Modulators of fpr1 and methods of use thereof

Abstract

The present disclosure provides compounds of Formula I, compositions including the same, and methods of using the same, including uses for treating a disease, disorder, or condition mediated by signaling of formyl peptide receptor 1 (FPR1).

Description

Technical Field

[0001] This disclosure relates to compounds that can be used to treat diseases. More specifically, this disclosure relates to compounds that bind to formyl peptide receptors (FPRs) (such as FPR1) to modulate their activity in order to reduce or eliminate disproportionate FPR-mediated signaling (a potential pathogenesis of a range of diseases, including, for example, diseases or disorders of the central nervous system (CNS), such as stroke, traumatic brain injury (TBI), glioblastoma, and malignant glioma). Background Technology

[0002] Restoring homeostasis after injury or pathogen infection is crucial for the survival of an organism. Physiological wound healing and innate immune responses are initiated by the release of soluble mediators from invasive pathogens or damaged lesions. The repair process involves thermoregulatory interactions involving numerous chemokines, cytokines, acute-phase proteins, infiltrating and resident cells, fibroblasts, nerve cells, and the vascular system. If the injury persists or is extensive, physiological wound repair or the anti-infective response can become pathological, leading to excessive inflammation, edema, unwanted fibrotic repair, organ dysfunction, acute respiratory distress syndrome (ARDS), sepsis, and ultimately, organ failure and / or death. Therefore, effective regulation of the degree and duration of inflammation and the resolution response may be 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) are released from invasive pathogens, injured cells, and diseased tissues. Three formyl peptide receptors (FPR1, FPR2, and FPR3) serve as key sensors for these chemokines and activators in the human body. These FPR receptors are highly expressed on 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 recruits leukocytes, stimulates the production of superoxide dismutase and cytokines, activates microglia and astrocytes, and facilitates other inflammatory and remission responses for damage repair and host defense.

[0003] On the other hand, pathological inflammatory responses resulting from disproportionate FPR receptor-mediated signaling are the cause of a variety of disease states following injury or infection, including, for example, cerebral edema, functional impairment, and organ failure following stroke or traumatic brain injury. Furthermore, chronic activation of FPR receptor-mediated signaling induced by invasive pathogens, tissue stress, and tissue damage is involved in the pathogenesis of brain cancer, gastric cancer, and Parkinson's syndrome.

[0004] Stroke is a leading cause of death worldwide, with limited treatment options. The FPR receptor is highly expressed in microglia, astrocytes, and the vascular system. Following an 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 inflammatory response after injury, contributing to the development of perihematoma edema and the aggravated mass effect in stroke.

[0005] Globally, traumatic brain injury (TBI) is a leading cause of disability. The estimated global incidence of TBI is 200 per 100,000 people per year. Severe injuries often result in 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.

[0006] 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 cerebral vascular system. The interaction of the FPR receptor with chemokines from injury, stress, and pathogens is involved in the pathophysiology of brain cancer.

[0007] Given the above, there is still a need for new therapeutic agents and alternative mechanisms that can effectively address the limited effective treatment options currently available for at least stroke, TBI, glioblastoma, and glioma. Summary of the Invention

[0008] One aspect of this disclosure provides compounds selected from formulas I, IIa, IIb, III, IV, V, VI, and VII, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, which may be used to treat diseases mediated by formyl peptide receptor 1 (FPR1) signaling. For example, compounds of formula I are disclosed herein:

[0009]

[0010] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0011] Z 1 and Z 2 Both are either O or N and Z 3 It is C or N; where:

[0012] When Z 3 When it is C, then Z 1 It is O and Z 2 Is it N or Z? 1 It is N and Z 2 It is O;

[0013] When Z 3 When it is N, then Z 1 and Z 2 Both are N;

[0014] Connecting ring A to the rest of formula I There is no system such that equation I includes a spirocyclic system or It is a single key;

[0015] Ring A is an aromatic ring or a non-aromatic ring, wherein:

[0016] X a and X b Each is independently a C, N, or bond; and

[0017] X 1 X 2 X 3 and X 4 Each can be either C or N independently;

[0018] Ring B is either an aromatic ring or a non-aromatic ring, wherein:

[0019] Y a It is C, N, non-existent, or a key; and

[0020] Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be either C or N independently;

[0021] Ring C is selected from C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl and 5- to 10-membered heteroaryl;

[0022] R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), (C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)ORk -NR h C(=O)NR i R j -NR h S(=O) p R k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl; wherein:

[0023] The R 1 R 2 and R 3 The C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups of any one of the C1-C6 alkyl groups and the C1-C6 alkyl group of the -C(=O)(C1-C6 alkyl) group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) p R k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i and C3-C6 cycloalkyl; the R 1 R 2 and R3 any of the C3-C 12 The carbocyclic group, the 3- to 12-membered heterocyclic group, the phenyl group, and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C1-C4 alkyl, -NR h R i and -OR k ;

[0024] R h R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; wherein:

[0025] The R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0026] R k For each occurrence, it is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; wherein: the R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0027] k and m are each an independent integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0028] n is an integer selected from 0, 1, 2, 3, 4, and 5; and

[0029] p is an integer selected from 1 and 2.

[0030] In one aspect of this disclosure, the compounds of Formula I are selected from compounds 1 to 4 shown below, their tautomers, deuterated derivatives of the compounds or the tautomers, or the pharmaceutically acceptable salts of the foregoing.

[0031] In some embodiments, this disclosure provides pharmaceutical compositions comprising compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers thereof. In some embodiments, the pharmaceutical composition may comprise compounds selected from compounds 1 to 4 shown below, their tautomers, said compounds or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts thereof. These compositions may further comprise additional active pharmaceutical agents.

[0032] Another aspect of this disclosure provides a method for treating a subject for a disease, disorder, or condition mediated by formyl peptide receptor 1 (FPR1) signaling, the method comprising administering a therapeutically effective amount of a compound of formula I, IIa, IIb, III, IV, V, VI, and VII, its tautomers, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the treatment method comprises administering to a subject a compound selected from compounds 1 to 4 shown below, its tautomers, said compound or a deuterated derivative of said tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing.

[0033] In some embodiments, the treatment method includes administering to a subject in need an additional active pharmaceutical agent in the same pharmaceutical composition or in a separate composition as compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, the treatment method includes administering a compound selected from compounds 1 to 4 as shown below, their tautomers, said compounds or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts thereof, with at least one additional active pharmaceutical agent in the same composition or in a separate composition.

[0034] This document also discloses a method for modulating FPR1 activity, the method comprising administering to a subject a therapeutically effective amount of a compound of formula I, IIa, IIb, III, IV, V, VI, and VII, its tautomers, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method for modulating FPR1 comprises administering to a subject a compound selected from compounds 1 to 4 as shown below, its tautomers, the compound or the deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method for modulating FPR1 activity comprises contacting the FPR1 with a compound of formula I, IIa, IIb, III, IV, V, VI, and VII, its tautomers, the compound or the deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of adjusting FPR1 includes contacting FPR1 with a compound selected from compounds 1 to 4 listed below, its tautomers, deuterated derivatives of the compound or the tautomers, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. Attached Figure Description

[0035] Figure 1 This is a schematic diagram depicting a procedure for evaluating the efficacy of the compounds disclosed herein in a mouse model of induced intracerebral hemorrhage (ICH). Detailed Implementation

[0036] I. Definition

[0037] When referring to nouns as used herein, the term "a / an" encompasses the expression "at least one / one," and therefore covers both the singular and plural units of the noun. For example, "another drug" means one or two or more additional drug preparations.

[0038] As used herein, the term “FPR1” or “formyl peptide receptor 1” refers to the cell surface receptor protein encoded by the FPR1 gene in humans. FPR1 regulates a wide variety of neutrophil functional responses and plays an important role in the pathogenesis of various diseases, including those described above.

[0039] As used herein, the term "FPR1 modulator" refers to a small organic chemical molecule (≤10 kDa) having the ability to alter any one or more FPR1-mediated immune responses or signaling from their native state, and can be an FPR1 agonist or an FPR1 antagonist. If the FPR1 modulator is an agonist, the compound has the ability to increase any one or more FPR1-mediated immune responses or signaling from their native state (e.g., by binding to a receptor to activate the receptor). If the FPR1 modulator is an antagonist, the compound has the ability to decrease or inhibit any one or more FPR1-mediated immune responses or signaling from their native state (e.g., by blocking agonist binding sites on the receptor to achieve a decreasing or inhibiting effect).

[0040] When referring to compounds of this disclosure, the term "compound" means a collection of molecules having the same chemical structure, unless otherwise indicated 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), except that isotopic variations may exist between the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that compounds represented by a particular chemical structure containing the indicated deuterium atom will also contain a smaller amount of isotopes having hydrogen atoms at one or more designated deuterated positions in the structure. The relative amount of such isotopes in the compounds of this disclosure will depend on a variety of factors, including, for example, the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of all such isotopes will be less than 49.9% of the compound. In other embodiments, the relative amounts of all such isotopes 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.

[0041] As used herein, “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted” refers to the substitution of a hydrogen group in a given structure with a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substituted position of the group, and the substituents may be the same or different at each position when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this disclosure are those combinations that result in the formation of stable or chemically viable compounds.

[0042] The term "isotope" refers to a substance whose chemical structure differs only in its isotopic composition. Furthermore, 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, compounds having the structures of this invention (except for replacing hydrogen with deuterium or tritium, or using...) 13 C or 14 All C substitutions for carbon are within the scope of this disclosure.

[0043] Unless otherwise indicated, the structures described herein are also intended to include all isomers of said 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 the present invention are within the scope of this disclosure. Unless otherwise stated, all tautomers of the compounds of this disclosure are within the scope of this disclosure.

[0044] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that are in equilibrium together and are readily interchangeable by migration of atoms (e.g., hydrogen atoms) or groups within the molecule.

[0045] As used in this article, “stereoisomer” refers to enantiomers and diastereomers.

[0046] 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 will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance occurs in the synthetic compounds. The concentration of the stable hydrogen isotope in natural abundance (despite this variation) is small and insignificant compared to the degree of stable isotopic 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 far exceeding its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives disclosed herein The material has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4500 (67.5% deuterium doping), 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 atom), at least 6333.3 (95% deuterium doping at each specified deuterium atom), at least 6466.7 (97% deuterium doping at each specified deuterium atom), or at least 6600 (99% deuterium doping at each specified deuterium atom) for each deuterium atom.

[0047] As used in this article, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance.

[0048] As used herein, the term "alkyl" means a fully saturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, an alkyl group contains 1 to 30 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms. And in yet another embodiment, the alkyl group contains 1 to 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 straight-chain, branched, or unbranched. In some embodiments, the alkyl group is branched.

[0049] The term "cycloalkyl" refers to a fully saturated monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons, wherein any single ring in the bicyclic system has 3 to 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 to C4. 12 Cycloalkyl. In some embodiments, the cycloalkyl group is a C3 to C8 cycloalkyl group. In some embodiments, the cycloalkyl group is a C3 to C6 cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0050] The term "carbocycloyl" encompasses the term "cycloalkyl" and refers to a fully saturated or partially saturated (due to the presence of one or more unsaturated units, but not aromatic) monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons, wherein any individual ring in the bicyclic system has 3 to 7 members. The bicyclic carbocyclic group includes combinations with 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 to C4. 12 Carbocyclic group. In some embodiments, the carbocyclic group is C3 to C4. 10 Carbocyclic group. In some embodiments, the carbocyclic group is a C3 to C8 carbocyclic group.

[0051] As used herein, the term "alkenyl" means 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 straight-chain, branched, or unbranched. In some embodiments, the alkenyl group is branched.

[0052] As used herein, the term "heterocyclic group" means a non-aromatic (i.e., fully saturated or partially saturated, as it contains one or more unsaturated units, but which are not aromatic), monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic system, wherein one or more ring members are independently selected heteroatoms. Bicyclic heterocyclic groups include, for example, combinations of the following monocyclic groups: 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 to 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 system contains 3 to 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 heteroatom, which is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom, which is an 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- to 12-membered heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 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, piperazine, tetrahydropyranyl, azacyclic butyl, tetrahydrothiophene 1,1-dioxide, etc.

[0053] The term "heteroatom" means one or more of the following: oxygen, sulfur, and nitrogen (including oxidized forms of nitrogen or sulfur) or silicon; any basic nitrogen in a quaternized form; or a heterocyclic substituted nitrogen, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR. +(e.g., in N-substituted pyrroleyl groups).

[0054] As used herein, the term "unsaturated" means a portion having one or more unsaturated units or degrees. Unsaturation refers to a state in which not all available valence bonds in a compound are satisfied by substituents, and therefore the compound contains double or triple bonds.

[0055] 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.

[0056] The term "halogen" includes F, Cl, Br, and I, namely fluorine, chlorine, bromine, and iodine.

[0057] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0058] As used herein, "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. "Non-aromatic" rings refer to carbon rings or heterocycles that do not satisfy the requirements set forth above for aromatic rings, and may be fully saturated or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings as further defined below.

[0059] The term "aryl," used alone or as part of a larger part (such as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl"), refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic system having a total of five to fourteen ring members, wherein each ring in the system is an aromatic ring containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic system contains 3 to 7 ring members. Non-limiting examples of aryl include phenyl (C6) rings and naphthyl (C6) rings. 10 The aryl group is substituted in some embodiments. In some embodiments, the aryl group is unsubstituted.

[0060] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is an aromatic ring, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic system contains 3 to 7 ring members. Bicyclic heteroaryls include, for example, combinations of the following monocyclic rings: 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 five ring members. In some embodiments, the heteroaryl is a monocyclic system having six ring members. In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl group is a 3- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3- to 8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 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.

[0061] A "spirocyclic system" refers to a ring system with two or more rings, where each pair of rings shares a common atom.

[0062] 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), hexane, 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).

[0063] Non-limiting examples of suitable bases that may 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).

[0064] This document discloses pharmaceutically acceptable salts of the disclosed compounds. The salts of the compounds are formed between an acidic and a basic group (such as an amino functional group) of the compound or between a base and an acidic group (such as a carboxyl functional group) of the compound.

[0065] As used herein, the term "pharmaceutical acceptable" means a component that, to a reasonable extent medical judgment, is suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. "Pharmaceutical acceptable salt" means any non-toxic salt that, upon administration to a recipient, can directly or indirectly provide the compounds of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SMBerge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1–19.

[0066] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, dihydrotartaric acid, ascorbic acid, maleic acid, besylic 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, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butyn-1,4-diacids. Hexyne-1,6-dicarboxylate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, 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).

[0067] Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates) formed using counterions. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0068] The term "subject" refers to animals, including but not limited to humans.

[0069] The term "therapeutic effective amount" refers to the amount of a compound that, when applied, produces the desired effect (e.g., improving symptoms of diseases, disorders, and conditions mediated by FPR1 signaling, reducing the severity of diseases, disorders, and conditions mediated by FPR1 signaling or their symptoms, and / or reducing the progression of diseases, disorders, and conditions mediated by FPR1 signaling or their symptoms). The exact amount of the therapeutic effective amount will depend on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0070] As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. As used herein, “treatment” and its cognates include, but are not limited to, the following: complete or partial remission; a lower risk of disease, disorder, and symptom mediated by FPR1 signaling, as well as disease-related complications. Improvement or reduction of the severity of any of these symptoms can be readily assessed using methods and techniques known in or subsequently developed in the art.

[0071] When used in conjunction with the dosage, amount, or weight percentage of an ingredient in a composition or dosage form, the terms “about” and “approximately” include a specified dosage, amount, or weight percentage value or a range of dosage, amount, or weight percentage that provides a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage, as recognized by a person skilled in the art.

[0072] II. Compounds and Compositions

[0073] In the first embodiment, the compound of this disclosure is a compound with the following structural formula I:

[0074]

[0075] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0076] Z 1 and Z 2 Both are either O or N and Z 3 It is C or N; where:

[0077] When Z 3 When it is C, then Z 1 It is O and Z 2 Is it N or Z? 1 It is N and Z 2 It is O;

[0078] When Z3 When it is N, then Z 1 and Z 2 Both are N;

[0079] Connecting ring A to the rest of formula I There is no system such that equation I includes a spirocyclic system or It is a single key;

[0080] Ring A is an aromatic ring or a non-aromatic ring, wherein:

[0081] X a and X b Each is independently a C, N, or bond; and

[0082] X 1 X 2 X 3 and X 4 Each can be either C or N independently;

[0083] Ring B is either an aromatic ring or a non-aromatic ring, wherein:

[0084] Y a It is C, N, non-existent, or a key; and

[0085] Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be either C or N independently;

[0086] Ring C is selected from C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl and 5- to 10-membered heteroaryl;

[0087] R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), (C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) p R k -ORk -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl; wherein:

[0088] The R 1 R 2 and R 3 The C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups of any one of the C1-C6 alkyl groups and the C1-C6 alkyl group of the -C(=O)(C1-C6 alkyl) group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) p R k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i and C3-C6 cycloalkyl; the R 1 R 2 and R 3 any of the C3-C 12 The carbocyclic group, the 3- to 12-membered heterocyclic group, the phenyl group, and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C1-C4 alkyl, -NR h Ri and -OR k ;

[0089] R h R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; wherein:

[0090] The R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0091] R k For each occurrence, it is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; wherein: the R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0092] k and m are each an independent integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0093] n is an integer selected from 0, 1, 2, 3, 4, and 5; and

[0094] p is an integer selected from 1 and 2.

[0095] In the second embodiment, the compound of this disclosure has one of the following structural formulas, IIa or IIb:

[0096]

[0097]

[0098] Its tautomers, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; and all other variables not specifically defined herein are as defined in the first embodiment.

[0099] In the third embodiment, the compound of this disclosure has the following structural formula III:

[0100]

[0101] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; wherein ring A and ring B are each an aromatic ring; and all other variables not specifically defined herein are as defined in either the first or second embodiment.

[0102] In the fourth embodiment, the compound of this disclosure has the following structural formula IV:

[0103]

[0104] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; wherein:

[0105] X a X b X 1 X 2 and X 3 No more than 3 of them are N; and

[0106] Y a Y 1 Y 2 Y 3 and Y 4 No more than 3 of them are N;

[0107] Furthermore, all other variables not specifically defined herein are defined as in any of the first, second, and third implementation schemes.

[0108] In the fifth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure:

[0109] X a X b X 1 X 2 and X 3 No more than two of them are N; and

[0110] Y a Y 1 Y 2 Y 3 and Y 4 No more than two of them are N;

[0111] Furthermore, all other variables not specifically defined herein are defined as in any of the first, second, third, and fourth implementation schemes.

[0112] In the sixth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure:

[0113] X a and X b Each is independently C or N; and

[0114] Y a It is C or N;

[0115] Furthermore, all other variables not specifically defined herein are defined as in any of the first, second, third, fourth, and fifth implementation schemes.

[0116] In the seventh embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure, ring A is surrounded by k R... 1 The pyridyl or pyrimidinyl group is substituted; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth and sixth embodiments.

[0117] In the eighth embodiment, the compound of this disclosure has the following structural formula V:

[0118]

[0119] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; wherein X 1 It is C or N; and all other variables not specifically defined herein are defined as in any of the first, second, third, fourth, fifth, sixth and seventh embodiments.

[0120] In the ninth embodiment, the compound of this disclosure has the following structural formula VI:

[0121]

[0122] Its tautomers, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salts; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth, sixth, seventh and eighth embodiments.

[0123] In the tenth embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure, the ring C is surrounded by n R... 3 Group-substituted C5-C6 cycloalkyl or 5- to 6-membered heterocyclic groups; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth embodiments.

[0124] In the eleventh embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, the ring C is surrounded by n R... 3 A group-substituted C5-C6 cycloalkyl or 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains one or two heteroatoms selected from O and N; and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and tenth embodiments.

[0125] In the twelfth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring C is surrounded by n R... 3 A group-substituted cyclohexyl or 6-membered heterocyclic group, wherein the 6-membered heterocyclic group contains one or two heteroatoms selected from O and N; and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth and eleventh embodiments.

[0126] In the thirteenth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, the ring C is surrounded by n R... 3 The tetrahydro-2H-pyranyl group is substituted with a functional group; and all other variables not specifically defined herein are those defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth embodiments.

[0127] In the fourteenth embodiment, the compound of this disclosure has the following structural formula VII:

[0128]

[0129] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; wherein:

[0130] Ring A and ring B are each aromatic rings;

[0131] X a X b X 1 X 2 and X 3 No more than 3 of them are N; and

[0132] Y a Y 1 Y 2 Y 3 and Y 4 No more than 3 of them are N.

[0133] Furthermore, all other variables not specifically defined herein are defined as in either the first or second implementation scheme.

[0134] In the fifteenth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure:

[0135] X a X b X 1 X 2 and X 3 No more than two of them are N; and

[0136] Y a Y 1 Y 2 Y 3 and Y 4 No more than two of them are N;

[0137] Furthermore, all other variables not specifically defined herein are defined as in the fourteenth implementation scheme.

[0138] In the sixteenth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure:

[0139] X a and X b Each is independently C or N; and

[0140] Y a It is C or N;

[0141] Furthermore, all other variables not specifically defined herein are defined as in either of the fourteenth and fifteenth embodiments.

[0142] In the seventeenth embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure, ring A is surrounded by k R... 1 The pyridyl or pyrimidinyl group is substituted; and all other variables not specifically defined herein are as defined in any of the fourteenth, fifteenth and sixteenth embodiments.

[0143] In the eighteenth embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure, ring B is surrounded by m R... 2 A phenyl group substituted with a functional group; and all other variables not specifically defined herein are as defined in any of the first, fourteenth, fifteenth, sixteenth and seventeenth embodiments.

[0144] In the nineteenth embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. a It is a C1-C2 alkyl group that is hydrogen or optionally substituted with one or two groups selected from halogens, -CN and -OH; and all other variables not specifically defined herein are as defined in any of the first, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and nineteenth embodiments.

[0145] In the twentieth embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. a It is hydrogen; and all other variables not specifically defined herein are defined as in any of the first, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and nineteenth embodiments.

[0146] In the twenty-first embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)NR h R i -NR h R i -OR k -S(=O)2R k -S(=O)2NR h R i C3-C6 cycloalkyl, 5- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl; wherein:

[0147] The R 1 R 2 and R 3 The C1-C6 alkyl and C1-C6 alkoxy groups of any one of the groups and the C1-C6 alkyl group of the -C(=O)(C1-C6 alkyl) group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C(=O)OR k and -OR k ;

[0148] The R 1 R 2 and R 3 The C3-C6 cycloalkyl, 5- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups of any one of them are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C1-C4 alkyl, and -OR. k ;

[0149] R h and R i For each occurrence, each is independently selected from hydrogen and C1-C4 alkyl groups; wherein:

[0150] The R h and R i The C1-C4 alkyl group of any one of them is optionally substituted by one to three groups selected from the following groups: halogen, cyano, and -OH; and

[0151] R k For each occurrence, each is independently selected from hydrogen and C1-C4 alkyl groups; wherein: R h and R i The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano and -OH;

[0152] Furthermore, all other variables not specifically defined herein are defined as in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and twentieth implementation schemes.

[0153] In the twenty-second embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR h R i -NR h R i and -OR k ;in:

[0154] The R 1 R 2 and R 3 The C1-C4 alkyl and C1-C4 alkoxy groups of any one of the C1-C4 alkyl groups and the C1-C4 alkyl group of the -C(=O)(C1-C4 alkyl) group are optionally substituted by 1 to 3 groups selected from the group consisting of halogen, cyano, and -OR. k ;

[0155] R h and R i Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups; and

[0156] R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups;

[0157] Furthermore, all other variables not specifically defined herein are defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and twenty-first implementation schemes.

[0158] In the twenty-third embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), and -OR. k ;in:

[0159] The R 1 R 2 and R 3 Any one of the C1-C4 alkyl groups may optionally be substituted with one to three halogen groups; and

[0160] R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups;

[0161] Furthermore, all other variables not specifically defined herein are defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, and twenty-second implementation schemes.

[0162] In the twenty-fourth embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 1 For each occurrence, it is independently selected from F, Cl, Br, C1-C2 alkyl, and -OR. k ;in:

[0163] The R 1 The C1-C2 alkyl group is optionally substituted with one to three halogen groups; and

[0164] R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups;

[0165] Furthermore, all other variables not specifically defined herein are defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, and twenty-third implementation schemes.

[0166] In the twenty-fifth embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 1 For each occurrence, it is independently selected from F, -CH3, and -OH; and all other variables not specifically defined herein are defined as in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, and twenty-fourth embodiments.

[0167] In the twenty-sixth embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 2 For each occurrence, it is independently selected from F, Cl, Br, and C1-C2 alkyl groups; wherein:

[0168] R 1 The C1-C2 alkyl group is optionally replaced by 1 to 3 halogens;

[0169] Furthermore, all other variables not specifically defined herein are defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, and twenty-fifth implementation schemes.

[0170] In the twenty-seventh embodiment, R is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure. 2 For each occurrence, it is independently selected from Cl and -CF3; and all other variables not specifically defined herein are defined as in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, and twenty-sixth embodiments.

[0171] In the twenty-eighth embodiment, k is an integer selected from 0, 1, and 2 in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, and twenty-seventh embodiments.

[0172] In the twenty-ninth embodiment, m is an integer selected from 1 and 2 in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, and twenty-eighth embodiments.

[0173] In the thirtieth embodiment, n is 0 in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of this disclosure; and all other variables not specifically defined herein are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, and twenty-ninth embodiments.

[0174] In some embodiments, at least one compound of this disclosure is selected from compounds 1 to 4 described in Table 1, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof.

[0175] Table 1. Compounds 1 to 4

[0176]

[0177] Another aspect of this disclosure provides pharmaceutical compositions comprising at least one compound selected from: compounds of formulas I, IIa, IIb, III, IV, V, VI and VII, compounds 1 to 4, their tautomers, deuterated derivatives of the compounds or the tautomers, or pharmaceutical compositions comprising any of the foregoing pharmaceutically acceptable salts, or pharmaceutical compositions comprising any of the foregoing and at least one pharmaceutically acceptable carrier.

[0178] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable mediators and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0179] It will also be understood that the pharmaceutical compositions of this disclosure can be used in combination therapies; that is, the pharmaceutical compositions described herein may further comprise additional active pharmaceutical agents. Alternatively, a pharmaceutical composition (comprising compounds selected from formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutical compositions comprising pharmaceutically acceptable salts of the foregoing, or any of the foregoing) may be administered as a separate composition simultaneously, before, or after a composition comprising additional active pharmaceutical agents.

[0180] As described above, the pharmaceutical compositions disclosed herein comprise pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may be selected from adjuvants and mediators. As used herein, pharmaceutically acceptable carriers may, for example, be selected from any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for a desired particular dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, eds. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, discloses various carriers for formulating pharmaceutical compositions and known techniques for preparing said carriers. Unless any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effects or otherwise interacting in a harmful manner with any one or more other components of the pharmaceutical composition, its use is contemplated 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 metaglycerides of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine 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 sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), astragalus 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, flavoring agents, aroma agents, preservatives and antioxidants.

[0181] III. Treatment and Usage

[0182] In another aspect of this disclosure, compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts (including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof) as described herein are disclosed for the treatment of diseases, disorders, or conditions mediated by FPR1 signaling. In another aspect, this disclosure discloses the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts (including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, said compounds or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof) as described herein for the manufacture of medicaments for the treatment of diseases, disorders, or conditions mediated by FPR1 signaling. On another aspect, this document discloses a method for treating a subject for a disease, disorder, or condition mediated by FPR1 signaling, the method comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0183] In some implementations, the disease, disorder, or ailment is related to the central nervous system (CNS). In some implementations, the disease, disorder, or condition is selected from stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, epileptic disorder, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sach's disease, Sandoff's disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedrich's ataxia, Wilson's disease, Menke's Sx disease, CADASIL (autosomal dominant hereditary arteriosclerosis with subcortical infarction); spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau disease. Lindau, Fragile X disease, spastic paraplegia, tuberous sclerosis, Wardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette's syndrome, ataxia syndrome, Shy Drager disease, olivopontocerebellar degeneration, nigrostriatal degeneration, Gullian Barre syndrome Syndrome, burning pain, type I and II complex regional pain syndromes, diabetic neuropathy, 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, prion disease, myelitis, radiculitis, diabetes mellitus associated with adverse proteinemia, thyroxine-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, herpes zoster-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, multiple cranial neuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain damage, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0184] In one embodiment, the disease, disorder, or condition is stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constriction, and venous). In one embodiment, the disease, disorder, or condition is traumatic brain injury. In one embodiment, the disease, disorder, or condition is a malignant glioma. In one embodiment, the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglion glioma. In one embodiment, the malignant glioma is glioblastoma.

[0185] In another aspect of this disclosure, compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts (including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof) as described herein are used to manufacture agents for modulating FPR1 activity. In another aspect, this disclosure discloses the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts (including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, said compounds or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof) as described herein in the manufacture of medicaments for modulating FPR1 activity. In another aspect, this document discloses a method for modulating FPR1 activity, the method comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, said compounds or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof. In yet another aspect, this document discloses a method for modulating FPR1 activity, the method comprising exposing a subject to an FPR1 compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt (including compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, said compounds or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof).

[0186] Compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered once, twice, or three times daily, for example, to treat diseases, disorders, or conditions mediated by FPR1 signaling.

[0187] In some embodiments, compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are administered once daily, twice daily, or three times daily at doses of 2 mg to 1500 mg or 5 mg to 1000 mg.

[0188] Compounds of formulas I, IIa, IIb, III, IV, V, VI, and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered, for example, or via oral, parenteral, sublingual, topical, rectal, nasal, buccal, vaginal, transdermal, patch, pump, or via implanted reservoir. The pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration. Parenteral administration can be performed by continuous infusion over a selected period of time. Other forms of application considered in this disclosure are described in international patent applications WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0189] Useful or therapeutically effective doses of the compounds described 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 No. 4,938,949.

[0190] Those skilled in the art will recognize that when a certain amount of a compound is disclosed, the relevant amount of the pharmaceutically acceptable salt form of said compound is the amount equivalent to the concentration of the free base of said compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, 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 Formula I and its pharmaceutically acceptable salts includes 1000 mg of a compound of Formula I and the concentration of a pharmaceutically acceptable salt of a Formula I compound equivalent to 1000 mg of a compound of Formula I."

[0191] Example

[0192] To provide a fuller understanding of the disclosure herein, the following embodiments are provided. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the scope of this disclosure in any way.

[0193] Example 1. Synthesis of an exemplary compound

[0194] The compounds disclosed herein may be manufactured in accordance with standard chemical practice or as described herein (including the following synthetic schemes) and in the description of compounds selected from formulas I, IIa, IIb, III, IV, V, VI and VII, compounds 1 to 4, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts.

[0195] Using compounds 1 and 2 as representative examples, the method for preparing compounds of formula I includes the general reaction steps as described in scheme 1.

[0196] Compounds 1 and 2

[0197] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazo-6-one

[0198] (Compound 1)

[0199] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazo-6-one

[0200] (Compound 2)

[0201] Option 1

[0202]

[0203] General Step A: Preparation of 1-(2-(benzyloxy)-5-methylphenyl)ethyl-1-one

[0204] (Chloromethyl)benzene (7.81 g, 56 mmol) was added to a solution of 1-(2-hydroxy-5-methylphenyl)ethyl ketone (4.25 g, 28 mmol) and potassium carbonate or K₂CO₃ (7.81 g, 56 mmol) in dimethylformamide DMF (50 mL), and the resulting solution was stirred at 40 °C for 16 h under nitrogen (N₂). Water (100 mL) was added to the reaction mixture, and the aqueous solution was extracted with ethyl acetate or EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over sodium sulfate or Na₂SO₄, and filtered. The filtrate was concentrated to dryness under vacuum to give the desired product, 1-(2-(benzyloxy)-5-methylphenyl)ethyl-1-one (6 g, 88%), as a brown oil. Mass (m / z): 240.9 [M+H] + .

[0205] General Step B: Preparation of Ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutyrate

[0206] Bis(trimethylsilyl)aminolithium LiHMDS (1.0 M, 20.8 mL, 20.8 mmol in THF) was added dropwise to a solution of 1-(2-(benzyloxy)-5-methylphenyl)ethyl-1-one (5 g, 20.8 mmol) and diethyl oxalate (3.04 g, 20.8 mmol) in tetrahydrofuran or THF (80 mL) at -78 °C under N2. The reaction mixture was slowly heated to room temperature (rt) and stirred at room temperature for 1 h. The reaction was quenched with water (150 mL) and then the aqueous solution was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate or PE:EA = 2:1, followed by dichloromethane:methanol or DCM:MeOH = 20:1) to give the product ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutyrate (7 g, 90%) as a yellow solid. Mass (m / z): 340.9 [M+H] + .

[0207] General Step C: Preparation of racemic-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one

[0208] Catalytic acetic acid or HOAc (two drops) was added to a solution of 4-(trifluoromethyl)benzaldehyde (1.13 g, 6.49 mmol) and tetrahydro-2H-pyran-4-amine (656 mg, 6.49 mmol) in EtOH (15 mL) under N2, and the reaction mixture was then stirred at 60 °C for 3.5 h. The reaction mixture was cooled to room temperature, and then ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutyrate (2 g, 5.9 mmol) was added. The reaction mixture was further stirred at 60 °C under N2 for 16 h. The solid precipitate was collected by filtration and dried to give a white solid product, racemic-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one (1.3 g, 40%). Mass (m / z): 551.7 [M+H] + .

[0209] General steps D and E: Preparation of racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (compound 1) and racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 2)

[0210] A mixture of racemic-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one (500 mg, 0.91 mmol), hydroxylamine hydrochloride (125 mg, 1.82 mmol), and sodium bicarbonate or NaHCO3 (153 mg, 1.82 mmol) in EtOH (20 mL) was stirred at 95 °C under nitrogen or N2 for 16 h, and then cooled to room temperature. Concentrated sulfuric acid or H2SO4 (5 mL) was added dropwise to the reaction mixture, and the resulting solution was further stirred at 100 °C under N2 for 5 h. The solution was cooled to room temperature and then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini-C18 150x 21.2 mm, 5 μm; ACN--H2O (0.1% FA), 55%-60%) to give the product racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (compound 1) (48 mg, 12%, white solid) and racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 2) (8 mg, 2%, white solid).

[0211] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (compound 1): mass (m / z): 458.7 [M+H] + .

[0212] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 2): mass (m / z): 458.8 [M+H] + .

[0213] The methods for preparing compounds 3 and 4 are described below.

[0214] Compounds 3 and 4

[0215] Racemic-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazo-6-one

[0216] (Compound 3)

[0217] Option 2

[0218]

[0219] Step 1. Prepare 1-(2-(benzyloxy)-5-fluorophenyl)ethyl-1-one (2) (6.4 g, 100%), which is a yellow oil, according to general step A.

[0220] Step 2. Prepare ethyl 4-(2-(benzyloxy)-5-fluorophenyl)-2,4-dioxobutyrate (4) (7.0 g, 98%, crude product) as a yellow oil according to general step B.

[0221] Step 3. Following general step C, prepare racemic-4-(2-(benzyloxy)-5-fluorobenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one (7) (400 mg, 43%, crude product), as a colorless oil. Mass (m / z): 556.1 [M+H] + .

[0222] Steps 4 and 5. Following general steps D and E, prepare racemic 3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 3) (5 mg, 2%) as a white solid. Mass (m / z): 463.0 [M+H] + .

[0223] Compound 4

[0224] Racemic-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 6)

[0225] Option 3

[0226]

[0227] Step 1. According to general step C, prepare racemic-4-(2-(benzyloxy)-5-fluorobenzoyl)-5-(4-chlorophenyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-2H-pyrrole-2-one (4) (300 mg, 35%, crude product) as a colorless oil. Mass (m / z): 522.0 [M+H] + .

[0228] Steps 2 and 3. Following general steps D and E, prepare racemic-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (compound 4) (5 mg, 2%) as a white solid. Mass (m / z): 429.0 [M+H] + .

[0229] Example 2. In vitro assay for detecting and measuring the regulation of FPR1-mediated calcium signaling by compounds 1 to 4.

[0230] As illustrated in the exemplary embodiments in Table 2, the effects of the compounds of this disclosure on the regulation of FPR1-mediated cell signaling were measured by monitoring changes in cellular calcium levels. The dose response of the illustrated embodiments was explicitly reported using the following sorting criteria: ***(IC 50 ≤100nM); **(IC 50 ≥100 to ≤1000 nM); *(IC 50 ≥1000 to ≤10,000 nM); ND - Not detected.

[0231] Expression of human or mouse FPR1 in 293T cells

[0232] The coding DNA sequences (CDS) of human FPR1 (NM_001193306) and mouse FPR1 (NM_013521) were cloned and inserted into the lentiviral vector GV367 via pCMV promoter transduction (vector information: http: / / www.genechem.com.cn / index / supports / tool_search.html?keywords=GV367). 293T cells were cultured in H-DMEM supplemented with 10% FBS and 1% penicillin-streptomycin (PS) at 37°C in a 5% CO2 incubator. 293T cells were transfected with the lentiviral vector GV367 containing the CDS of human or mouse FPR1 for 24 h, and then cultured in complete medium for another 48 h. 72 h post-transfection, cells were passaged, and 5 μg / ml puromycin was added to select for FPR1-transfected 293T cells. Overexpression of human or mouse FPR1 in 293T cells was detected by immunostaining with anti-mouse or human FPR1 antibodies (Biolegend or Antibody Online).

[0233] Measurement of intracellular calcium concentration mediated by fMLP-FPR1 in 293T cells

[0234] Cultured 293T cells overexpressing hFPR1 or mFPR1 were labeled with 1 μM INDO-1AM calcium sensor dye (eBioscience) at 37°C for 30 min. After washing with 1×PBS, the cells were resuspended in H-DMEM containing 3% FBS and maintained on ice before measuring intracellular calcium concentration. To measure the inhibitory potency of the designed potential FPR1 antagonist, 293T cells overexpressing hFPR1 or mFPR1 were incubated with the compound at room temperature for 10 min. Cytoplasmic calcium levels were then measured at 37°C by FACS Aria III before and after fMLP stimulation. The immunofluorescence intensity of indo-1AM before fMLP addition was defined as the baseline value, and for each sample, the intensity at the peak immunofluorescence reduction after fMLP addition was defined as the minimum value. The change in intracellular calcium was calculated as follows: (baseline value - minimum value) / baseline value × 100%. After inputting a series of intracellular calcium changes at multiple concentration gradients (from 0 nM to 100 μM), the IC50 of each compound inhibiting fMLP-FPR1-mediated intracellular calcium concentration in 293T cells was automatically calculated using Prism software (GraphPad). 50 .

[0235] Table 2. Potency of exemplary compounds in calcium signal transduction assays

[0236] Compound No. IC 50 (nM) 1 * 2 ** 3 N.D. 4 N.D.

[0237] Example 3. Preclinical efficacy of an in vivo mouse model of intracerebral hemorrhage (ICH)

[0238] The efficacy of the compounds of this disclosure in protecting against brain damage and improving brain function after stroke and / or brain injury was demonstrated in experiments using compound 1 as a representative compound in an experimental ICH mouse model, as described below.

[0239] Preparation of experimental mouse ICH model

[0240] The protective benefits of the compounds in this disclosure were demonstrated using a mouse model of intracerebral hemorrhage (ICH), and Figure 1 The procedure for preparing this model is described. As previously described, ICH was induced in C57 B / L6 male mice by injection of autologous blood or collagenase (Lauer et al., Circulation 124:1654-1662 (2011); Rynkowski et al., Nat. Protoc. 3:122-128 (2008)). Mice were anesthetized with isoflurane inhalation and fixed to a stereotactic frame. A burr hole was drilled on the right side of the skull, 2.3 mm lateral to the midline and 0.5 mm anterior to the anterior fontanelle. For the autologous blood model, 30 μl of unheparinized blood was aspirated from the medial canthal vein. The first 5 μl of blood was injected at a depth of 3 mm below the burr hole at a rate of 1 μl / min, and the remaining 25 μl of blood was injected at a depth of 3.7 mm below the burr hole. In the collagenase model, 0.038 U of bacterial collagenase (in 0.5 μl saline) was infused into the striatum (0.5 mm anterior, 2.3 mm lateral, and 3.5 mm depth relative to the anterior fontanelle) at a rate of 0.5 μl / min. An equal volume of saline was injected into mice in the sham control group. Body temperature was maintained at 37°C using a thermostat throughout the procedure. Mice were observed post-surgery with free access to food and water. The compound was dissolved in DMSO and administered intraperitoneally at a dose of 5 mg / kg twice daily at a volume of 1 ml / kg body weight. The first dose was administered 1 hour after the onset of ICH.

[0241] Neurological functional assessment

[0242] Neurological functional assessments were performed by researchers unaware of the two treatment groups. Modified Neurological Severity Score (mNSS), angle-turning test, and rotarod test were used to assess neurological deficits in ICH mice at defined time points, as described in (Li et al., Proc. Nat. Acad. Sci. USA 114: E396-E405 (2017)). Motor function (muscular and abnormal movement), sensory function (visual, tactile, and proprioceptive), and reflexes (auricular, corneal, and startle reflex) were assessed in mice. Scores ranged from 0 to 18 and were defined as follows: severe impairment (13 to 18); moderate impairment (7 to 12); and mild impairment (1 to 6). The angle-turning test was used to assess sensorimotor impairment to quantify turning deviation (right or left) at angles approaching 30°. Impaired mice typically exhibited turning deviations correlated with the degree of striatal damage. The procedure was repeated 10 times per mouse, with at least 30 seconds between tests. The percentage of ipsilateral turning was then calculated. The rotarod test was used to assess motor coordination and balance. Mice were trained one week prior to ICH induction. At a designated time point after ICH, mice were placed on a rotarod apparatus. The rotarod was 3 cm in diameter and had a rough surface. The length of the rotarod was 30 cm, and it was positioned 20 cm above the base. Each mouse was placed on the rotarod at a speed of 4 rpm (rotations / minute) (accelerating to 40 rpm over 5 minutes). The duration of each mouse on the rotarod was recorded. Each mouse was tested in three consecutive trials (with 15-minute intervals). Results were reported as the average of the three trials.

[0243] Reduced edema on MRI neuroimaging

[0244] As described in (Li et al., 2017), total lesion volume was measured on a 7T small animal MRI scanner (Bruker, Corp., USA). T2-weighted water imaging was recorded using the following parameters: repetition time (TR) = 4500 ms, echo time (TE) = 65.5 ms, field of view (FOV) = 28 x 28 mm. 2 Image matrix = 256×256, slice thickness = 0.5 mm. Magnetic susceptibility weighted imaging (SWI) was used to measure hematoma. Parameters were set as follows: TR = 30 ms and TE = 10 ms, flip angle = 25°, FOV = 32×32×16 mm. 3 The image matrix was 256×256. Volume was manually summarized and calculated using MIPAV software by multiplying the sum of the volumes by the distance between the parts (0.5 mm). PHE volume was calculated as the total lesion volume minus the hematoma volume. MRI data were analyzed by two researchers unaware of the experimental group's findings.

[0245] Brain water content assessment

[0246] Brain water content was measured on day 1 after ICH. In short, without perfusion, brain tissue was removed and divided into three parts: the ipsilateral hemisphere, the contralateral hemisphere, and the cerebellum. The brain tissue was weighed to obtain wet weight and then dried at 100°C for 24 hours to obtain dry weight. Brain water content was calculated using the following formula: (wet weight - dry weight) / wet weight × 100%.

[0247] Infiltrating cells were measured by flow cytometry.

[0248] Single-cell suspensions of brain tissue were prepared and stained with fluorescently conjugated antibodies. The brain tissue was digested with 1% collagenase (Sigma-Aldrich) at 37°C for 30 min, and then myelin was removed by density gradient centrifugation at 700 rpm in 30% Percoll (Sigma-Aldrich) for 10 min. For neutrophil staining, cells were incubated at 4°C for 30 min with anti-mouse CD45 (catalog number 103108; RRID: AB_312973, Biolegend, 1:100), anti-mouse Ly-6G (catalog number 127616; RRID: AB_1877271, Biolegend, 1:100), and anti-mouse CD11b (catalog number 553311; RRID: AB_394775, BDBiosciences, 1:100) according to their respective instructions. Flow cytometry measurements were performed on FACS Aria III (BDBioscience), and analysis was conducted using Flowjo 7.6 software (Informer Technologies, Ashland, Oregon, USA).

[0249] 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 in the following claims.

[0250] This application relates to the following technical solutions:

[0251] 1. A compound with the following structural formula I:

[0252]

[0253] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0254] Z 1 and Z 2 Both are either O or N and Z 3 It is C or N; where:

[0255] When Z3 When it is C, then Z 1 It is O and Z 2 Is it N or Z? 1 It is N and Z 2 It is O;

[0256] When Z 3 When it is N, then Z 1 and Z 2 Both are N;

[0257] Connecting ring A to the rest of formula I There is no system such that equation I includes a spirocyclic system or It is a single key;

[0258] Ring A is an aromatic ring or a non-aromatic ring, wherein:

[0259] X a and X b Each is independently a C, N, or bond; and

[0260] X 1 X 2 X 3 and X 4 Each can be either C or N independently;

[0261] Ring B is either an aromatic ring or a non-aromatic ring, wherein:

[0262] Y a It is C, N, non-existent, or a key; and

[0263] Y 1 Y 2 Y 3 Y 4 and Y 5 Each can be either C or N independently;

[0264] Ring C is selected from C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl and 5- to 10-membered heteroaryl;

[0265] R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), (C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k-NR h C(=O)NR i R j -NR h S(=O) p R k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl; wherein:

[0266] The R 1 R 2 and R 3 The C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups of any one of the C1-C6 alkyl groups and the C1-C6 alkyl group of the -C(=O)(C1-C6 alkyl) group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) p R k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) p R k -S (=O) p NR h R i and C3-C6 cycloalkyl groups;

[0267] The R 1 R2 and R 3 any of the C3-C 12 The carbocyclic group, the 3- to 12-membered heterocyclic group, the phenyl group, and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C1-C4 alkyl, -NR h R i and -OR k ;

[0268] R h R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; wherein:

[0269] The R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0270] R k Each occurrence is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0271] in:

[0272] The R h R i and R j The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH;

[0273] k and m are each an independent integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0274] n is an integer selected from 0, 1, 2, 3, 4, and 5; and

[0275] p is an integer selected from 1 and 2.

[0276] 2. The compound according to claim 1, wherein the compound has one of the following structural formulas IIa or IIb:

[0277]

[0278] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof.

[0279] 3. The compound according to claim 1 or 2, wherein the compound has the following structural formula III:

[0280]

[0281] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0282] Ring A and ring B are each aromatic rings.

[0283] 4. The compound according to any one of claims 1 to 3, wherein the compound has the following structural formula IV:

[0284]

[0285] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0286] X a X b X 1 X 2 and X 3 No more than 3 of them are N; and

[0287] Y a Y 1 Y 2 Y 3 and Y 4 No more than 3 of them are N.

[0288] 5. A compound, tautomer, deuterated derivative, or pharmaceutical product according to any one of items 1 to 4.

[0289] The above acceptable salts, wherein:

[0290] X a X b X 1 X 2 and X 3 No more than two of them are N; and

[0291] Y a Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0292] 6. A compound, tautomer, deuterated derivative, or pharmaceutical product according to any one of items 1 to 5.

[0293] The above acceptable salts, wherein:

[0294] X a and X b Each is either C or N; and

[0295] Y a It is C or N.

[0296] 7. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 6, wherein: ring A is bounded by k R 1 The pyridyl or pyrimidinyl group is substituted with a functional group.

[0297] 8. The compound according to any one of claims 1 to 7, wherein the compound has the following structural formula V:

[0298]

[0299] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof; wherein X 1 It is C or N.

[0300] 9. The compound according to any one of claims 1 to 8, wherein the compound has the following structural formula VI:

[0301]

[0302] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof.

[0303] 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 9, wherein: ring C is separated by n R 3 Group-substituted C5-C6 cycloalkyl or 5- to 6-membered heterocyclic groups.

[0304] 11. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 10, wherein: ring C is separated by n R 3 A group-substituted C5-C6 cycloalkyl or 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains one or two heteroatoms selected from O and N.

[0305] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 11, wherein: ring C is a ring having n R groups. 3 The group is a cyclohexyl or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group contains one or two heteroatoms selected from O and N.

[0306] 13. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 12, wherein: ring C is separated by n R 3 Tetrahydro-2H-pyranyl group substituted with a functional group.

[0307] 14. The compound according to claim 1 or 2, wherein the compound has the following structural formula VII:

[0308]

[0309] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0310] Ring A and ring B are each aromatic rings;

[0311] X a X b X 1 X 2 and X 3 No more than 3 of them are N; and

[0312] Y a Y 1 Y 2 Y 3 and Y 4 No more than 3 of them are N.

[0313] 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to item 14, wherein:

[0314] X a X b X 1 X 2 and X 3 No more than two of them are N; and

[0315] Y a Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0316] 16. The compound, tautomer, deuterated derivative, or drug according to any one of items 14 or 15

[0317] Scientifically acceptable salts, of which:

[0318] X a and X b Each is either C or N; and

[0319] Y a It is C or N.

[0320] 17. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 14 to 16, wherein: ring A is bounded by k R 1 The pyridyl or pyrimidinyl group is substituted with a functional group.

[0321] 18. A compound, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt according to any one of items 1 and 14 to 17, wherein: ring B is separated by m R 2 A phenyl group substituted with a radical.

[0322] 19. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 and 14 to 18, wherein: R a It is hydrogen or a C1-C2 alkyl group optionally substituted with one or two groups selected from the following groups: halogen, -CN, and -OH.

[0323] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 and 14 to 19, wherein: R a It is hydrogen.

[0324] 21. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 20, wherein: R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)NR h R i -NR h R i -OR k -S(=O)2R k -S(=O)2NR h R i C3-C6 cycloalkyl, 5- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl; wherein:

[0325] The R 1 R 2 and R 3 The C1-C6 alkyl and C1-C6 alkoxy groups of any one of the groups and the C1-C6 alkyl group of the -C(=O)(C1-C6 alkyl) group are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C(=O)OR k and -OR k ;

[0326] The R 1 R 2 and R3 The C3-C6 cycloalkyl, 5- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups of any one of them are each optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, C1-C4 alkyl, and -OR. k ;

[0327] R h and R i For each occurrence, each is independently selected from hydrogen and C1-C4 alkyl groups; wherein:

[0328] The R h and R i The C1-C4 alkyl group of any one of them is optionally substituted by one to three groups selected from the following groups: halogen, cyano, and -OH; and

[0329] R k For each occurrence, each is independently selected from hydrogen and C1-C4 alkyl groups; wherein:

[0330] The R h and R i The C1-C4 alkyl group of any one of them may optionally be substituted by 1 to 3 groups selected from the following groups: halogen, cyano, and -OH.

[0331] 22. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 21, wherein: R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR h R i -NR h R i and -OR k ;in:

[0332] The R 1 R 2 and R 3 The C1-C4 alkyl and C1-C4 alkoxy groups of any one of the C1-C4 alkyl groups and the C1-C4 alkyl group of the -C(=O)(C1-C4 alkyl) group are optionally substituted by 1 to 3 groups selected from the group consisting of halogen, cyano, and -OR. k ;

[0333] R h and R i Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups; and

[0334] R kEach of these is independently selected from hydrogen and C1-C2 alkyl groups.

[0335] 23. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 22, wherein: R 1 R 2 and R 3 For each occurrence, it is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), and -OR. k ;in:

[0336] The R 1 R 2 and R 3 Any one of the C1-C4 alkyl groups may optionally be substituted with one to three halogen groups; and

[0337] R k Each of these is independently selected from hydrogen and C1-C2 alkyl groups.

[0338] 24. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 23, wherein: R 1 For each occurrence, it is independently selected from F, Cl, Br, C1-C2 alkyl, and -OR. k ;in:

[0339] The R 1 The C1-C2 alkyl group is optionally substituted with one to three halogen groups; and

[0340] R k Each of these is independently selected from hydrogen and C1-C2 alkyl groups.

[0341] 25. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 24, wherein: R 1 For each occurrence, it is independently selected from F, -CH3, and -OH.

[0342] 26. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 25, wherein: R 2 For each occurrence, it is independently selected from F, Cl, Br, and C1-C2 alkyl groups; wherein:

[0343] The R 1 The C1-C2 alkyl group is optionally replaced by 1 to 3 halogens.

[0344] 27. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 26, wherein: R 2 For each occurrence, it is independently selected from Cl and -CF3.

[0345] 28. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 27, wherein: k is an integer selected from 0, 1, and 2.

[0346] 29. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 28, wherein m is an integer selected from 1 and 2.

[0347] 30. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of items 1 to 29, wherein n is 0.

[0348] 31. The compound according to claim 1, wherein the compound is selected from:

[0349]

[0350] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof.

[0351] 32. A pharmaceutical composition comprising a compound, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier according to any one of claims 1 to 31.

[0352] 33. A method of treating a subject for a disease, disorder, or symptom mediated by formyl peptide receptor 1 (FPR1) signaling, the method comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt or pharmaceutical composition according to any one of claims 1 to 31, or according to claim 32.

[0353] 34. The method according to item 33, wherein the disease, disorder, or condition is related to the CNS and is selected from stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, epileptic disorder, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sachs disease, Sandoff's disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedrich's ataxia, Wilson's disease. Menkes Sx disease, autosomal dominant cerebral arteriosclerosis with subcortical infarction (CADASIL); spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Touss disease, neurofibromatosis, von Hippel-Lindau disease, fragile X disease, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Charcot-Touss disease, olivopontocerebellar degeneration, nigrostriatal degeneration Sexual dysfunction, Guillain-Barré syndrome, burning pain, type I and II complex regional pain syndromes, diabetic neuropathy, 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, prion disease, myelitis, radiculitis, diabetes mellitus associated with adverse 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, multiple cranial neuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain damage, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0354] 35. The method according to item 33 or 34, wherein the disease, disorder or condition is stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, and venous).

[0355] 36. The method according to item 33 or 34, wherein the disease, disorder or symptom is traumatic brain injury.

[0356] 37. The method according to item 33 or 34, wherein the disease, disorder or symptom is a malignant glioma.

[0357] 38. The method according to claim 37, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglion glioma.

[0358] 39. The method according to claim 38, wherein the malignant glioma is glioblastoma.

Claims

1. A compound, its tautomer, or a pharmaceutically acceptable salt thereof, wherein said compound is a compound of the following structural formula IIa: Formula IIa, in: Z 1 It is O and Z 2 Is it N or Z? 1 It is N and Z 2 It is O; Ring A is an aromatic ring, in which: X a X b X 1 X 2 X 3 and X 4 It is C; Ring B is an aromatic ring, in which: Y a 、Y 1 、Y 2 、Y 3 、Y 4 and Y 5 are C; The ring C is tetrahydro-2H-pyranyl; R 1 R 2 and R 3 For each occurrence, it is independently selected from C1-C4 alkyl groups and -OR. k ;in: The R 1 R 2 and R 3 Any one of the C1-C4 alkyl groups may optionally be substituted with one to three halogen groups; and R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; and n is an integer selected from 0, 1, 2, 3, 4, and 5.

2. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: R 1 For each occurrence, it is independently selected from C1-C2 alkyl groups and -OR. k ;in: The R 1 The C1-C2 alkyl group is optionally substituted with one to three halogen groups; and R k Each of these is independently selected from hydrogen and C1-C2 alkyl groups.

3. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: R 1 For each occurrence, it is independently selected from -CH3 and -OH.

4. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: R 2 For each occurrence, it is a C1-C2 alkyl group. The C1-C2 alkyl group is optionally substituted with one to three halogens.

5. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: R 2 For each occurrence, it is -CF3.

6. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: k is an integer selected from 0, 1, and 2.

7. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: m is an integer selected from 1 and 2.

8. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: n is 0.

9. The compound of claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

11. Use of the compound, its tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating a subject with a disease, disorder, or symptom mediated by formyl peptide receptor 1 (FPR1) signaling, wherein said treatment comprises administration of a therapeutically effective amount of the compound, its tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10.

12. The use according to claim 11, wherein the disease, disorder, or condition is related to the CNS and is selected from stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, normal pressure hydrocephalus, epilepsy, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Ty-Sachs disease, Sandoff's disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedrich's ataxia, Wilson's disease, and Menkes Sx disease.

1. Autosomal dominant cerebral arteriosclerosis with subcortical infarction (CADASIL); muscular dystrophy, Charcot-Marie-Touss disease, neurofibromatosis, von Hippel-Lindau disease, Fragile X disease, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Charcot-Deutsche disease, olivopontocerebellar degeneration, nigrostriatal degeneration, Guillain-Barré syndrome. Syndrome, burning pain, type I and II complex regional pain syndromes, diabetic neuropathy, alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, traumatic brain injury, traumatic spinal cord injury, radiation-induced brain injury, multiple sclerosis, postmeningitis syndrome, prion disease, myelitis, radiculitis, diabetes mellitus associated with adverse proteinemia, thyroxine-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, herpes zoster-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, multiple cranial neuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain damage, chronic fatigue syndrome, and malignant glioma.

13. The use according to claim 11, wherein the disease, disorder or symptom is a spinal cord disease.

14. The use according to claim 11, wherein the disease, disorder or condition is epilepsy disorder.

15. The use according to claim 11, wherein the disease, disorder or symptom is a brain disease.

16. The use according to claim 11, wherein the disease, disorder, or symptom is spinal muscular atrophy.

17. The use according to claim 12, wherein the dementia is frontotemporal dementia or vascular dementia.

18. The use according to claim 11, wherein the disease, disorder or ailment is a stroke.

19. The use according to claim 18, wherein the stroke is a thrombotic stroke, an embolic stroke, a vascular embolic stroke, a hemorrhagic stroke, a venous constrictive stroke, or a venous stroke.

20. The use according to claim 11, wherein the disease, disorder or symptom is traumatic brain injury.

21. The use according to claim 11, wherein the disease, disorder or symptom is a malignant glioma.

22. The use according to claim 21, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglion glioma.

23. The use according to claim 22, wherein the malignant glioma is glioblastoma.

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