FPR1 modulator and how to use it

Abstract

The disclosure provides compounds of formula I, compositions comprising same, and methods of using same, including for use in treating diseases, disorders, or conditions mediated by formyl peptide receptor 1 (FPR1) signaling. JPEG2024507672000039.jpg90170

Description

[Technical Field]

[0001] This disclosure relates to compounds useful for treating diseases. More specifically, this disclosure relates to compounds that bind to formyl peptide receptors (FPRs), such as FPR1, and modulate their activity, thereby reducing or eliminating unbalanced FPR-mediated signaling, which is the underlying pathogenesis of a range of diseases, such as central nervous system (CNS) diseases or disorders, including stroke, traumatic brain injury (TBI), glioblastoma, and malignant glioma. [Background technology]

[0002] The restoration of bodily homeostasis after injury or pathogen infection is critical to ensuring the survival of the organism. Physiological wound healing and the innate immune response are initiated by the release of soluble signaling molecules from the invading pathogen or damaged lesion. Temporarily regulated, interactive repair processes involve, for example, many chemokines, cytokines, acute-phase proteins, invasive and tissue-specific cells, fibroblasts, nerve cells, and the vascular system. If the injury is persistent or extensive, physiological trauma repair or the anti-infective response can become pathological, leading to excessive inflammation, edema, improper fibrous repair, organ failure, acute respiratory distress syndrome (ARDS), sepsis, and ultimately organ failure and / or death. Therefore, effective regulation of the scale and duration of inflammation and the resolution response can be critical in injury repair. Following tissue injury or pathogen infection (by bacteria, viruses, fungi, and / or microorganisms), a series of formyl peptides, damage-associated molecular pattern molecules (DMAPs), inflammatory lipid mediators (e.g., leukotrienes and lipoxins), and acute-phase proteins (e.g., annexins) are released from invading pathogens, damaged cells, and diseased tissue. Three formyl peptide receptors (FPR1, FPR2, and FPR3) function as major sensors for these chemotactic and activating molecules in humans. These FPR receptors are highly expressed on neutrophils, macrophages, T lymphocytes, dendritic cells, epithelial cells, fibroblasts, microglia, and astrocytes. Binding of these chemoactive molecules and acute proteins to FPR receptors attracts leukocytes, stimulates the production of superoxide and cytokines, and activates microglia, astrocytes, and other inflammatory and resolution responses for damage repair and host defense.

[0003] On the other hand, pathological inflammatory responses stemming from unbalanced FPR receptor-mediated signaling are responsible for numerous post-injury or post-infection conditions, including, for example, cerebral edema, dysfunction, and organ failure following stroke or traumatic brain injury. In addition, chronic activation of FPR receptor-mediated signaling from invading pathogens, tissue stress, and tissue injury has been linked to the pathogenesis of brain cancer, gastric cancer, and Parkinson's syndromes.

[0004] Stroke is the leading cause of death worldwide, and treatment options are limited. FPR receptors are highly expressed in microglia, astrocytes, and the cerebrovascular system. Following the onset of induced intracerebral hemorrhage (ICH), infiltrating leukocytes, activated platelets, microglia, and astrocytes release a range of pro-inflammatory neurotransmitters, acute-phase proteins, and DMAP from dying cells. Leukocyte infiltration, reactive oxygen species (ROS) production, and cytokine release induced by FPR1 activation may be the first wave of the post-injury inflammatory response and contribute to the development of perihematoma edema and aggravated mass effects in stroke.

[0005] Traumatic brain injury (TBI) is the leading cause of disability worldwide. The global incidence of TBI is estimated at 200 cases per 100,000 people per year. Severe injuries often result in behavioral problems, 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. With an annual incidence of approximately 6 cases per 100,000 people, there is currently no effective treatment for malignant glioma. The FPR1 receptor is highly expressed in glial cells, astrocytes, and the cerebral vascular system. The interaction of the FPR receptor with chemotactic ligands due to injury, stress, and pathogens is involved in the pathophysiology of brain cancer. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International patent application WO2013 / 075083 [Patent Document 2] International patent application WO2013 / 075084 [Patent Document 3] International patent application WO2013 / 078320 [Patent Document 4] International patent application WO2013 / 120104 [Patent Document 5] International patent application WO2014 / 124418 [Patent Document 6] International patent application WO2014 / 151142 [Patent Document 7] International patent application WO2015 / 023915 [Patent Document 8] U.S. Patent No. 4,938,949 [Non-patent literature]

[0008] [Non-Patent Document 1] S.M. Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19. [Non-Patent Document 2] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-Patent Document 3] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia. [Non-Patent Document 4] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York [Non-Patent Document 5] Lauer et al., Circulation, Vol. 124: pp. 1654-1662 (2011) [Non-Patent Document 6] Rynkowski et al., Nat. Protoc. 3:122–128 (2008) [Non-Patent Document 7] Li et al., Proc. Nat. Acad. Sci. USA114: E396-E405 (2017) [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Considering the foregoing, there is still a need for novel therapeutic agents and alternative mechanisms that can effectively address the limited and currently available effective treatment options for at least stroke, TBI, glioblastoma, and glioma. [Means for solving the problem]

[0010] One aspect of the present disclosure provides compounds selected from the compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, which can be used to treat diseases mediated by formyl peptide receptor 1 (FPR1) signaling. For example, the compound of the following structural formula I:

[0011] [ka]

[0012] [In formula: R a is a C1-C4 alkyl group which is hydrogen or optionally substituted with 1-3 groups selected from halogens, -CN, -OH, and -COOH, and which bonds ring A to the remainder of formula I.

[0013] [ka]

[0014] It does not exist, or, so that formula I does not contain a spirocyclic ring system.

[0015] [ka]

[0016] is a single bond, ring A is an aromatic or non-aromatic ring, X a and X b are each independently C, N, or a bond, X 1 , X 2 , X 3 and X 4 are each independently C or N, ring B is an aromatic or non-aromatic ring, Y a is C, N, absent, or a bond, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently C or N, ring C is C3 - C 10 cycloalkyl or a 4 - 10 member heterocyclyl, provided that ring C is not tetrahydro - 1,1 - dioxido - 3 - thienyl, R 1 , R 2 and R 3 are, for each occurrence, independently 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 Selected from carbocyclyl, 3-12 member heterocyclyl, phenyl, and 5-10 member heteroaryl, R 1 , R 2 , and R 3 Any one of the C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups, as well as the C1-C6 alkyl group of -C(=O)(C1-C6 alkyl), is a halogen, cyano, or -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 optionally substituted with 1 to 3 groups selected from C3-C6 cycloalkyl groups, R 1 , R 2 , and R 3 one of the following C3~C 12Carbocyclic, 3- to 12-membered heterocyclic, phenyl, 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR h R i , and -OR k ; and R h , R i , and R j are each independently selected, for each occurrence, from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R h , R i , and R j wherein any one of the C1-C4 alkyls is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R k is each independently selected, for each occurrence, from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R h , R i , and R j wherein any one of the C1-C4 alkyls is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; when ring C is cyclopropyl, cyclopentyl, or cyclohexyl, n is an integer selected from 1, 2, 3, 4, and 5; when ring C is a C4-C 10 cycloalkyl other than cyclopentyl, or when ring C is a 4- to 10-membered heterocyclic, n is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 1 and 2; its tautomer, its compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the foregoing is disclosed herein.

[0017] In one aspect of this disclosure, the compound of formula I is selected from the compounds 1 to 16 shown below, their tautomers, deuterated derivatives of the compound or its tautomer, or the aforementioned pharmaceutically acceptable salts.

[0018] In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts, and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical compositions may comprise compounds selected from the following compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts. These compositions may further comprise additional pharmaceutically active agents.

[0019] Another aspect of the present disclosure provides a method for treating a disease, disorder, or condition mediated by formyl peptide receptor 1 (FPR1) signaling in a subject, comprising administering a therapeutically effective amount of a compound of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, its tautomers, deuterated derivatives of the compound or 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 the following compounds 1 to 16, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing.

[0020] In some embodiments, the treatment method involves administering an additional pharmaceutically active agent to a subject requiring it, either as part of the same pharmaceutical composition as the compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or as a separate composition. In some embodiments, the treatment method involves administering an additional pharmaceutically active agent, either as part of the same pharmaceutical composition as the compounds 1 to 16 listed below, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or as a separate composition.

[0021] Methods for modulating FPR1 activity are also disclosed herein, comprising administering a therapeutically effective amount of a compound of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, its tautomers, deuterated derivatives of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing. In some embodiments, the method for modulating FPR1 comprises administering a compound selected from the following compounds 1 to 16, its tautomers, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing. In some embodiments, a method for modulating FPR1 activity includes contacting FPR1 with a compound of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt as described above, or a pharmaceutical composition containing any of the above. In some embodiments, a method for modulating FPR1 includes contacting FPR1 with a compound selected from the following compounds 1 to 16, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt as described above, or a pharmaceutical composition containing any of the above. [Brief explanation of the drawing]

[0022] [Figure 1] This is a schematic diagram illustrating the procedure for evaluating the efficacy of the compounds disclosed herein in a mouse model of induced intracerebral hemorrhage (ICH). [Figure 2A] These are MRI images for quantifying lesion volume and perihematoma edema (PHE) volume one day after induction of ICH in mice. Mice were administered a vehicle (n=15 / group, one-sided t-test). [Figure 2B] These are MRI images for quantifying lesion volume and perihematoma edema (PHE) volume one day after induction of ICH in mice. Compound 1 was administered to the mice (n=15 / group, one-sided t-test). [Figure 3A] This bar graph illustrates the brain water content 24 hours after administration of either the vehicle or compound 1 (n=15 / group, one-sided t-test) to ICH mice. [Figure 3B] This bar graph illustrates the brain water content 24 hours after administration of either the vehicle or compound 1 (n=15 / group, one-sided t-test) to ICH mice. [Figure 4] Figure 4A. A line graph illustrating the nervous system scores of ICH mice administered either the vehicle or compound 1, one day and three days after ICH induction (n=15 / group, Sidak multiple comparison test). Figure 4B. A line graph illustrating the nervous system scores of ICH mice administered either the vehicle or compound 1, one day and three days after ICH induction (n=15 / group, Sidak multiple comparison test). Figure 4C. A line graph illustrating the nervous system scores of ICH mice administered either the vehicle or compound 1, one day and three days after ICH induction (n=15 / group, Sidak multiple comparison test). [Figure 5] This line graph illustrates the number of brain-infiltrating neutrophils in ICH mice administered either the vehicle or compound 1, one and three days after ICH induction (n=15 / group, Sidac multiple comparison test, data presented as mean ± sem*p<0.05; **p<0.01). [Modes for carrying out the invention]

[0023] I. Definition When used herein to refer to a noun, the terms "a" or "an" encompass the expression "at least one" and therefore include both singular and plural units of the noun. For example, "additional medication" means one or more additional medications.

[0024] The terms "FPR1" or "formyl peptide receptor 1," as used herein, refer to the cell surface receptor protein encoded by the FPR1 gene in humans. FPR1 modulates a wide variety of neutrophil functional responses and plays a crucial role in the pathogenesis of various diseases, including, for example, those described above.

[0025] The term "FPR1 modulator," as used herein, refers to an organic small molecule compound (≤10 kDa) that has the ability to alter one or more FPR1-mediated immune responses or signaling pathways from their native state and can be either an FPR1 agonist or an FPR1 antagonist. When an FPR1 modulator is an agonist, the compound has the ability to increase one or more FPR1-mediated immune responses or signaling pathways from their native state, for example, by binding to and activating the receptor. When an FPR1 modulator is an antagonist, the compound has the ability to decrease or inhibit one or more FPR1-mediated immune responses or signaling pathways from their native state, for example, by blocking the agonist binding site on the receptor to achieve a reduction or inhibition of its action.

[0026] The term “compound” in the context of the compounds of this disclosure refers to a group of molecules having the same chemical structure, unless otherwise noted as a group of stereoisomers (e.g., a group of racemates, a group of cis / trans stereoisomers, or a group of (E) and (Z) stereoisomers), provided that isotopic variations may exist between the constituent atoms of the molecules. It will also be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom may contain a lower amount of isotopologes having a hydrogen atom at one or more of the designated deuterium positions within its structure. The relative amount of such isotopologes in the compounds of this disclosure depends on several factors, including, for example, the purity of the isotopes in the reagents used to produce the compound and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopologes is less than 49.9% of the compound overall. In other embodiments, the relative amount of such isotopologues is 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 overall.

[0027] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” Generally, the term “substituted” refers to replacing a hydrogen group in a given structure with a group of a specified substituent. Unless otherwise noted, an “optionally substituted” group may have substituents at each substitutedable position of the group, and more than one position in any given structure may be substituted with more than one substituent selected from the specified group, and the substituents may be the same or different at all positions. The substituent combinations envisioned herein are combinations that result in the formation of stable or chemically possible compounds.

[0028] The term "isotopologie" refers to species that differ only in their chemical structure in terms of their isotopic composition. Furthermore, unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen being replaced by deuterium or tritium, or carbon being 13 C or 14 Compounds having the structure of the present invention are within the scope of this disclosure, except that they are replaced by C.

[0029] Unless otherwise noted, the structures shown herein are also intended to include all isomeric forms, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise noted, all tautomeral forms of the compounds of this disclosure are within the scope of this disclosure.

[0030] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the movement of atoms, such as hydrogen atoms, or intramolecular groups.

[0031] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0032] As used herein, “deuterated derivative” means having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or 「2This refers to compounds in which hydrogen is replaced by deuterium. Depending on the origin of the chemicals used in the synthesis, it is recognized that some variations of the natural isotopic abundance may occur in the synthesized compounds. The concentrations of naturally abundant and stable hydrogen isotopes are low and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein, despite these variations. Therefore, unless otherwise stated, when a “deuterated derivative” of a compound in this disclosure is referred to, at least one hydrogen atom is replaced by deuterium at a level well above its natural isotopic abundance of approximately 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium bonding at each designated deuterium), at least 4500 (67.5% deuterium bonding at each designated deuterium), at least 5000 (75% deuterium bonding at each designated deuterium), at least 5500 (82.5% deuterium bonding at each designated deuterium), at least 6000 (90% deuterium bonding at each designated deuterium), at least 6333.3 (95% deuterium bonding at each designated deuterium), at least 6466.7 (97% deuterium bonding at each designated deuterium), or at least 6600 (99% deuterium bonding at each designated deuterium).

[0033] As used herein, the term "isotope enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a given isotope.

[0034] As used herein, the term "alkyl" means a straight-chain or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains from 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group contains from 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains from 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains from 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains from 1 to 4 alkyl carbon atoms. In other embodiments, the alkyl group contains from 1 to 3 alkyl carbon atoms. And in still other embodiments, the alkyl group contains from 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 or linear or unbranched. In some embodiments, the alkyl group is branched.

[0035] The term "cycloalkyl" refers to a fully saturated, monocyclic C 3~8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 hydrocarbon, wherein any individual ring in the bicyclic system has from 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 is C3-C 12 cycloalkyl. In some embodiments, the cycloalkyl is C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is C3-C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0036] The term "carbocyclic" encompasses the term "cycloalkyl" and refers to a monocyclic C 3~8 hydrocarbon that is fully saturated or partially saturated by containing one or more unsaturated units but is not aromatic, or a spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14This refers to hydrocarbons, where any individual ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclyls include, for example, combinations of monocyclic carbocyclics condensed with phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is C3-C 12 It is carbocyclyl. In some embodiments, carbocyclyl is C3-C 10 It is a carbocyclyl. In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl.

[0037] As used herein, the term "alkenyl" means a linear or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear, linear, or unbranched. In some embodiments, the alkenyl group is branched.

[0038] The term “heterocyclyl,” as used herein, means a non-aromatic (i.e., fully saturated or partially saturated, containing one or more unsaturated units, but not aromatic), monocyclic, spirocyclic, condensed, or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected from heteroatoms. Examples of bicyclic heterocyclyls include the following combinations of monocyclic rings: a monocyclic heteroaryl condensed onto a monocyclic heterocyclyl; a monocyclic heterocyclyl condensed onto another monocyclic heterocyclyl; a monocyclic heterocyclyl condensed onto phenyl; a monocyclic heterocyclyl condensed onto a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl condensed onto a monocyclic carbocyclyl / cycloalkyl. In some embodiments, the “heterocyclyl” group contains 3 to 14 ring members, one or more of which are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a 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 independently has one heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle independently has two heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycle independently has three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocycle is a 3 to 12-membered heterocycle. In some embodiments, the heterocycle is a 4 to 10-membered heterocycle. In some embodiments, the heterocycle is a 3 to 8-membered heterocycle. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl.In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranil, azetidinyl, tetrahydrothiophenyl, and 1,1-dioxide.

[0039] The term "heteroatom" refers to nitrogen or sulfur in any oxidized form, or silicon; any basic nitrogen in a quaternized form; or a substituteable nitrogen in a heterocyclic ring, e.g., N (in the case of 3,4-dihydro-2H-pyrrolyl, etc.), NH (in the case of pyrrolidinyl, etc.), or NR + This refers to one or more of oxygen, sulfur, and nitrogen, including (in the case of N-substituted pyrrolidinyl, etc.).

[0040] As used herein, the term "unsaturated" means that a part has one or more unsaturated units or degrees of unsaturation. Unsaturated means that not all available valence bonds in a compound are filled with substituents, and therefore the compound contains double or triple bonds.

[0041] 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, but the oxygen atom is linked between two carbon atoms.

[0042] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodine, respectively.

[0043] As used herein, the "cyano" or "nitrile" group refers to -C≡N.

[0044] As used herein, “aromatic ring” refers to a carbocyclic or heterocyclic ring containing a conjugated, planar ring system having a delocalized pi electron orbital composed of [4n+2]p orbital electrons (wherein n is an integer from 0 to 6). A “non-aromatic” ring refers to a carbocyclic or heterocyclic ring that does not satisfy the requirements set forth above for aromatic rings and may be fully saturated or partially saturated. Non-restrictive examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows:

[0045] The term "aryl," used alone or as part of a larger term such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or spirocyclic, condensed, or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, where all rings in the system are aromatic rings containing only carbon atoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C6). 10 Examples include rings. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0046] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Examples of bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5 or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, etc.

[0047] A "spirocyclic ring system" refers to a ring system having two or more cyclic rings, where every pair of rings shares only one common atom.

[0048] Suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (SiO), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

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

[0050] pharmaceutically acceptable salts of the disclosed compounds are disclosed herein. Salts of the compounds are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0051] As used herein, the term "pharmaceutically acceptable" refers to a component that is within the bounds of sound medical judgment, suitable for use in contact with human and other mammalian tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable profit-benefit ratio. "pharmaceutically acceptable salt" means any non-toxic salt that can be directly or indirectly provided to a recipient by administration. A suitable pharmaceutically acceptable salt is, for example, the salt disclosed in S.M. Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19.

[0052] 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, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, vitaltric 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, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexin-1,6 Examples of salts include dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include salts formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and salts formed with organic acids, such as maleic acid.

[0053] Examples of pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4Examples include alkyl)4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

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

[0055] The term "therapeutic dose" refers to the amount of compound administered to produce the desired effect (e.g., improving the symptoms of a disease, disorder, or condition mediated by FPR1 signaling, reducing the severity of a disease, disorder, or condition mediated by FPR1 signaling or its symptoms, and / or reducing the progression of a disease, disorder, or condition mediated by FPR1 signaling or its symptoms). The exact amount of the therapeutic dose depends on the purpose of the treatment 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).

[0056] As used herein, the term “treatment” and its related terms mean slowing or halting disease progression. “Treatment” and its related terms, as used herein, include, but are not limited to, complete or partial remission, a reduction in the risk of diseases, disorders, and conditions mediated by FPR1 signaling, and disease-related complications. Improving or reducing the severity of any of these symptoms can be readily assessed or subsequently developed according to methods and techniques known in the art.

[0057] When used in relation to the dose, volume, or mass percentage of an ingredient in a composition or dosage form, the terms "about" and "approximately" include a specified dose, volume, or mass percentage value or range of dose, volume, or mass percentage that is recognized by those skilled in the art as producing a pharmacological effect equivalent to that obtained from a specified dose, volume, or mass percentage.

[0058] II. Compounds and Compositions In the first embodiment, the compound of the present disclosure is a compound having the following structural formula I:

[0059] [ka]

[0060] [In formula: R a is a C1-C4 alkyl group which is hydrogen or optionally substituted with 1-3 groups selected from halogens, -CN, -OH, and -COOH, and which bonds ring A to the remainder of formula I.

[0061] [ka]

[0062] It does not exist, or, so that formula I does not contain a spirocyclic ring system.

[0063] [ka]

[0064] It is a single bond, Ring A is either an aromatic or non-aromatic ring. X a and X b Each of these is independently C, N, or a bond. X 1 , X 2 , X 3 , and X 4 Each of them is independently either C or N, Ring B is either an aromatic or non-aromatic ring. Y a is C, N, nonexistent, or bonded. Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of them is independently either C or N, Ring C is C3~C 10 It is a cycloalkyl or a 4- to 10-membered heterocyclyl, provided that the carbon atom of ring C is not tetrahydro-1,1-dioxide-3-thienyl. R 1 , R 2 , and R 3 For each occurrence, independently, 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)NRh R i -S(=O) p R k -S(=O) p NR h R i , C3~C 12 Selected from carbocyclyl, 3-12 member heterocyclyl, phenyl, and 5-10 member heteroaryl, R 1 , R 2 , and R 3 Any one of the C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups, as well as the C1-C6 alkyl group of -C(=O)(C1-C6 alkyl), is a halogen, cyano, or -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 optionally substituted with 1 to 3 groups selected from C3-C6 cycloalkyl groups, R 1 , R 2 , and R 3 one of the following C3~C 12 Carbocyclyl, 3-12 member heterocyclyl, phenyl, 5-10 member heteroaryl, halogen, cyano, C1-C4 alkyl, -NR hR i , and -OR k Each of the following is substituted depending on the case: R h , R i , and R j For each occurrence, each is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl. R h , R i , and R j Any one of the C1-C4 alkyl groups is optionally substituted with 1-3 groups selected from halogens, cyano, and -OH groups. R k Each occurrence is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl. R h , R i , and R j Any one of the C1-C4 alkyl groups is optionally substituted with 1-3 groups selected from halogens, cyano, and -OH groups. k and m are each independently integers selected from 0, 1, 2, 3, 4, 5, and 6. If ring C is cyclopropyl, cyclopentyl, or cyclohexyl, then n is an integer selected from 1, 2, 3, 4, and 5. Ring C is C4-C other than cyclopentyl 10 If it is a cycloalkyl group, or if the ring C is a 4- to 10-membered heterocycline, then n is an integer selected from 0, 1, 2, 3, 4, and 5. [where p is an integer selected from 1 and 2] The tautomer, the compound or deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt.

[0065] In a second embodiment, the compound of the present disclosure is one of the following compounds with structural formula IIa or IIb:

[0066] [ka]

[0067] [wherein ring A of formula IIb is a non-aromatic ring, and all other variable elements not specifically defined herein are as defined in the first embodiment] its tautomer, its compound or deuterated derivative of its tautomer, or the pharmaceutically acceptable salt described above.

[0068] In a third embodiment, the compound of the present disclosure is the compound of the following structural formula III:

[0069] [ka]

[0070] [wherein ring A and ring B are each aromatic rings], its tautomers, its compounds or deuterated derivatives of its tautomers, or the pharmaceutically acceptable salts described herein, all other variable elements not specifically defined herein are as defined in either one of the first or second embodiments.

[0071] In the fourth embodiment, the compound of the present disclosure has the following structural formula IV:

[0072] [ka]

[0073] [In formula: X a , X b , X 1 , X 2 , and X 3 If three or fewer of these are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4[Three or fewer of these are N], its tautomers, deuterated derivatives of its compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, and all other variable elements not specifically defined herein are as defined in any one of the first, second, and third embodiments.

[0074] In the fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X a , X b , X 1 , X 2 , and X 3 Two or fewer of these are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 Two or fewer of these are N, All other variable elements not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0075] In the sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X a and X b Each of them is independently either C or N, Y a is C or N, All other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, and fifth embodiments.

[0076] In the seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is R 1 A pyridinyl or pyrimidinyl substituted with a k-group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, and sixth embodiments.

[0077] In the eighth embodiment, the compound of the present disclosure is a compound having the following structural formula V:

[0078] [ka]

[0079] [In formula: X 1 is C or N, R a is hydrogen, or a C1-C2 alkyl group optionally substituted with one or two groups selected from halogens, -CN, and -OH. All other variable elements not specifically defined herein are their tautomers, deuterated derivatives of their compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, as defined in any one of the first, second, third, fourth, fifth, sixth, and seventh embodiments.

[0080] In the ninth embodiment, the compound of the present disclosure is a compound having the following structural formula Via:

[0081] [ka]

[0082] The tautomers thereof, deuterated derivatives of the compound or tautomer thereof, or the pharmaceutically acceptable salts described herein, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments.

[0083] In the tenth embodiment, the compound of the present disclosure is a compound having the following structural formula VIb:

[0084] [ka]

[0085] The tautomers thereof, deuterated derivatives of the compound or tautomer thereof, or the pharmaceutically acceptable salts described herein, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, and eighth embodiments.

[0086] In the eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is R 3 A C5-C6 cycloalkyl or 5-6 membered heterocycline substituted with an n group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth embodiments.

[0087] In the twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is R 3 A C5-C6 cycloalkyl or 5-6 membered heterocycline substituted with an n group, wherein the 5-6 membered heterocycline contains one or two heteroatoms selected from O and N, and all other variable elements 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.

[0088] In the 13th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is R 3 A cyclohexyl or six-membered heterocycline having n groups, wherein the six-membered heterocycline contains one or two heteroatoms selected from O and N, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth embodiments.

[0089] In the fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, the ring C is R 3 The elements are cyclohexyl, tetrahydro-2H-pyranyl, or piperidinyl substituted with an n group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and thirteenth embodiments.

[0090] In the 15th embodiment, the compound of the present disclosure is one of the following compounds with structural formulas VIIa to VIIc:

[0091] [ka]

[0092] [In formula: Rings A and B are both aromatic rings. X a , X b , X 1 , X 2 , and X 3 Three or fewer of these are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 Three or fewer of these are N, and all other variable elements not specifically defined herein are as defined in any one of the first, second, and third embodiments] their tautomers, deuterated derivatives of the compound or tautomer, or the pharmaceutically acceptable salts described herein.

[0093] In the sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X a , X b , X 1 , X 2 , and X 3 Two or fewer of these are N, Ya , Y 1 , Y 2 , Y 3 , and Y 4 Two or fewer of these are N, And all other variable elements not specifically defined herein are as defined in the 15th embodiment.

[0094] In the seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X a and X b Each of them is independently either C or N, Y a is C or N, All other variable elements not specifically defined herein are as defined in either one of the 15th and 16th embodiments.

[0095] In the 18th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is R 1 A pyridinyl or pyrimidinyl substituted with a k-group, and all other variable elements not specifically defined herein are as defined in any one of the 15th, 16th, and 17th embodiments.

[0096] In the 19th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is R 2 A phenyl substituted with an m group, and all other variable elements not specifically defined herein are as defined in any one of the first, fifteenth, sixteenth, seventeenth, and eighteenth embodiments.

[0097] In the 20th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R ais hydrogen or a C1-C2 alkyl group optionally substituted with one or two groups selected from halogens, -CN, and -OH, and all other variable elements not specifically defined herein are as defined in any one of the first, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth embodiments.

[0098] In the 21st embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is hydrogen, and all other variable elements not specifically defined herein are as defined in any one of the first, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and twentyth embodiments.

[0099] In the 22nd embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 , R 2 , and R 3 For each occurrence, independently, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), and -C(=O)NR h R i , -NR h R i , -OR k -S(=O)2R k -S(=O)2NR h R i Selected from C3-C6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, R 1 , R 2 , and R 3 Any one of the C1-C6 alkyl and C1-C6 alkoxy groups, as well as the C1-C6 alkyl group of -C(=O)(C1-C6 alkyl), is a halogen, cyano, or C(=O)OR k , and -OR k Each of the following is substituted depending on the case: R 1 , R 2 , and R 3Any one of the following C3-C6 cycloalkyl, 5-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl elements may be halogens, cyano, C1-C4 alkyl, and -OR k Each of the following is substituted depending on the case: R h and R i For each occurrence, hydrogen and C1-C4 alkyl are independently selected. R h and R i Any one of the C1-C4 alkyl groups is optionally substituted with 1-3 groups selected from halogens, cyano, and -OH groups. R k For each occurrence, hydrogen and C1-C4 alkyl are independently selected. R h and R i Any one of the C1-C4 alkyl groups is optionally substituted with 1-3 groups selected from halogens, cyano, and -OH groups. All other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentyth, and twenty-first embodiments.

[0100] In the 23rd embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 , R 2 , and R 3 For each occurrence, independently, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), and -C(=O)NR h R i , -NR h R i , and -OR k Selected from, R 1 , R 2 , and R 3Any one of the C1-C4 alkyl and C1-C4 alkoxy groups, as well as the C1-C4 alkyl group in -C(=O)(C1-C4 alkyl), may be substituted with a halogen, cyano, and -OR. k It is optionally replaced by 1 to 3 elements selected from the following: R h and R i Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups. R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups. All other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentyth, twenty-first, and twenty-second embodiments.

[0101] In the 24th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 , R 2 , and R 3 Each occurrence independently represents a halogen, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), and -OR. k Selected from, R is substituted in some cases. 1 , R 2 , and R 3 One of the C1-C4 alkyl groups is optionally substituted with 1-3 halogen groups. R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups. All other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentyth, twenty-first, twenty-second, and twenty-third embodiments.

[0102] In the 25th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 For each occurrence, independently, F, Cl, Br, C1-C2 alkyl, and -OR k Selected from, R is substituted in some cases. 1 The C1-C2 alkyl group is sometimes substituted with 1-3 halogen groups. R k Each occurrence is independently selected from hydrogen and C1-C2 alkyl groups. All other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentyth, twenty-first, twenty-second, twenty-third, and twenty-fourth embodiments.

[0103] In the 26th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 For each occurrence, is independently selected from F, -CH3, and -OH, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, and 25th embodiments.

[0104] In the 27th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 For each occurrence, independently selected from F, Cl, Br, and C1-C2 alkyl groups, R 1The C1-C2 alkyl groups are optionally substituted with 1-3 halogens, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, and 26th embodiments.

[0105] In the 28th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 For each occurrence, is independently selected from Cl and -CF3, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, and 27th embodiments.

[0106] In the 29th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 For each occurrence, the elements are independently selected from C1-C2 alkoxy and -C(=O)(C1-C2 alkyl), and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, and 28th embodiments.

[0107] In the 30th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3For each occurrence, is independently selected from -OCH3 and -C(=O)CH3, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, and 29th embodiments.

[0108] In the 31st embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, k is an integer selected from 0, 1, and 2, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, and 30th embodiments.

[0109] In the 32nd embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the Disclosure, m is an integer selected from 1 and 2, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, and 31st embodiments.

[0110] In the 33rd embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, n is an integer selected from 0, 1, and 2, and all other variable elements not specifically defined herein are as defined in any one of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, and 32nd embodiments.

[0111] In certain embodiments, at least one compound of the present disclosure is selected from Compounds 1-16 shown in Table 1, tautomers thereof, deuterated derivatives of the compound or tautomers, or pharmaceutically acceptable salts thereof as described above.

[0112]

Table 1

[0113] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the compounds of Formula I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, Compounds 1-16, tautomers thereof, deuterated derivatives of the compound or tautomers, or pharmaceutically acceptable salts thereof as described above, or any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0114] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0115] It should also be recognized that the pharmaceutical compositions of this disclosure can be used in combination therapy, that is, the pharmaceutical compositions described herein may further contain additional pharmaceutically active agents. Alternatively, a pharmaceutical composition comprising compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of those compounds or tautomers, or compounds selected from the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the foregoing, may be administered as a separate composition, in parallel with, before or after, a composition containing additional pharmaceutically active agents.

[0116] As described above, the pharmaceutical compositions disclosed herein include pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. When used herein, the pharmaceutically acceptable carriers can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersants, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, adapted to a specific desired dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, discloses various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, for example, by producing any undesirable biological effect or by interacting with any other component of the pharmaceutical composition in a detrimental manner, its use is assumed to be within the scope of this disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), vegetable saturated fatty acids, water, salts, and partial glyceride mixtures of electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0117] III. Methods of Treatment and Use In another aspect of this disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are intended for use in treating diseases, disorders, or conditions mediated by FPR1 signaling. In another embodiment, the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, including compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts, is disclosed herein for the manufacture of pharmaceuticals for treating diseases, disorders, or conditions mediated by FPR1 signaling. In yet another embodiment, a method for treating a disease, disorder, or condition mediated by FPR1 signaling in a subject is disclosed herein, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, comprising a compound of formula I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compound 1 to 16, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt thereof as described herein.

[0118] In some embodiments, the disease, disorder, or condition is of the central nervous system (CNS). In some embodiments, the disease, disorder, or condition is of the stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, paroxysmal disorder, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Taysachs disease, Sandhoff disease. Diseases, familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, autosomal dominant cerebral arteriovenous disease with subcortical infarction (CADASIL), spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hipper-Lindau disease, fragile X syndrome, paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex focal pain syndromes type I and II, diabetic neuropathy, and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal Arangela is selected from neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, post-meningitis syndrome, prion disease, myelitis, radiculitis, diabetes associated with protein abnormalities, trans tyretin-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, compression neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0119] In one embodiment, the disease, disorder, or condition is a stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, 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 oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma. In one embodiment, the malignant glioma is a glioblastoma.

[0120] In another aspect of this disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1-16, their tautomers, deuterated derivatives of their compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are for use in modulating FPR1 activity. In another aspect, the use of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1-16, their tautomers, deuterated derivatives of their compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for the manufacture of a pharmacopoeia for modulating FPR1 activity is disclosed herein. In yet another embodiment, a method for modulating FPR1 activity is disclosed herein, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, comprising the compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts. In yet another embodiment, a method for modulating FPR1 activity is disclosed herein, comprising contacting FPR1 with a subject with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, including compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition thereof.

[0121] Compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts, 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.

[0122] In some embodiments, compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in amounts of 2 mg to 1500 mg or 5 mg to 1000 mg, are administered once, twice, or three times a day.

[0123] Compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1-16, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or the aforementioned pharmaceutically acceptable salts, or their pharmaceutical compositions may be administered, for example, orally, parenterally, sublingually, topically, rectally, transnasally, intraoral buccally, transvaginally, transdermally, by patch, pump, or via implanted reservoir, and the pharmaceutical compositions are formulated accordingly. Parenteral administration modes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, transnasal, intrapulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration may also be performed by continuous infusion over a selected period. Other forms of administration envisioned in this disclosure are described in international patent applications WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142, and WO2015 / 023915.

[0124] The useful dose or therapeutically effective dose of the compounds or pharmaceutically acceptable salts thereof described herein can be determined by comparing their in vitro activity with their in vivo activity 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.

[0125] Those skilled in the art will recognize that, when a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is equivalent to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the compounds of formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of the compound of formula I) and an equivalent concentration of a pharmaceutically acceptable salt of the compound of formula I. [Examples]

[0126] Examples are disclosed herein to provide a more complete understanding of the disclosure as described herein. These examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0127] (Example 1) Synthesis of Exemplary Compounds The compounds of this disclosure can be prepared in accordance with standard chemical practices or, including the following synthetic schemes, as described herein in the description for preparing compounds of formulas I, IIa, IIb, III, IV, V, VIa, VIb, VIIa, VIIb, and VIIc, compounds 1 to 16, their tautomers, deuterated derivatives of those compounds or tautomers, or compounds selected from the pharmaceutically acceptable salts described herein.

[0128] A method for preparing the compound of formula I using compounds 1 to 3 as representative examples includes general reaction steps as described in Scheme 1. Compounds 1, 2, 3 Rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (Compound 1) (S)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-1) (Compound 2) (R)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-2) (Compound 3)

[0129] [ka]

[0130] General Step A: Preparation of 1-(2-(benzyloxy)-5-methylphenyl)ethane-1-one 1-(2-Hydroxy-5-methylphenyl)ethenone (4.25 g, 28 mmol) and potassium carbonate or K2CO3 (7.81 g, 56 mmol) were added to a solution of (chloromethyl)benzene (7.81 g, 56 mmol) in dimethylformamide DMF (50 mL). The resulting solution was then stirred at 40 °C for 16 h under nitrogen gas N2. Water (100 mL) was added to the reaction mixture, and then the aqueous solution was extracted with ethyl acetate or EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over sodium sulfate or Na2SO4, and filtered. The filtrate was concentrated and dried under vacuum to obtain the desired product 1-(2-(benzyloxy)-5-methylphenyl)ethan-1-one as a brown oily substance (6 g, 88%). Mass (m / z): 240.9 [M+H] + .

[0131] General step B: Preparation of ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutanoate To a solution of 1-(2-(benzyloxy)-5-methylphenyl)ethan-1-one (5 g, 20.8 mmol) and diethyl oxalate (3.04 g, 20.8 mmol) in tetrahydrofuran or THF (80 mL), lithium bis(trimethylsilyl)amide LiHMDS (1.0 M in THF, 20.8 mL, 20.8 mmol) was added dropwise at -78 °C under N2. The reaction mixture was slowly warmed 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 flash column chromatography (petroleum ether:ethyl acetate or PE:EA = 2:1, then dichloromethane:methanol or DCM:MeOH = 20:). The product ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutanoate was obtained as a yellow solid (7 g, 90%). Mass (m / z): 340.9 [M+H] + .

[0132] It should be noted that in the translation of the reaction steps, some chemical operation expressions may not be in the most standard chemical language, but this is to conform to the form of the original text. For example, "石油エーテル:酢酸エチル又はPE:EA=2:1" is translated as "petroleum ether:ethyl acetate or PE:EA = ", which may not be a very common way of expression in chemical literature, but it is to keep the original form. If you have any further questions, please feel free to let me know.General step C: Preparation of rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one 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), two drops of the catalyst acetic acid or HOAc were added under N2 conditions, and the reaction mixture was stirred at 60°C for 3.5 hours. After the reaction mixture was cooled to room temperature, ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutanoate (2 g, 5.9 mmol) was added. The reaction mixture was further stirred under N2 conditions at 60°C for 16 hours. The solid was precipitated, collected by filtration, and dried to obtain the product rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one as a white solid (1.3 g, 40%). Mass (m / z): 551.7 [M+H] + .

[0133] General Step D: Preparation of rac-3-(2-(benzyloxy)-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one To a solution of rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one (1.7 g, 3.1 mmol) in HOAc (10 mL), hydrazine (80% aqueous solution, 372 mg, 9.3 mmol) was added, and the resulting solution was stirred under N2 at 100°C for 1 hour. The reaction mixture was diluted with water (50 mL) and then extracted with siRNA (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 to obtain the product rac-3-(2-(benzyloxy)-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one as a yellow solid (1.3 g, 40%). Mass (m / z): 547.8 [M+H] + .

[0134] General step E: Preparation of rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 1) To a solution of rac-3-(2-(benzyloxy)-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (21.3 g, 39 mmol) in MeOH (200 mL), 10% Pd / C (4.2 g, 20% wt / wt) was added. The reaction mixture was stirred at room temperature under hydrogen gas (H2) for 16 hours. The mixture was filtered through Celite, and the filtrate was concentrated and dried under vacuum to obtain the product rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 1) as a white solid (16 g, 90%). Mass (m / z): 457.8 [M+H]+ .

[0135] General step F: Chiral separation of rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (Example 1) and its enantiomer (S)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4 -(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-1) (compound 2) and (R)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-2) (compound 3) are obtained. Rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 1) (200 mg, 0.44 mmol) was separated by SFC [chiralpak-OD, CO2 (30%) ~ MeOH (NH3H2O)] to obtain (S)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-( 4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-1) (compound 2) (70 mg, recovery rate 70%, white solid) and (R)-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-2) (compound 3) (60 mg, recovery rate 60%, white solid) were obtained. Isomer-1: Mass (m / z): 457.8[M+H] + . Retention time: 2.28 minutes. Isomer-2: Mass (m / z): 457.8[M+H] +. Retention time: 2.92 minutes.

[0136] The process for preparing compounds 4-16 is described below.

[0137] Compounds 4 and 5 Rac-3-(2-hydroxy-5-methylphenyl)-5-(piperidine-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 4) Rac-5-(1-acetylpiperidine-4-yl)-3-(2-hydroxy-5-methylphenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 5)

[0138] [ka]

[0139] Step 1. Following general Step C, rac-tert-butyl 4-(3-(2-(benzyloxy)-5-methylbenzoyl)-4-hydroxy-5-oxo-2-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-yl)piperidine-1-carboxylate was prepared as a white solid (2.0 g, 56%). Mass (m / z): 594.6[M-C4H8+H] + .

[0140] Step 2. Following general Step D, rac-3-(2-(benzyloxy)-5-methylphenyl)-5-(piperidine-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a white solid (400 mg, 72%). Mass (m / z): 546.8 [M+H] + .

[0141] Step 3. Following general step E, rac-3-(2-hydroxy-5-methylphenyl)-5-(piperidine-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 4) was prepared as a white solid (50 mg, 30%). Mass (m / z): 456.9 [M+H] + .

[0142] Step 4. Preparation of rac-5-(1-acetylpiperidine-4-yl)-3-(2-(benzyloxy)-5-methylphenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one: A solution of rac-3-[2-(benzyloxy)-5-methylphenyl]-5-(piperidine-4-yl)-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrrolo[3,4-c]pyrazole-6-one (200 mg, 0.37 mmol), Ac2O (57 mg, 0.56 mmol), and N,N-diisopropylethylamine (95 mg, 0.74 mmol) in DCM (10 mL) was stirred at 25°C for 18 hours. The mixture was concentrated under vacuum, and the residue was purified by combi-flash elution with PE:EA = 5:1 to obtain the desired product, rac-5-(1-acetylpiperidine-4-yl)-3-(2-(benzyloxy)-5-methylphenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one, as a white solid (100 mg, 41%). Mass (m / z): 588.8 [M+H] + .

[0143] Step 5. Following general step E, rac-5-(1-acetylpiperidine-4-yl)-3-(2-hydroxy-5-methylphenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 5) was prepared as a white solid (50 mg, 59%). Mass (m / z): 498.8 [M+H] + .

[0144] compound 6 Rac-3-(2-methoxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 6)

[0145] [ka]

[0146] Step 1. Preparation of rac-3-(2-methoxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 6): rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl) -4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (100 mg, 0.22 mmol), MeOH (11 mg, 0.33 mmol), and triphenylphosphine or PPh3 (69 mg, 0.264 mmol) were dissolved in THF (15 mL). Diisopropyl azodicarboxylate or DIAD (46 mg, 0.264 mmol) was added at 0°C, and the reaction mixture was stirred under N2 at room temperature for 16 hours. The mixture was diluted with water (50 mL), and the aqueous solution was extracted with SiO2 (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 flash column chromatography (DCM:MeOH=20:1) to obtain the product rac-3-(2-methoxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 6) as a white solid (60 mg, 58%). Mass (m / z): 471.8 [M+H] + .

[0147] compound 7 Rac-3-(2-hydroxy-5-methylphenyl)-5-((1S,4S)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 7

[0148] [ka]

[0149] Step 1. Preparation of (1S,4S)-4-methoxycyclohexane-1-amine: A mixture of (1S,4S)-4-methoxycyclohexane-1-amine hydrochloride (1.0 g, 6.1 mmol) and sodium carbonate or Na2CO3 (2.0 g, 18.9 mmol) in MeOH (20 mL) was stirred at 25°C for 3 hours and then filtered. The filtrate was concentrated under vacuum, and the residue was used directly for the next step without purification.

[0150] Step 2. Following general Step C, rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-((1S,4S)-4-methoxycyclohexyl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one was prepared as a white solid (500 mg, 41%). Mass (m / z): 579.7 [M+H] + .

[0151] Step 3. Following general Step D, rac-3-(2-(benzyloxy)-5-methylphenyl)-5-((1S,4S)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a white solid (200 mg, 60%). Mass (m / z): 575.7 [M+H] + .

[0152] Step 4. Following general step E, rac-3-(2-hydroxy-5-methylphenyl)-5-((1S,4S)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 7) was prepared as a white solid (50 mg, 29%). Mass (m / z): 485.7 [M+H] + .

[0153] compound 8 Rac-3-(2-hydroxy-5-methylphenyl)-5-((1r,4r)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 8)

[0154] [ka]

[0155] Step 1. Preparation of (1R,4R)-4-methoxycyclohexane-1-amine: A mixture of (1R,4R)-4-methoxycyclohexane-1-amine hydrochloride (1.0 g, 6.1 mmol) and Na2CO3 (2.0 g, 18.9 mmol) in MeOH (20 mL) was stirred at 25°C for 3 hours and then filtered. The filtrate was concentrated under vacuum, and the residue was used directly for the next step without purification.

[0156] Step 2. Following general Step C, rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-((1R,4R)-4-methoxycyclohexyl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one was prepared as a white solid (1.0 g, 40%). Mass (m / z): 579.9 [M+H] + .

[0157] Step 3. Following general Step D, rac-3-(2-(benzyloxy)-5-methylphenyl)-5-((1R,4R)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a white solid (200 mg, 89%). Mass (m / z): 575.7 [M+H] + .

[0158] Step 4. Following general step E, rac-3-(2-hydroxy-5-methylphenyl)-5-((1R,4R)-4-methoxycyclohexyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 8) was prepared as a white solid (50 mg, 29%). Mass (m / z): 485.8 [M+H] + .

[0159] compound 9 Rac-3-(5-chloro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 9)

[0160] [ka]

[0161] Step 1. Following general Step A, 1-(2-(benzyloxy)-5-chlorophenyl)ethane-1-one was prepared as a white solid (2.5 g, 80%). Mass (m / z): 283.1 [M+Na] + .

[0162] Step 2. Following general Step B, ethyl 4-(2-(benzyloxy)-5-chlorophenyl)-2,4-dioxobutanoate was prepared as a yellow solid (3.75 g, 80%). Mass (m / z): 382.8 [M+Na] + .

[0163] Step 3. Following general Step C, rac-4-(2-(benzyloxy)-5-chlorobenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrole-2-one was prepared as a brown solid (6.2 g, 80%). Mass (m / z): 571.6 [M+H] + .

[0164] Step 4. Following general Step D, rac-3-(2-(benzyloxy)-5-chlorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a brown solid (5 g, 60%). Mass (m / z): 567.5 [M+H] + .

[0165] General Step E1: Preparation of rac-3-(5-chloro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 9) A solution of rac-3-(2-(benzyloxy)-5-chlorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (5.95 g, 10.5 mmol) in trifluoroacetic acid or TFA (50 mL) was stirred at 70°C for 16 hours under N2. The solution was concentrated under vacuum, and the residue was purified by flash column chromatography (DCM:MeOH=20:1) to obtain the product rac-3-(5-chloro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 9) as a brown solid (3 g, 60%). Mass (m / z):477.6[M+H] + .

[0166] Compounds 10, 11, 12 Rac-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 10) (S)-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-1) (compound 11) (R)-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-2) (compound 12)

[0167] [ka]

[0168] Step 1. Following general Step A, 1-(2-(benzyloxy)-5-fluorophenyl)ethane-1-one was prepared as a yellow oily substance (6.4 g, 100%).

[0169] Step 2. Following general Step B, ethyl 4-(2-(benzyloxy)-5-fluorophenyl)-2,4-dioxobutanoate was prepared as a yellow oily substance (7.0 g, 98%, crude product).

[0170] Steps 3 and 4. Following general steps C and D, rac-3-(2-(benzyloxy)-5-fluorophenyl)-4-(4-chlorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a yellow oily substance (2.3 g, 38%). Mass (m / z): 518.1 [M+H] + .

[0171] Step 5. Following general step E1, rac-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 10) was prepared as a white solid (56 mg, 21%). Mass (m / z): 428.0 [M+H] + .

[0172] Step 6. Following general step F, (S)-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-1) (compound 11) and (R)-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro Pyrrolo[3,4-c]pyrazole-6(2H)-one (isomer-2) (compound 12) was obtained by chiral separation of rac-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 10) [SFC, chiral column: chiralpak-AD; eluate: CO2 (30%)-EtOH (DEA)]. Isomer-1: Mass (m / z): 428.0[M+H] + . Retention time: 2.27 minutes Isomer-2: Mass (m / z): 428.0[M+H] + . Retention time: 2.87 minutes

[0173] compound 13 Rac-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 13)

[0174] [ka]

[0175] Steps 1 and 2. Following general steps C and D, rac-3-(2-(benzyloxy)-5-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a yellow oily substance (2.1 g, 32%). Mass (m / z): 552.1 [M+H] + .

[0176] Step 3. Following general step E1, rac-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 13) was prepared as a white solid (56 mg, 13%). Mass (m / z): 462.1 [M+H] + .

[0177] compound 14 Rac-4-(4-chlorophenyl)-3-(pyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 14)

[0178] [ka]

[0179] Step 1. Following general Step B, ethyl 2,4-dioxo-4-(pyridine-2-yl)butanoate was prepared as a yellow solid (1.5 g, purity: 80%, 70%). Mass (m / z): 222.0 [M+H] + .

[0180] Step 2. Following general Step C, rac-5-(4-chlorophenyl)-4-picolinoyl-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2,3-dione was prepared as a brown solid (870 mg, 26%). Mass (m / z): 398.7 [M+H] + .

[0181] Step 3. Following general Step D, rac-4-(4-chlorophenyl)-3-(pyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 14) was prepared as a white solid (120 mg, 14%). Mass (m / z): 394.8 [M+H] + .

[0182] compound 15 Rac-3-(3-hydroxypyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 15)

[0183] [ka]

[0184] Step 1. Following general Step A, 1-(3-(benzyloxy)pyridine-2-yl)ethane-1-one was prepared as a yellow oily substance (3 g, 63%). Mass (m / z): 228.2 [M+H] + .

[0185] Step 2. Following general Step B, ethyl 4-(3-(benzyloxy)pyridine-2-yl)-2,4-dioxobutanoate was prepared as a yellow solid (1.9 g, 42%). Mass (m / z): 328.1 [M+H] + .

[0186] Step 3. Following general Step C, rac-4-(3-(benzyloxy)picolinoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-2H-pyrrole-2-one was prepared as a black solid (177 mg, 15%). Mass (m / z): 555.2 [M+H] + .

[0187] Step 4. Following general Step D, rac-3-(3-(benzyloxy)pyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a black oily substance (160 mg, 85%). Mass (m / z): 551.3 [M+H] + .

[0188] Step 5. Following general step E, rac-3-(3-hydroxypyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 15) was prepared as an off-white solid (55 mg, 45%). Mass (m / z): 461.1 [M+H] + .

[0189] compound 16 Rac-3-(3-hydroxypyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(5-(trifluoromethyl)pyridine-2-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 16)

[0190] [ka]

[0191] Step 1. Following general Step C, rac-4-(3-(benzyloxy)picolinoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)pyridine-2-yl)-1,5-dihydro-2H-pyrrole-2-one was prepared as a black oily substance (1.0 g, 57%). Mass (m / z): 540.0 [M+H] + .

[0192] Step 2. Following general Step D, rac-3-(3-(benzyloxy)pyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(5-(trifluoromethyl)pyridine-2-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one was prepared as a black oily substance (800 mg, 73%). Mass (m / z): 536.0 [M+H] + .

[0193] Step 3. Following general step E, rac-3-(3-hydroxypyridine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-4-(5-(trifluoromethyl)pyridine-2-yl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one (compound 16) was prepared as a white solid (350 mg, 35%). Mass (m / z): 445.8 [M+H] + .

[0194] (Example 2) In vitro assay for detecting and measuring the modulation of FPR1-mediated calcium signaling by compounds 1-16 As illustrated in the exemplary examples in Table 2, the effects of the compounds of this disclosure on the regulation of FPR1-mediated cellular signaling were measured by monitoring changes in cellular calcium levels. The dose-response of the exemplary examples was reported using the following ranking criteria as categories: ***(IC 50 ≤100nM);**(IC 50 ≥100~≦1000nM);*(IC 50≧1000~≦10,000nM);ND-Undetermined.

[0195] Expression of human or mouse FPR1 in 293T cells The coding DNA sequences (CDS) of human FPR1 (NM_001193306) and mouse FPR1 (NM_013521) were cloned, induced with the pCMV promoter, and inserted into the lentiviral vector GV367 (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) in an incubator at 37°C and 5% CO2. 293T cells were transfected with lentiviral vector GV367 containing human or mouse FPR1 CDS for 24 hours, and then cultured in complete medium for a further 48 hours. 72 hours after transfection, the cells were passaged, and 5 μg / ml of puromycin was added to screen for FPR1-transfected 293T cells. Overexpression of human or mouse FPR1 in T cells was detected by immunohistochemistry using anti-mouse or human FPR1 antibodies (Biolegend or Antibody Online).

[0196] Measurement of fMLP-FPR1-mediated intracellular calcium concentration in 293T cells Cultured 293T cells overexpressing hFPR1 or mFPR1 were labeled with 1 μM INDO-1 AM calcium sensor dye (eBioscience) at 37°C for 30 minutes. After washing with 1×PBS, the cells were resuspended in H-DMEM containing 3% FBS, maintained on ice, and intracellular calcium concentration was measured. To measure the inhibitory efficacy of the designed potential FPR1 antagonist, 293T cells overexpressing hFPR1 or mFPR1 were incubated with the compound at room temperature for 10 minutes. Plasma calcium levels were then measured at 37°C using FACS Aria III before and after fMLP stimulation. For each sample, the immunofluorescence intensity of indo-1 AM before fMLP addition was defined as the baseline value, and the intensity at which peak immunofluorescence decreased 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 changes in intracellular calcium under multiple concentration gradients (from 0 nM to 100 μM), the IC50 of each compound in inhibiting fMLP-FPR1-mediated intracellular calcium concentration in 293T cells was measured. 50 This was automatically calculated using the Prism 8.0.2 software (GraphPad).

[0197] [Table 2]

[0198] (Example 3) In vivo preclinical efficacy in a mouse model of intracerebral hemorrhage (ICH). Compound 1 was used as a representative compound in an experimental ICH mouse model to demonstrate the efficacy of the compound in protecting brain damage after stroke and / or brain injury, and in improving brain function, in the experiments described below.

[0199] Preparation of an experimental mouse ICH model The protective benefits of the compounds disclosed herein were illustrated using a mouse model of intracerebral hemorrhage (ICH). Figure 1 illustrates the procedure for preparing this model. As previously described, ICH was induced in C57B / L6 male mice by injection of autologous blood or collagenase (Lauer et al., Circulation, vol. 124: pp. 1654-1662 (2011); Rynkowski et al., Nat. Protoc. 3: pp. 122-128 (2008)). Mice were anesthetized using isoflurane inhalation and fixed to a stereotactic frame. Burr holes were drilled on the right side of the skull, 2.3 mm transversely to the midline and 0.5 mm anterior to the bregma. For the autologous blood model, 30 μl of unheparinized blood was collected from the angular vein. The first 5 μl of blood was injected to a depth of 3 mm below the hole, and the remaining 25 μl of blood was injected at a rate of 1 μl / min to 3.7 mm below the hole. In the collagenase model, 0.038 U of bacterial collagenase (in 0.5 μl of saline) was injected into the striatum (0.5 mm anteriorly, 2.3 mm laterally, and 3.5 mm deep relative to the bregma) at a rate of 0.5 μl / min. Mice used as surrogate controls were injected with an equal volume of saline. Throughout the procedure, body temperature was maintained at 37°C using a thermothermal blanket. Postoperatively, mice were kept under observation with free access to feed and water. The compound was dissolved in DMSO and administered twice daily at a dose of 5 mg / kg body weight via intraperitoneal injection (at a dose of 1 ml / kg body weight). The first dose was administered 1 hour after the start of ICH.

[0200] Assessment of nervous system function Nervous system function was assessed by the researchers as a blinded test for two treatment groups. A modified Neurological Severity Score (mNSS), a corner turning test, and a rotarod test were used to assess neurological deficiency in ICH mice at defined time points as described (Li et al., Proc. Nat. Acad. Sci. USA114: E396-E405 (2017)). Mice were evaluated for motor function (muscle and abnormal movement), sensory function (vision, touch, and proprioception), and reflexes (auricle, corneal, and startle reflex). The score ranged from 0 to 18 and was defined as follows: severe injury (13-18); moderate injury (7-12); mild injury (1-6). The corner turning test was used to assess sensorimotor injury by quantifying the priority of turning (right or left) when approaching a 30° corner. Lesioned mice typically exhibit a bending priority that correlates with the extent of striatal damage. Each mouse underwent this procedure 10 times, with at least a 30-second interval between trials. The percentage of bending on the same side was then calculated. Motor coordination and balance were assessed using the rotorod test. Mice were trained for one week prior to ICH induction. At a specified time point after ICH, the mice were placed on the rotorod apparatus. The rotating rod was 3 cm in diameter and had a non-slip surface. The rod was 30 cm long and positioned 20 cm above the base. Each mouse was placed on the rod at a speed of 4 rpm (revolutions per minute). This speed was accelerated to 40 rpm over 5 minutes. The duration each mouse spent on the rod was recorded. Each mouse was tested in three consecutive trials, each at 15-minute intervals. Results were reported as the average of the three trials.

[0201] Edema reduction in MRI neuroimaging As described (Li et al., 2017), the total lesion volume was measured using a 7T small animal MRI scanner (Bruker, USA). T2-weighted aqueous images were recorded using the following parameters: repetition count (TR) = 4500 ms, echo count (TE) = 65.5 ms, field of view (FOV) = 28 × 28 mm.2 Image matrix = 256 × 256, 0.5 mm slice thickness). Hematoma was measured using susceptibility-weighted imaging (SWI). The configuration parameters were as follows: TR = 30 ms and TE = 10 ms, flip angle = 25°, FOV = 32 × 32 × 16 mm 3 The image matrix was 256 x 256. Volumes were estimated manually and then calculated using MIPAV software by multiplying the total volume by the distance between sections (0.5 mm). PHE volume was calculated as the total lesion volume minus the hematoma volume. MRI data were analyzed by two researchers in a blinded manner for the experimental group.

[0202] Evaluation of brain water content The water content of the brain was measured one day after ICH. The brain tissue was removed quickly and without perfusion and divided into three parts: the ipsilateral hemisphere, the contralateral hemisphere, and the cerebellum. The brain tissue was weighed for its wet mass and then dried for its dry mass at 100°C for 24 hours. The water content of the brain was calculated using the following formula: (wet mass - dry mass) / wet mass × 100%.

[0203] Measurement of brain infiltrating cells by flow cytometry Single-cell suspensions of brain tissue were prepared and stained with fluorescent dye-conjugate antibodies. The brain tissue was degraded using 1% collagenase (Sigma-Aldrich) at 37°C for 30 minutes, and then the myelin sheath was removed by density gradient centrifugation in 30% Percoll (Sigma-Aldrich) at 700 rpm for 10 minutes. For neutrophil staining, cells were incubated with anti-mouse CD45 (Cat#103108;RRID:AB_312973, Biolegend, 1:100), anti-mouse Ly-6G (Cat#127616;RRID:AB_1877271, Biolegend, 1:100), and anti-mouse CD11b (Cat#553311;RRID:AB_394775, BD Biosciences, 1:100) at 4°C for 30 minutes according to the instructions. Flow cytometry measurements were performed using FACS Aria III (BD Bioscience), and the data was analyzed using Flowjo 7.6 software (Informer Technologies, Ashland, OR, USA).

[0204] Significant preclinical efficacy At 5 mg / kg / day (administered via ip injection 1 hour after the start of ICH), compound 1 significantly reduced perihematoma edema (PHE) size and total cerebral water content, along with improving the nervous system in ICH mice (Figures 2A-2B and 3A-3B). In Figures 2A and 2B, dark shadows on brain MRI images represent hematomas, and perihematoma edema of the brain is the area between the gray line and the contour of the dark shadow. Three days after ICH, perihematoma edema was significantly reduced in the group treated with compound 14. There was no difference in hematoma size, indicating that administration of compound 14 reduced brain injury induced by similar hematoma sizes. In addition, both the modified neurological symptom score (mNSS) and motor function scores (corner turning test, rotarod test) improved (Figures 4A-4C). The total number of neutrophils infiltrating the brain decreased by 47% on day 1 and 54% on day 3 (Figure 5). The mNSS is a scoring system for neurological deficits to assess overall neurological deficits in motor function (muscle and abnormal movement), sensory function (visual, tactile, and proprioceptive), and reflexes (auricle, corneal, and startle reflexes). Higher scores suggest greater severity of neurological deficits after brain injury in mice. Motor function scores (corner turning test, rotarod test) were used to assess unilateral abnormalities in sensory and motor function in mice with brain injury. The less severe the brain injury after ICH in mice, the lower the rate of ipsilateral turning in the corner turning test, while the running time during the rotarod test increased. These data support the development of the compounds of this disclosure for the treatment of stroke and other diseases, disorders, and conditions mediated by FPR1 signaling.

[0205] Those skilled in the art will readily recognize that a variety of variations, modifications, and alterations can be made within the scope and spirit of this disclosure as defined in the following claims, without departing from the intent and scope of this disclosure.

Claims

1. The compound with structural formula IV below: 【Chemistry 1】 [In formula: R a C is either hydrogen or optionally substituted with one to three groups selected from halogens, -CN, -OH, and -COOH. 1 ~C 4 It is alkyl, Ring A is an aromatic ring, X a and X b Each of these is independently C, N, CH, or a bond. X 1 , X 2 , and X 3 These are, independently, C, CH, or N. Ring B is an aromatic ring, Y a is C, N, CH, or a bond, Y 1 , Y 2 , Y 3 , and Y 4 These are, independently, C, CH, or N. Ring C is C 3 ~C 10 It is a cycloalkyl or a 4- to 10-membered heterocyclyl, provided that the carbon atom of the ring is not tetrahydro-1,1-dioxide-3-thienyl. R 1 , R 2 , and R 3 For each occurrence, independently, halogen, cyano, and C are present. 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 1 ~C 6 Alkoxy, -C(=O)(C 1 ~C 6 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 , C 3 ~C 12 Selected from carbocyclyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, R 1 、R 2 、and R 3 any one of C 1 to C 6 alkyl, C 2 to C 6 alkenyl, and C 1 to C 6 alkoxy, and -C(=O)(C 1 to C 6 alkyl) of C 1 to C 6 alkyl is 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 C 3 to C 6 cycloalkyl, respectively optionally substituted with 1 to 3 groups selected from R 1 、R 2 、and R 3 any one of C 3 to C 12 carbocyclic ring, 3- to 12-membered heterocyclic ring, phenyl, 5- to 10-membered heteroaryl is optionally substituted by one to three groups selected from halogen, cyano, C 1 to C 4 alkyl, -NR h R i and -OR k respectively, and is optionally substituted R h , R i , and R j For each occurrence, hydrogen and C appear independently. 1 ~C 4 Alkyl and C 3 ~C 6 Selected from cycloalkyl groups, R h , R i , and R j any one of C 1 ~C 4 The alkyl group is optionally substituted with one to three groups selected from halogens, cyanos, and -OH groups. R k For each occurrence, hydrogen and C appear independently. 1 ~C 4 Alkyl and C 3 ~C 6 Selected from cycloalkyl groups, k and m are integers independently selected from 0, 1, 2, 3, 4, and 5. If ring C is cyclopropyl, cyclopentyl, or cyclohexyl, then n is an integer selected from 1, 2, 3, 4, and 5. The ring C is a C other than cyclopentyl and cyclohexyl. 4 ~C 10 If it is a cycloalkyl group, or if the ring C is a 4- to 10-membered heterocycline, then n is an integer selected from 0, 1, 2, 3, 4, and 5. [where p is an integer selected from 1 and 2], its tautomer, its compound or deuterated derivative of its tautomer, or the aforementioned pharmaceutically acceptable salt.

2. X a , X b , X 1 , X 2 , and X 3 0 to 3 of these is N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein 0 to 3 of the atoms are N.

3. X a , X b , X 1 , X 2 , and X 3 Two of these are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or 2, wherein 0 to 2 of the atoms are N.

4. X a and X b However, each is independently C, CH, or N. Y a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein is C, CH, or N.

5. Ring A has k R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 4, which is a pyridinyl or pyrimidinyl substituted with .

6. The compound with the following structural formula V: 【Chemistry 2】 [In formula: X 1 is C, CH, or N, R a C is hydrogen, or optionally substituted with one or two groups selected from halogens, -CN, and -OH. 1 ~C 2 The compound according to any one of claims 1 to 5, which is alkyl, a tautomer thereof, a deuterated derivative thereof or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

7. The compound with the following structural formula Via: 【Transformation 3】 The compound according to any one of claims 1 to 4 and 6, which is the tautomer, the compound or a deuterated derivative of the tautomer, or the pharmaceutically acceptable salt described above.

8. The compound with the following structural formula VIb: 【Chemistry 4】 The compound according to any one of claims 1 to 6, which is the tautomer, the compound or a deuterated derivative of the tautomer, or the pharmaceutically acceptable salt described above.

9. Ring C has n R 3 C is replaced by 5 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 8, which is a cycloalkyl or a 5-6 membered heterocyclyl.

10. Ring C has n R 3 C is replaced by 5 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein the compound is a cycloalkyl or a 6-membered heterocycline, the 6-membered heterocycline containing one or two heteroatoms selected from O and N.

11. Ring C has n R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, comprising a cyclohexyl or a 5-6 membered heterocyclil, wherein the 5-6 membered heterocyclil contains one or two heteroatoms selected from O and N.

12. Ring C has n R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 11, which is substituted with cyclohexyl, tetrahydro-2H-pyranyl, or piperidinyl.

13. One of the following compounds with structural formulas VIIa to VIIc: 【Transformation 5】 [In formula: Rings A and B are both aromatic rings. X a , X b , X 1 , X 2 , and X 3 0 to 3 of these is N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 The compound according to claim 1 or 2, wherein 0 to 3 of the elements are N, a tautomer thereof, a deuterated derivative of the compound or tautomer thereof, or a pharmaceutically acceptable salt thereof.

14. X a , X b , X 1 , X 2 , and X 3 Two of these are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13, wherein 0 to 2 of the atoms are N.

15. X a and X b However, each is independently C, CH, or N. Y a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13 or 14, wherein is C, CH, or N.

16. Ring A has k R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 13 to 15, which is a pyridinyl or pyrimidinyl substituted with.

17. Ring B has m R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 13 to 16, wherein the phenyl is substituted with .

18. R a C is either hydrogen or optionally substituted with one or two groups selected from halogens, -CN, and -OH. 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 13 to 16, which is alkyl.

19. R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 13 to 18, wherein is hydrogen.

20. R 1 , R 2 , and R 3 However, for each occurrence, halogen, cyano, and C appear independently. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -C(=O)(C 1 ~C 6 Alkyl), -C(=O)NR h R i , -NR h R i , -OR k -S(=O) 2 R k -S(=O) 2 NR h R i , C 3 ~C 6 Selected from cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, R 1 , R 2 , and R 3 any one of C 1 ~C 6 Alkyl and C 1 ~C 6 Alkoxy, and -C(=O)(C 1 ~C 6 C of alkyl 1 ~C 6 Alkyl, halogen, cyano, -C(=O)OR k , and -OR k Each of the following is substituted depending on the case: R 1 , R 2 , and R 3 any one of C 3 ~C 6 Cycloalkyl, 5-6 member heterocyclyl, phenyl, and 5-6 member heteroaryl are halogens, cyano, and C 1 ~C 4 Alkyl and -OR k Each of the following is substituted depending on the case: R h and R i However, for each appearance, hydrogen and C appear independently. 1 ~C 4 Selected from alkyl groups, R h and R i any one of C 1 ~C 4 The alkyl group is optionally substituted with 1 to 3 groups selected from halogens, cyanos, and -OH groups. R k For each occurrence, hydrogen and C appear independently. 1 ~C 4 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 19.

21. R 1 , R 2 , and R 3 However, for each occurrence, halogen, cyano, and C appear independently. 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 Alkyl), -C(=O)NR h R i , -NR h R i , and -OR k Selected from, R 1 , R 2 , and R 3 any one of C 1 ~C 4 Alkyl and C 1 ~C 4 Alkoxy, and -C(=O)(C 1 ~C 4 C of alkyl 1 ~C 4 Alkyl can be halogen, cyano, and -OR depending on the case. k It is replaced by 1 to 3 groups selected from the following: R h and R i However, for each appearance, hydrogen and C appear independently. 1 ~C 2 Selected from alkyl groups, R k However, for each appearance, hydrogen and C appear independently. 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 20.

22. R 1 , R 2 , and R 3 However, for each occurrence, halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 Alkyl), and -OR k Selected from, R 1 , R 2 , and R 3 any one of C 1 ~C 4 The alkyl group is sometimes substituted with one to three halogen groups. R k However, for each appearance, hydrogen and C appear independently. 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 21.

23. R 1 However, for each occurrence, F, Cl, Br, and C appear independently. 1 ~C 2 Alkyl and -OR k Selected from, R 1 C 1 ~C 2 The alkyl group is sometimes substituted with one to three halogen groups. R k However, for each appearance, hydrogen and C appear independently. 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 22.

24. R 1 However, for each occurrence, independently, F and -CH 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, selected from , and -OH.

25. R 2 However, for each occurrence, independently, F, Cl, Br, and C 1 ~C 2 Selected from alkyl groups, R 1 C 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24, wherein the alkyl group is optionally substituted with one to three halogens.

26. R 2 However, for each occurrence, Cl and -CF are independent. 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of claims 1 to 25.

27. R 3 However, for each occurrence, independently, C 1 ~C 2 Alkoxy and -C(=O)(C 1 ~C 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 26, selected from alkyl.

28. R 3 However, for each occurrence, independently, -OCH 3 and -C(=O)CH 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of claims 1 to 27.

29. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 28, wherein k is an integer selected from 0, 1, and 2.

30. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 29, wherein m is an integer selected from 1 and 2.

31. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 30, wherein n is an integer selected from 0, 1, and 2.

32. Compounds selected from the following: 【Transformation 6】 The compound according to claim 1, selected from the tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt.

33. A pharmaceutical composition comprising a compound, tautomer, dimethylated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 32, and at least one pharmaceutically acceptable carrier.

34. An agent for treating a disease, disorder, or condition mediated by formyl peptide receptor 1 (FPR1) signaling in a subject, comprising a therapeutically effective amount of a compound, tautomer, dimethylated derivative, or pharmaceutically acceptable salt described in any one of claims 1 to 32.

35. The disease, disorder, or condition is related to the CNS and includes stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, paroxysmal disorders, amyotrophic lateral sclerosis (ALS), Tay-Sachs disease, Sandhoff disease, familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, autosomal dominant cerebral arteriovenous disease with subcortical infarction (CADASIL), spinal muscular atrophy, muscular dystrophy, and Jalcor-Marie-Tooth disease, neurofibromatosis, von Hipper-Lindau disease, fragile X, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex focal pain syndromes type I and II, diabetic neuropathy, and Alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, post-meningitis syndrome, prion diseases, myelitis, radiculitis, trans tyretin-induced neuropathy, HIV-related neuropathy The agent according to claim 34, selected from neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant gliolam.

36. The agent according to claim 34 or 35, wherein the disease, disorder, or condition is a stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, and venous).

37. The agent according to claim 34 or 35, wherein the disease, disorder, or condition is traumatic brain injury.

38. The agent according to claim 34 or 35, wherein the disease, disorder, or condition is malignant gliomas.

39. The agent according to claim 38, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglioglioma.

40. The agent according to claim 39, wherein the malignant glioma is glioblastoma.

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