 [M+H] + .1 H NMR (400 MHz, CDCl3) δ 7.77 -7.52 (m, 3H), 7.51 - 7.33 (m, 2H), 7.24 - 6.73 (m, 3H), 6.17 - 5.80 (m, 1H), 5.72 - 5.47 (m, 1H), 4.68 - 4.45 (m, 2H), 4.34- 3.91 (m, 4H), 1.34 - 1.21 (m, 9H), 1.08 - 0.81 (m, 9H).

[0329] Compound 5: (S)-((4-cyano-N-(5-((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)phenyl)sulfonamido)methyl-2-methyl-3-(nitrooxy)-2-((nitrooxy)methyl)propionate Option 6 Step 1. Preparation of 2-methyl-3-(nitro)-2-((nitro)methyl)propionic acid: Fuming nitric acid (3.54 g, 56.2 mmol) was added to acetic acid (9 mL) at 0 °C, and the solution was stirred for 10 min. Then, a solution of ethyl acetate (EA) (9 mL) of 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (1 g, 7.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 20 min. The mixture was extracted with 3N HCl (35 mL) and EA (35 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oily target compound (1.3 g, yield 77.3%). 1 H NMR (400 MHz, CDCl3) δ 4.73 - 4.57 (m, 4H), 1.44 (d, J = 3.5 Hz, 3H).

[0330] Step 2. Preparation of chloromethyl 2-methyl-3-(nitoxy)-2-((nitoxy)methyl)propionate: To a solution of 2-methyl-3-(nitoxy)-2-[(nitoxy)methyl]propionic acid (1.3 g, 5.8 mmol) in DCM (20 mL), NaHCO3 (1.95 g, 23.2 mmol) and tetrabutylammonium hydrogen sulfate (0.2 g, 0.58 mmol) were added, followed by water (20 mL). The mixture was stirred at room temperature for 10 minutes and then cooled to 0 °C. A solution of chloro[(chlorosulfonyl)oxy]methane (1.24 g, 7.54 mmol) in DCM (4 mL) was added dropwise. The reaction was stirred at 0 °C for 1 hour and then at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL × 2). The organic phases were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oily target product (1.4 g, yield 87.9%). 1 H NMR (400 MHz, CDCl3) δ 5.77 (s, 2H), 4.70 (d, J = 10.8 Hz, 2H), 4.62 (d, J = 10.8 Hz, 2H), 1.41 (s, 3H).

[0331] Step 3. Preparation of (S)-((4-cyano-N-(5-(((3,3-dimethylbut-2-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)phenyl)sulfonamido)methyl-2-methyl-3-(nitrooxy)-2-((nitrooxy)methyl)propionate: NaI (110 mg, 0.734 mmol) was added to a solution of chloromethyl 2-methyl-3-(nitrooxy)-2-[(nitrooxy)methyl]propionate (100 mg, 0.367 mmol) in acetone (5 mL). The mixture was stirred at 60 °C for 16 hours under nitrogen protection. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). 4-[(4-cyanobenzene)sulfonamido]-N-[(2S)-3,3-dimethylbut-2-yl]-5-(4-fluorophenyl)-2-methylpyrazole-3-carboxamide (88.7 mg, 0.183 mmol) was added, followed by t-BuOK (82.3 mg, 0.734 mmol). The resulting solution was stirred at 60 °C for 16 hours under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with EA (20 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative grade thin-layer chromatography (PE / EA = 2:1) to give the desired product as a white solid (44.7 mg, yield 16.9%). Mass spectrometry (m / z): 719.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75-7.50 (m, 3H), 7.48-7.43 (m, 2H), 7.11-6.75 (m, 3H), 5.96-5.78 (m, 1H), 5.73-5.61 (m, 1H), 4.73-4.57 (m, 4H), 4.12-3.91 (m, 4H), 1.42-1.36 (m, 6H), 1.08-0.95 (m, 9H).

[0332] Nitric oxide (NO) release assay Griess' reagent (Phygene, PLM053-50mL) is prepared by mixing equal volumes of solution A and solution B. Nitrite (NO2) - The standard curve is obtained using a series of NO2... - A series of NO2 prepared from standards - Standard products are NO2 -The standard stock solution (50 μg / mL, water as solvent, Macklin, catalog number 821126) was diluted with water to obtain NO2 concentrations of 0.01, 0.03, 0.05, 0.07, 0.09, 0.2, and 0.4 μg / mL. - Standard solutions: Take 100 μL of each standard solution, mix with 25 μL of Griess reagent, and incubate at room temperature for 10 minutes. Record the absorbance (OD) at 540 nm and plot the standard curve. Nitric oxide release assay: Dissolve 15 mg of cysteine ​​(Aladdin, C108238) in 24.7 mL of PBS buffer (pH 7.4) to prepare a saturated cysteine ​​(5 mM)-PBS buffer. Then dissolve the compound in DMSO and further dilute with 5 mM cysteine-PBS buffer to a final concentration of 100 μM. Incubate the solution at 37°C. After 1 hour, take 200 μL of the solution, mix with 50 μL of Griess reagent, and react at room temperature for 10 minutes. Record the absorbance (OD) at 540 nm and calculate NO2 based on the standard curve. - Concentration. Isosorbide mononitrate (ISMN) is a known prodrug of nitrogen oxides (NO) and is also used to treat cardiogenic chest pain, heart failure, and esophageal spasm. In this assay, ISMN was used as a positive control, and reference compounds A and B were used as negative controls. Nitric oxide (NO) release was expressed as NO2. - The amount is expressed as [quantity]. The results of the nitric oxide release assay are shown in Table 2 below.

[0333] Table 2. Results of the compounds in the nitric oxide (NO) release assay

[0334] The above results indicate that reference compounds A and B did not show any NO release. The NO release levels of compounds 1-5 disclosed herein were all higher than those of the positive control ISMN.

[0335] Cyclic adenosine monophosphate (cAMP) assay A stable cell line expressing human FPR1 (hFPR1-CHO) was incubated with different concentrations of test compounds in medium (F-12, 10% FBS, 200 μg / mL hygromycin B), and the inhibition of FPR1 was determined using the TR-FRET cAMP kit (PerkinElmer, TRF0264). Stimulation buffer was prepared according to the manufacturer's instructions. The compounds were dissolved in DMSO and diluted 10-fold with stimulation buffer. Confluent hFPR1-CHO cells were trypsinized and seeded at a density of 2000 cells / well in 384-well plates. A 10-fold concentration of the compound stock solution was added to each well, and the plates were incubated at 37°C for 10 min. Next, 2.5 μM Forskolin and 2.5 nM WKYMVm were added, and the plates were incubated at 37°C for 30 min to induce cAMP production. Subsequently, Eu-cAMP and ULit-anti-cAMP were diluted to working concentrations with assay buffer and added to the wells. The plate was incubated at room temperature for 1 hour, and the TR-FRET signal (excitation wavelength: 330 nm, emission wavelengths: 620 nm and 665 nm) was recorded on a TR-FRET microplate reader. The IC50 was calculated using GraphPad Prism software via nonlinear regression (dose-response-variable slope) fitting. 50 Values. The cAMP measurement results are shown in Table 3 below.

[0336] Table 3. Results of the compounds in cAMP assay

[0337] 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 may be made therein without departing from the spirit and scope of this disclosure as defined by the appended claims.

Claims

1. Compound 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: 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 ; Where R 4 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is either C or N; Y 1 Not present or selected from: bond, O, S and NR 5 ; Where R 5 Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; 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; R b Selected from: hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Each R c Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 2 Selected from: C(R) 6 2. O, S, and P, or they do not exist; Among them, each R 6 Independently selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Y 3 Selected from: ester bonds, amide bonds, sulfonamide bonds, sulfate ester bonds, phosphoramide bonds, phosphate ester bonds, ketone bonds, aryl groups, C(O)-(CH2)2-C(O)-, -OC(O)-(CH2)2-C(O)-, -OC(O)-CH=CH-C(O)-, -C(O)-CH=CH-C(O)- and the following groups: ， L 1 It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein Y 1 It is a key.

3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described in claim 1 or 2, wherein R a It is a 4'-substituted aryl group.

4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described in claim 1 or 2, wherein R a It is a 4'-substituted cycloalkyl group.

5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described in claim 1 or 2, wherein R a It is a heterocyclic group.

6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-5, wherein R b It is a 4'-substituted aryl group.

7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-6, wherein L 1 It is a straight-chain alkyl, branched alkyl, or cycloalkyl group containing nitrate.

8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-7, wherein L 1 It is -C(CH3)2-CH2-ONO2.

9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-7, wherein L 1 It is -C(CH3)-(CH2-ONO2)2.

10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-6, wherein L 1 It is isosorbide monohydrate.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (II): (II), 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; (vi) R 3 Not present or selected from: –OR” and –C(R”)3; (vii) R” is independently selected from: methylene, alkoxy, straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocycloalkyl, fused heterocycloalkyl, aryl and heteroaryl; (viii) R a It is a functional agent comprising at least one group selected from the following: -ONO2, -C(CH3)2-CH2-ONO2, -C(CH3)-(CH2-ONO2)2, -OC(CH3)2-CH2-ONO2, -OC(CH3)-(CH2-ONO2)2, -O-CH-(CH2-ONO2)2, -CH2-ONO2, -(CH2)2-ONO2, -O-(CH2)2-ONO2, -(CH2)3-ONO2, -O-(CH2)3-ONO2, -CH2-CH(CH3)-ONO2 group and isosorbide mononitrate; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 11, wherein R a for .

13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 11, wherein R a for .

14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 11, wherein R a for .

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (III): (III), 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; (vi) R” is selected from: hydrogen and optionally substituted straight-chain alkyl and branched-chain alkyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

16. The compound of claim 1 or 14, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IV-i): (IV-i), Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the aforementioned substances, wherein: (i) Ring A is selected from: optionally substituted 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (iv) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

17. The compound of any one of claims 1, 13, or 15, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IV-ii): (IV-ii), 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 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

18. The compound of any one of claims 1, 14, or 15, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IV-iii): (IV-iii), 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 6-membered 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, straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl groups; (v) R 2 Independently selected from: hydrogen, methyl, and cyclopropyl; The straight-chain alkyl, branched alkyl, cycloalkyl, fused bicycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by 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 5-membered heteroaryl and 6-membered heteroaryl.

19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-18, wherein ring A is .

20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-18, wherein ring A is... .

21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-18, wherein ring A is... .

22. 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.

23. A pharmaceutical composition comprising the compound of any one of claims 1-22, a tautomer, a deuterated derivative and / or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

24. A method of treating or alleviating a disease, symptom, or condition mediated by FPR1 protein regulation, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-22, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 23.

25. 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 1-22, a tautomer, a deuterated derivative, and / or a pharmaceutically acceptable salt or the pharmaceutical composition of claim 23.

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