Modulator of FPR1 and method of using the same

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. JPEG2024504713000029.jpg72170

Description

Technical Field

[0001] The present disclosure relates to compounds useful for the treatment of diseases. More specifically, the present disclosure relates to compounds that bind to formyl peptide receptors (FPRs), such as FPR1, and modulate their activities to reduce or eliminate imbalanced FPR-mediated signal transduction, which is, for example, the underlying cause of a series of diseases including central nervous system (CNS) diseases or disorders such as stroke, traumatic brain injury (TBI), glioblastoma, and malignant glioma.

Background Art

[0002] Restoration of body homeostasis after injury or pathogen infection is crucial to ensure the survival of organisms. Physiological wound healing and innate immune responses are initiated by the release of soluble mediators from invading pathogens or damaged lesions. A temporarily regulated interactive repair process involves, for example, many chemokines, cytokines, acute-phase proteins, infiltrating and tissue-resident cells, fibroblasts, neurons, and the vascular system. When the injury persists or is large in scale, physiological trauma repair or anti-infection responses can become pathological, leading to excessive inflammation, edema, inappropriate fibrotic repair, organ dysfunction, acute respiratory distress syndrome (ARDS), sepsis, and ultimately organ failure and / or death. Therefore, effective regulation of the scale and duration of the inflammatory and resolution responses can be critical in injury repair. After tissue injury or pathogen infection (by bacteria, viruses, fungi, and / or microorganisms), a series of formyl-peptides, damage-associated molecular pattern molecules (DMAP), inflammatory lipid mediators (e.g., leukotrienes and lipoxins), and acute-phase proteins (e.g., annexin) are released from invading pathogens, damaged cells, and lesion tissues. 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. The binding of these chemoactive molecules and acute proteins to FPR receptors mobilizes leukocytes, stimulates the production of superoxide and cytokines, and activates microglia, astrocytes, and other inflammatory and resolution responses for injury repair and host defense.

[0003] On the other hand, pathological inflammatory responses from unbalanced FPR receptor-mediated signaling contribute to a number of pathologies after injury or infection, including, for example, cerebral edema, dysfunction, and organ failure after stroke or traumatic brain injury. In addition, chronic activation of FPR receptor-mediated signaling from invading pathogens, tissue stress, and tissue injury has been implicated in the etiology of brain cancer, gastric cancer, and Parkinson's syndrome.

[0004] Stroke is the leading cause of death worldwide, and treatment options are limited. The FPR receptor is highly expressed in microglia, astrocytes, and the cerebrovascular system. After the onset of induced intracerebral hemorrhage (ICH), infiltrating leukocytes, activated platelets, microglia, and astrocytes release a series of pro-inflammatory mediators, acute-phase proteins, and DAMPs 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 perifocal edema and the worsening mass effect in stroke.

[0005] Traumatic brain injury (TBI) is the leading cause of disability worldwide. The global incidence of TBI is predicted to be 200 per 100,000 people per year. Severe injuries often result in behavioral disorders, brain atrophy, dementia, permanent damage, and ultimately death. TBI has limited treatment options, and activation of FPR1 is involved in mediating the initial inflammatory process of TBI.

[0006] Glioblastoma and malignant glioma are the most common primary brain tumors. Malignant glioma, with an annual incidence of approximately 6 per 100,000 individuals, currently has no effective treatment. The FPR1 receptor is highly expressed in glial cells, astrocytes, and the cerebrovascular system. Interaction of the FPR receptor with chemotactic ligands due to injury, stress, and pathogens is involved in the pathophysiology of brain cancer.

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

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

[0009] [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 D.B. Troy, Lippincott Williams & Wilkins, Philadelphia [Non-Patent Document 4] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. 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

Non-Patent Document 7

Summary of the Invention

Means for Solving the Problems

[0010] One aspect of the present disclosure provides a compound selected from the compounds of Formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used for the treatment of diseases mediated by the signal transduction of formyl peptide receptor 1 (FPR1). For example, the compound of Structural Formula I below:

[0011]

Chemical Formula

[0012] [Wherein: Z 1 and Z 2 are both O or N respectively, Z 3 is C or N, Z 3 When Z 1 is C, Z 2 is O, and Z 1 is N, or Z 2 is N, and Z Z 3 When Z 1 is N, Z 2 and Z The ring A is bonded to the remainder of Formula I

[0013]

Chemical Formula

[0014] does not exist, thus, formula I contains a spirocyclic ring system, or

[0015]

Chemical formula

[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 selected from C3 - C 12 carbocyclic, 3 - 12 membered heterocyclic, phenyl, and 5 - 10 membered heteroaryl, 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 Rk 、 -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 is selected from C3 - C12 carbocyclic ring, 3 - 12 membered heterocyclic ring, phenyl, and 5 - 10 membered heteroaryl, R 1 、 R 2 、 and R 3 any one of C1 - C6 alkyl, C2 - C6 alkenyl, and C1 - C6 alkoxy, and the C1 - C6 alkyl of -C(=O)(C1 - C6 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 optionally substituted by 1 - 3 groups selected from C3 - C6 cycloalkyl, R 1 、 R 2 、 and R 3Any one of C3 to C 12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl, 5- to 10-membered heteroaryl is each optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR h R i , and -OR k and is each optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR R h , R i , and R j is, for each occurrence, independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R h , R i , and R j any one of C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH, R k is, for each occurrence, independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R h , R i , and R j any one of C1-C4 alkyl 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, 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 the present disclosure, the compound of formula I is selected from compounds 1 to 4 shown below, its tautomer, its compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0018] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from Compounds 1-4 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. These compositions may further comprise an additional pharmaceutically active agent.

[0019] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition mediated by the signaling of formyl peptide receptor 1 (FPR1) in a subject, the method comprising administering a therapeutically effective amount of a compound of Formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a pharmaceutical composition comprising a compound selected from Compounds 1-4 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing.

[0020] In some embodiments, the method of treatment comprises administering an additional pharmaceutically active agent to a subject in need thereof, either as the same pharmaceutical composition as the compound of Formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or as a separate composition. In some embodiments, the method of treatment comprises administering at least one additional pharmaceutically active agent in either the same composition or a separate composition with a compound selected from Compounds 1-4 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0021] A method of modulating FPR1 activity, comprising administering to a subject a therapeutically effective amount of a compound of formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing is also disclosed herein. In some embodiments, the method of modulating FPR1 comprises administering to a subject a compound selected from Compounds 1-4 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of modulating FPR1 activity comprises contacting the FPR1 with a compound of formula I, IIa, IIb, III, IV, V, VI, and VII, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of modulating FPR1 comprises contacting the FPR1 with a compound selected from Compounds 1-4 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

Brief Description of the Drawings

[0022]

Figure 1

Modes for Carrying Out the Invention

[0023] I. Definitions As used herein when referring to a noun, the term "a" or "an" encompasses the expression "at least one" and thus encompasses both single and plural units of the noun. For example, "an additional agent" means a single or two or more additional agents.

[0024] The term "FPR1" or "formyl peptide receptor 1", as used herein, means the cell surface receptor protein encoded by the FPR1 gene in humans. FPR1 regulates a wide variety of neutrophil functional responses and plays an important role in the etiology of various diseases, including, for example, the diseases described above.

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

[0026] As used herein, the term "compound" refers to a group of molecules having the same chemical structure, unless otherwise indicated 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). However, it is assumed that there may be variations in isotopes among the constituent atoms of the molecule. Thus, it will be apparent to those skilled in the art that a compound represented by a specific chemical structure containing the indicated deuterium atoms may also contain a lower amount of isotopologues having hydrogen atoms at one or more of the deuterium positions specified within that structure. The relative amounts of such isotopologues within the compounds of the present disclosure depend on several factors, including, for example, the isotopic purity of the reagents used to generate the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as described above, the relative amounts of such isotopologues are less than 49.9% of the compound overall. In other embodiments, the relative amounts of such isotopologues are 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 within a given structure with a group of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and more than one position within 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 combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically possible compounds.

[0028] The term "isotopologue" refers to species that differ only in their isotopic composition in terms of chemical structure. Further, unless otherwise stated, 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, a compound having the structure of the present invention is within the scope of this disclosure except that hydrogen is replaced by deuterium or tritium, or carbon is 13 C or 14 C.

[0029] Unless otherwise indicated, the structures shown herein are also intended to include structures of all isomeric forms, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise stated, all tautomeric 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 migration of an atom, such as a hydrogen atom, or a group within the molecule.

[0031] "Stereoisomer" as used herein refers to enantiomers and diastereomers.

[0032] As used herein, a "deuterated derivative" has the same chemical structure as the reference compound, but one or more hydrogen atoms are deuterium atoms ("D" or 「2Refers to a compound in which H is replaced by. Depending on the origin of the chemical substances used in the synthesis, it is recognized that some variations in natural isotope abundances occur in the synthesized compounds. Despite these variations, the concentrations of naturally abundant stable hydrogen isotopes are low and not significant compared to the degree of stable isotope substitution of the deuterated derivatives described herein. Thus, unless otherwise stated, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced by deuterium at a level well above its natural isotope abundance of about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotope enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium bond in each designated deuterium), at least 4500 (67.5% deuterium bond in each designated deuterium), at least 5000 (75% deuterium bond in each designated deuterium), at least 5500 (82.5% deuterium bond in each designated deuterium), at least 6000 (90% deuterium bond in each designated deuterium), at least 6333.3 (95% deuterium bond in each designated deuterium), at least 6466.7 (97% deuterium bond in each designated deuterium), or at least 6600 (99% deuterium bond in each designated deuterium).

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

[0034] As used herein, the term "alkyl" means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains from 1 to 30 alkyl carbon atoms. In some embodiments, the 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 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 is fully saturated or partially saturated containing one or more unsaturated units, but is not aromatic, monocyclic C 3~8Hydrocarbons or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 refers to hydrocarbons, and any individual ring of the bicyclic system has 3 to 7 members. Bicyclic carbocyclyls include, for example, combinations of monocyclic carbon rings fused to 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 carbocyclyl. In some embodiments, the carbocyclyl is C3-C 10 carbocyclyl. In some embodiments, the carbocyclyl is C3-C8 carbocyclyl.

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

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

[0039] The term "heteroatom" means one or more of oxygen, sulfur, and nitrogen, including nitrogen or sulfur in any oxidation state, or silicon; any basic nitrogen in a quaternized form, or; replaceable nitrogen in a heterocyclic ring, such as in the case of N(3,4-dihydro-2H-pyrrolyl etc.), NH (in the case of pyrrolidinyl etc.) or NR + (in the case of N-substituted pyrrolidinyl etc.).

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

[0041] As used herein, the term "alkoxy" refers to an alkyl group as defined above, where one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that 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 iodo, respectively.

[0043] As used herein, the term "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 (where n is an integer from 0 to 6). "Non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the above-described requirements for an aromatic ring and may be fully saturated or partially saturated. Non-limiting 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 moiety such as in the case of "arylalkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic or spirocyclic, fused, 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 (C 10 ) 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, at least one ring in the system being aromatic, at least one ring in the system containing one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system containing 3 to 7 ring members. Examples of bicyclic heteroaryls include, for example, 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 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0047] The term "spirocyclic ring system" refers to a ring system having two or more cyclic rings, where the rings share only one common atom for every two rings.

[0048] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), 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 the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethylamine (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. The salts of the compounds are formed between an acid and a basic group of the compound, such as an amino functional group, etc., or a base and an acidic group of the compound, such as a carboxyl functional group, etc.

[0051] As used herein, the term "pharmaceutically acceptable" refers to a component that is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without producing excessive toxicity, irritation, allergic response, etc., and having a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" means any non-toxic salts that can directly or indirectly provide the compounds of the present disclosure upon administration to a recipient. Suitable pharmaceutically acceptable salts are, for example, the salts 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 sulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, vitatric 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. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and salts formed with organic acids such as maleic acid.

[0053] Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4(alkyl)4 salts are included. This disclosure also contemplates the quaternization of any basic nitrogen-containing groups 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 alkylsulfonate ions, and arylsulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

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

[0055] The term "therapeutically effective amount" refers to the amount of a compound that produces the desired effect for which the compound is administered (e.g., improving the symptoms of a disease, disorder, and condition mediated by FPR1 signaling, reducing the severity of a disease, disorder, and condition or its symptoms mediated by FPR1 signaling, and / or decreasing the progression of a disease, disorder, and condition or its symptoms mediated by FPR1 signaling). The exact amount of the therapeutically effective amount depends on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0056] As used herein, the term "treatment" and its cognates refer to slowing or halting disease progression. "Treatment" and its cognates, as used herein, include, but are not limited to, the following: complete or partial remission, diseases, disorders, and conditions mediated by FPR1 signaling, and a reduction in the risk of complications associated with the disease. Improvement or alleviation of the severity of any of these symptoms can be readily evaluated or subsequently developed according to methods and techniques known in the art.

[0057] The terms "about" and "approximately", when used in connection with the dosage, amount, or mass percentage of a component of a composition or dosage form, include the value of the specified dosage, amount, or mass percentage or the range of dosage, amount, or mass percentage that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to the pharmacological effect obtained from the specified dosage, amount, or mass percentage.

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

[0059]

Chemical formula

[0060] [Wherein: Z 1 and Z 2 are both each O or N, and Z 3 is C or N, Z 3 when Z is C, Z 1 is O, and Z 2 is N, or Z 1 is N, and Z 2 is O, Z 3 when Z is N, Z 1 and Z 2 are both N, linking ring A to the remainder of formula I

[0061] [Chemical formula]

[0062] does not exist. Thus, formula I either contains a spirocyclic ring system or

[0063] [Chemical formula]

[0064] 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 selected from C3-C 12 carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl, 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 hC(=O)NR i R j 、 -NR h S(=O) p R k 、 -OR k 、 -OC(=O)R k 、 -OC(=O)OR k 、 -OC(=O)NR h R i 、 -S(=O) p R k 、 -S(=O) p NR h R i 、 C3~C 12 carbocyclic, 3 - to 12 - membered heterocyclic, phenyl, and 5 - to 10 - membered heteroaryl, selected from R 1 、 R 2 、 and R 3 any one of C1 - C6 alkyl, C2 - C6 alkenyl, and C1 - C6 alkoxy, and C1 - C6 alkyl of -C(=O)(C1 - C6 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 iand each optionally substituted with 1 to 3 groups selected from C3-C6 cycloalkyl, R 1 、R 2 、and R 3 any one of C3-C 12 carbocyclic, 3- to 12-membered heterocyclic, phenyl, 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR h R i 、and -OR k respectively, and each optionally substituted with 1 to 3 groups selected from, R h 、R i 、and R j for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R h 、R i 、and R j any one of C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH, R k for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R h 、R i 、and R j any one of C1-C4 alkyl 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, 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.

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

[0066] [Chemical formula]

[0067] It is a tautomer, a compound thereof or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variable elements not specifically defined herein are as defined in the first embodiment.

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

[0069] [Chemical formula]

[0070] [wherein ring A and ring B are each an aromatic ring], a tautomer thereof, a compound thereof or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variable elements not specifically defined herein are as defined in either one of the first and second embodiments.

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

[0072] [Chemical formula]

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

[0074] In a fifth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, X a 、X b 、X 1 、X 2 、and X 3 Two or fewer of them are N, Y a 、Y 1 、Y 2 、Y 3 、and Y 4 Two or fewer of them are N, wherein all other variable elements not specifically defined herein are as defined in any one of the first, second, third, and fourth embodiments.

[0075] In a sixth embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, X a and X b are each independently C or N, Y a is C or N, wherein 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 a seventh embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is pyridinyl or pyrimidinyl substituted with k groups of R 1 wherein 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 of the following structural formula V:

[0078]

Chemical formula

[0079] its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt thereof [wherein X 1 is C or N], and all other variable elements not specifically defined herein are 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 of the following structural formula VI

[0081]

Chemical formula

[0082] its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt thereof, 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, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is a C5-C6 cycloalkyl or 5-6 membered heterocyclyl substituted with n groups of R 3 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, and ninth embodiments.

[0084] In the 11th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is a C5-C6 cycloalkyl or 5- to 6-membered heterocyclyl substituted with n groups of R 3 wherein the 5- to 6-membered heterocyclyl contains 1 or 2 heteroatoms selected from O and N, 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, and 10th embodiments.

[0085] In the 12th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is a cyclohexyl or 6-membered heterocyclyl having n groups of R 3 wherein the 6-membered heterocyclyl contains 1 or 2 heteroatoms selected from O and N, 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, and 11th embodiments.

[0086] In the 13th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring C is tetrahydro-2H-pyranyl substituted with n groups of R 3 wherein 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, and 12th embodiments.

[0087] In the 14th embodiment, the compound of the present disclosure is a compound of the following structural formula VII:

[0088]

Chemical formula

[0089] [wherein: ring A and ring B are each an aromatic ring, X a, X b , X 1 , X 2 , and X 3 Among them, three or less are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 Among them, three or less are N, its tautomers, its compounds or deuterated derivatives of the tautomers, or pharmaceutically acceptable salts of the foregoing, All other variable elements not specifically defined herein are as defined in any one of the first and second embodiments.

[0090] In the 15th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X a , X b , X 1 , X 2 , and X 3 Among them, two or less are N, Y a , Y 1 , Y 2 , Y 3 , and Y 4 Among them, two or less are N, And all other variable elements not specifically defined herein are as defined in the 14th embodiment.

[0091] In the 16th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X a and X b are each independently 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 14th and 15th embodiments.

[0092] In the 17th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is pyridinyl or pyrimidinyl substituted with k groups of R 1 wherein all other variable elements not specifically defined are as defined in any one of the 14th, 15th, and 16th embodiments.

[0093] In the 18th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is phenyl substituted with m groups of R 2 wherein all other variable elements not specifically defined are as defined in any one of the 1st, 14th, 15th, 16th, and 17th embodiments.

[0094] In the 19th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is hydrogen or C1-C2 alkyl optionally substituted with one or two groups selected from halogen, -CN, and -OH, wherein all other variable elements not specifically defined are as defined in any one of the 1st, 14th, 15th, 16th, 17th, 18th, and 19th embodiments.

[0095] In the 20th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is hydrogen, wherein all other variable elements not specifically defined are as defined in any one of the 1st, 14th, 15th, 16th, 17th, 18th, and 19th embodiments.

[0096] In the 21st embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 、R 2 、and R 3For each occurrence, independently, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)NR h R i 、-NR h R i 、-OR k 、-S(=O)2R k 、-S(=O)2NR h R i 、C3-C6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, and is selected from R 1 、R 2 、and R 3 Any one of C1-C6 alkyl and C1-C6 alkoxy, and the C1-C6 alkyl of -C(=O)(C1-C6 alkyl) is halogen, cyano, C(=O)OR k 、and -OR k and is optionally substituted by 1-3 groups selected from R 1 、R 2 、and R 3 Any one of C3-C6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is halogen, cyano, C1-C4 alkyl, and -OR k and is optionally substituted by 1-3 groups selected from R h and R i For each occurrence, are each independently selected from hydrogen and C1-C4 alkyl, R h and R i Any one of C1-C4 alkyl is optionally substituted by 1-3 groups selected from halogen, cyano, and -OH, R k For each occurrence, are each independently selected from hydrogen and C1-C4 alkyl, R h and R iAny one of C1-C4 alkyls is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. 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, and twentieth embodiments.

[0097] In the 22nd embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 , R 2 , and R 3 are each independently, for each occurrence, selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR h R i , -NR h R i , and -OR k , and R 1 , R 2 , and R 3 any one of C1-C4 alkyl and C1-C4 alkoxy of, and the C1-C4 alkyl of -C(=O)(C1-C4 alkyl) are each optionally substituted and optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OR k , R h and R i are each independently, for each occurrence, selected from hydrogen and C1-C2 alkyl, R k is each independently, for each occurrence, selected from hydrogen and C1-C2 alkyl, 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, twentieth, and twenty-first embodiments.

[0098] In the 23rd embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 , R 2 , and R 3 are, for each occurrence, independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), and -OR k , R 1 , R 2 , and R 3 of any one of the C1-C4 alkyl is optionally substituted and is optionally substituted with 1 to 3 groups of halogen, R k is, for each occurrence, independently selected from hydrogen and C1-C2 alkyl, 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, and 22nd embodiments.

[0099] In the 24th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is, for each occurrence, independently selected from F, Cl, Br, C1-C2 alkyl, and -OR k , R 1 of the C1-C2 alkyl is optionally substituted and is optionally substituted with 1 to 3 groups of halogen, R k is, for each occurrence, independently selected from hydrogen and C1-C2 alkyl, 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, and 23rd embodiments.

[0100] In the 25th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is, for each occurrence, 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, and 24th embodiments.

[0101] In the 26th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is, for each occurrence, independently selected from F, Cl, Br, and C1-C2 alkyl, R 1 wherein the C1-C2 alkyl of R is optionally substituted with 1 to 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, and 25th embodiments.

[0102] In the 27th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is, for each occurrence, 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, and 26th embodiments.

[0103] In the 28th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present 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, and 27th embodiments.

[0104] In the 29th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present 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, and 28th embodiments.

[0105] In the 30th embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, n is 0, 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.

[0106] In certain embodiments, at least one compound of the present disclosure is selected from Compounds 1-4 shown in Table 1, their tautomers, deuterated derivatives of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing.

[0107]

Table 1

[0108] 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, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0109] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0110] It should also be recognized that the pharmaceutical compositions of the present disclosure can be utilized in combination therapies, i.e., the pharmaceutical compositions described herein can further comprise an additional pharmaceutically active agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of Formula I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered, as a separate composition, parallel to, before, or after a composition comprising an additional pharmaceutically active agent.

[0111] As described above, the pharmaceutical compositions disclosed herein include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be selected from adjuvants and vehicles. The pharmaceutically acceptable carrier, as used herein, can be selected, for example, from any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants that are compatible with a particular desired dosage form. Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. The use of any conventional carrier is contemplated to be within the scope of the present disclosure, except when it is incompatible with the compounds of the present disclosure, for example, by producing any undesirable biological effects or otherwise interacting in a detrimental manner with any other component of the pharmaceutical composition.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.

[0112] III. Methods of Treatment and Use In another aspect of the disclosure, the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, are for use in treating diseases, disorders, or conditions mediated by FPR1 signaling. In another aspect, provided herein is the use of the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, for the manufacture of a medicament for treating diseases, disorders, or conditions mediated by FPR1 signaling. In yet another aspect, provided herein is a method of treating a disease, disorder, or condition mediated by FPR1 signaling in a subject, the method comprising administering a therapeutically effective amount of the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof.

[0113] In some embodiments, the disease, disorder, or condition is of the central nervous system (CNS). In some embodiments, the disease, disorder, or condition is selected from stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizure disorder, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sachs disease, Sandhoff diseases, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau disease, fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, essential tremor, late-onset dystonia, late-onset dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar atrophy, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex regional pain syndrome types I and II, diabetic neuropathy, and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Ménière's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathies, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, post-meningitis syndrome, prion disease, myelitis, neuritis, protein dyshomeostasis associated with diabetes, transthyretin-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, herpes zoster-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0114] 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 a 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 glioblastoma.

[0115] In another aspect of the disclosure, the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, are for use in modulating FPR1 activity. In another aspect, the use of the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, for the manufacture of a medicament for modulating FPR1 activity is disclosed herein. In yet another aspect, a method of modulating FPR1 activity is disclosed herein, the method comprising administering to a subject a therapeutically effective amount of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing. In yet another aspect, a method of modulating FPR1 activity is disclosed herein, the method comprising contacting the FPR1 with a subject with the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described herein, or pharmaceutical compositions thereof, of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0116] Compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof may be administered once, twice, or three times a day, for example, for the treatment of diseases, disorders, or conditions mediated by the signaling of FPR1.

[0117] In some embodiments, compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof in an amount of 2 mg to 1500 mg or 5 mg to 1000 mg are administered once, twice, or three times a day.

[0118] Compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, buccally, vaginally, transdermally, by patch, by pump, or via an implanted reservoir, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intralung, intrathecal, rectal, and topical modes of administration. Parenteral administration can also be carried out by continuous infusion over a selected period. Other forms of administration contemplated in the present disclosure are described in International Patent Application WO2013 / 075083, International Patent Application WO2013 / 075084, International Patent Application WO2013 / 078320, International Patent Application WO2013 / 120104, International Patent Application WO2014 / 124418, International Patent Application WO2014 / 151142, and International Patent Application WO2015 / 023915.

[0119] The useful dosage or therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof described herein can be determined by comparing their in vitro activities and in vivo activities in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art. See, for example, U.S. Patent No. 4,938,949.

[0120] One of ordinary skill in the art will recognize that when the amount of a compound is disclosed, the relevant amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "at least one compound selected from the compounds of Formula I and its pharmaceutically acceptable salts 1000 mg" includes 1000 mg of the compound of Formula I) and a concentration of the pharmaceutically acceptable salt of the compound of Formula I equivalent to 1000 mg of the compound of Formula I.

Examples

[0121] Examples are disclosed herein to provide a more complete understanding of the disclosure described herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way.

[0122] (Example 1) Synthesis of Exemplary Compounds The compounds of the present disclosure can be prepared according to standard chemical practices or as described herein, including the following synthetic schemes, and in the description for preparing compounds selected from the compounds of Formulas I, IIa, IIb, III, IV, V, VI, and VII, Compounds 1-4, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0123] As representative examples, the method for preparing the compounds of formula I using compounds 1 and 2 involves the general reaction steps as described in Scheme 1.

[0124] Compounds 1 and 2 Rac-3-(2-Hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (Compound 1) Rac-3-(2-Hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 2)

[0125]

Chemical formula

[0126] General step A: Preparation of 1-(2-(benzyloxy)-5-methylphenyl)ethan-1-one To a solution of 1-(2-hydroxy-5-methylphenyl)ethenone (4.25 g, 28 mmol) and potassium carbonate or K2CO3 (7.81 g, 56 mmol) in dimethylformamide DMF (50 mL), (chloromethyl)benzene (7.81 g, 56 mmol) was added, and then the resulting solution was 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 to dryness 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] + 。

[0127] 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 hour. 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 = 20:1) to afford the product ethyl 4-(2-(benzyloxy)-5-methylphenyl)-2,4-dioxobutanoate as a yellow solid (7 g, 90%). Mass (m / z): 340.9 [M+H] + 。

[0128] 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-pyrrol-2-one 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) was added with catalytic acetic acid or HOAc (2 drops) under N2, and then the reaction mixture was stirred at 60 °C for 3.5 h. 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 at 60 °C for 16 h under N2. The solid was precipitated, collected by filtration, and dried to give the product rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-one as a white solid (1.3 g, 40%). Mass (m / z): 551.7 [M+H] + .

[0129] General steps D and E: Preparation of rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (Compound 1) and rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 2) A mixture of rac-4-(2-(benzyloxy)-5-methylbenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-one (500 mg, 0.91 mmol), hydroxylamine hydrochloride (125 mg, 1.82 mmol) and sodium bicarbonate or NaHCO₃ (153 mg, 1.82 mmol) in EtOH (20 mL) was stirred at 95 °C for 16 h under nitrogen gas or N₂ and then cooled to room temperature. Concentrated sulfuric acid or H₂SO₄ (5 mL) was added dropwise to the reaction mixture, and the resulting solution was stirred at 100 °C for 5 h under N₂. The solution was cooled to room temperature and then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini-C18 150×21.2 mm, 5 μm; ACN-H₂O (0.1% FA), 55~60%) to obtain the product rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (Compound 1) (48 mg, 12%, white solid) and rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 2) (8 mg, 2%, white solid). rac-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one (Compound 1): mass (m / z): 458.7 [M+H] + 。 rac-3-(2-Hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 2): Mass (m / z): 458.8 [M+H] + 。

[0130] The methods for preparing Compounds 3 and 4 are described as follows.

[0131] Compounds 3 and 4 Rac-3-(5-Fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 3)

[0132]

Chem.

[0133] Step 1. According to General Step A, 1-(2-(benzyloxy)-5-fluorophenyl)ethan-1-one (2) was prepared as a yellow oily substance (6.4 g, 100%).

[0134] Step 2. According to General Step B, ethyl 4-(2-(benzyloxy)-5-fluorophenyl)-2,4-dioxobutanoate (4) was prepared as a yellow oily substance (7.0 g, 98%, crude product).

[0135] Step 3. According to General Step C, rac-4-(2-(benzyloxy)-5-fluorobenzoyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-5-(4-(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-one (7) was prepared as a colorless oily substance (400 mg, 43%, crude product). Mass (m / z): 556.1 [M+H] + 。

[0136] Steps 4 and 5. According to the general steps D and E, rac-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 3) was prepared as a white solid (5 mg, 2%). Mass (m / z): 463.0 [M+H] + 。

[0137] Compound 4 Rac-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 6)

[0138]

Chemical formula

[0139] Step 1. According to the general step C, rac-4-(2-(benzyloxy)-5-fluorobenzoyl)-5-(4-chlorophenyl)-3-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-2H-pyrrol-2-one (4) was prepared as a colorless oil (300 mg, 35%, crude product). Mass (m / z): 522.0 [M+H] + 。

[0140] Steps 2 and 3. According to the general steps D and E, rac-4-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]isoxazol-6-one (Compound 4) was prepared as a white solid (5 mg, 2%). Mass (m / z): 429.0 [M+H] + 。

[0141] (Example 2) In vitro assay for detecting and measuring the modulation of FPR1-mediated calcium signaling by Compounds 1-4 As illustrated in the exemplary embodiments of Table 2, the effect of the compounds of the present disclosure on the regulation of FPR1-mediated cellular signaling was measured by monitoring changes in the calcium levels of the cells. The following ranking criteria were used as categories to report the dose responses of the illustrated embodiments: *** (IC 50 ≤ 100 nM); ** (IC 50 ≥ 100 - ≤ 1000 nM); * (IC 50 ≥ 1000 - ≤ 10,000 nM); N.D. - not detected.

[0142] 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 and inserted into the lentiviral vector GV367 (vector information: http: / / www.genechem.com.cn / index / supports / tool_search.html?keywords=GV367) under the CMV promoter. 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 the lentiviral vector GV367 containing the CDS of human or mouse FPR1 for 24 hours and then cultured in complete medium for an additional 48 hours. 72 hours after transfection, the cells were passaged and 5 μg / ml puromycin was added to screen for FPR1-transfected 293T cells. Overexpression of human or mouse FPR1 in T cells was detected by immunostaining using anti-mouse or anti-human FPR1 antibody (Biolegend or Antibody Online).

[0143] 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 and maintained on ice, and then the intracellular calcium concentration was measured. To measure the inhibitory efficacy of the designed potential FPR1 antagonists, 293T cells overexpressing hFPR1 or mFPR1 were incubated with the compounds at room temperature for 10 minutes. Subsequently, the cytoplasmic calcium levels were measured by FACS Aria III at 37 °C before and after stimulation with fMLP. For each sample, the immunofluorescence intensity of indo-1 AM before adding fMLP was defined as the baseline value, and the intensity at the peak immunofluorescence decrease after adding fMLP 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 at multiple concentration gradients (from 0 nM to 100 μM), the IC 50 of each compound in the inhibition of fMLP-FPR1-mediated intracellular calcium concentration in 293T cells was automatically calculated using Prism software (GraphPad).

[0144]

Table 2

[0145] (Example 3) In vivo preclinical efficacy in an intracerebral hemorrhage (ICH) mouse model Compound 1 was used as a representative compound in an experimental ICH mouse model to demonstrate the efficacy of the compounds of the present disclosure in protecting against brain injury and improving brain function after stroke and / or brain injury in the experiments described below.

[0146] Preparation of an experimental mouse ICH model Using an intracerebral hemorrhage (ICH) model in mice, the protective merits of the compounds of the present disclosure were exemplified. Figure 1 represents 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: 1654-1662 (2011); Rynkowski et al., Nat. Protoc. 3: 122-128 (2008)). Using isoflurane inhalation, the mice were placed under anesthesia and fixed in a stereotaxic frame. A burr hole was drilled at a position 2.3 mm lateral to the midline and 0.5 mm anterior to bregma on the right side of the skull. For the autologous blood model, 30 μl of heparin-untreated blood was collected from the ophthalmic vein. The first 5 μl of blood was injected at a depth of 3 mm below the hole, and the remaining 25 μl of blood was injected at a rate of 1 μl / min at 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 anterior, 2.3 mm lateral, and 3.5 mm deep relative to bregma) at a rate of 0.5 μl / min. Mice for the sham control were injected with an equal volume of saline. Throughout the procedure, body temperature was maintained at 37 °C using a thermostatic blanket. After surgery, the mice were placed under observation while allowing free access to food and water. The compound was dissolved in DMSO and dosed at 5 mg / kg twice a day via intraperitoneal injection at a dose of 1 ml / kg body weight. The first dose was administered 1 hour after the start of ICH.

[0147] Evaluation of nervous system function The evaluation of neurological function was performed by blinded researchers for the two treatment groups. The modified neurological severity score (mNSS), corner turn test, and rotarod test were conducted to evaluate the neurological deficits of ICH mice at defined time points as described (Li et al., Proc. Nat. Acad. Sci. USA 114: E396-E405 (2017)). Mice were evaluated for motor function (muscle and abnormal movement), sensory function (vision, touch, and proprioception), and reflexes (pinna, corneal, and startle reflexes). The score range was 0 - 18 and was defined as follows: severe injury (13 - 18); moderate injury (7 - 12); mild injury (1 - 6). The corner turn test was used to evaluate sensorimotor injury that quantifies the preference (right or left) to turn when approaching a 30° corner. Lesioned mice typically have a turning preference that correlates with the extent of striatal injury. Each mouse repeated this procedure 10 times with at least 30 - second intervals between trials. Then, the percentage of turns to the same side was calculated. The rotarod test was used to evaluate motor coordination and balance. Mice were trained during the week prior to ICH induction. At specified time points after ICH, mice were placed on a rotarod apparatus. The rotating rod was 3 cm in diameter and had a smooth surface. The rod was 30 cm in length and was placed at a height of 20 cm from the base. Each mouse was placed on the rod at a speed of 4 revolutions per minute (rpm). This speed was accelerated to 40 rpm over 5 minutes. The duration that each mouse remained on the rod was recorded. Each mouse was tested in three consecutive trials at 15 - minute intervals. Results were reported as the average of the three trials.

[0148] Reduction of edema in MRI neuroimaging As described (Li et al., 2017), the total lesion volume was measured with a 7T small animal MRI scanner (Bruker, USA). T2 - weighted water images were recorded using the following parameters (repetition time (TR) = 4500 ms, echo time (TE) = 65.5 ms, field of view (FOV) = 28×28 mm2 (Image matrix = 256×256, slice thickness = 0.5 mm). Susceptibility-weighted imaging (SWI) was used to measure the hematoma. The acquisition parameters were as follows: TR = 30 ms and TE = 10 ms, flip angle = 25°, FOV = 32×32×16 mm 3 (Image matrix = 256×256). The volume was estimated manually and the total volume was calculated by multiplying the distance between sections (0.5 mm) using MIPAV software. The PHE volume was calculated as the total lesion volume minus the hematoma volume. The MRI data were analyzed by two investigators blinded to the experimental group.

[0149] Evaluation of brain water content The brain water content was measured 1 day after ICH. Briefly, without perfusion, the brain tissue was removed and divided into three parts: the ipsilateral cerebral hemisphere, the contralateral cerebral hemisphere, and the cerebellum. The brain tissue was weighed for wet mass and then dried at 100 °C for 24 h for dry mass. The brain water content was calculated using the following formula: (wet mass - dry mass) / wet mass × 100%.

[0150] Measurement of infiltrating cells by flow cytometry A single cell suspension of brain tissue was prepared and stained with a fluorescent dye-conjugated antibody. The brain tissue was digested with 1% collagenase (Sigma-Aldrich) at 37 °C for 30 minutes and then the myelin sheath was removed by density gradient centrifugation at 700 rpm for 10 minutes in 30% Percoll (Sigma-Aldrich). For neutrophil staining, the 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), anti-mouse CD11b (Cat#553311; RRID:AB_394775, BD Biosciences, 1:100) according to these instructions at 4 °C for 30 minutes. Flow cytometry measurements were performed on a FACS Aria III (BD Bioscience) and analyzed using Flowjo 7.6 software (Informer Technologies, Ashland, OR, USA).

[0151] Those skilled in the art will readily recognize that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims and from the disclosure as claimed, from the present disclosure and the claims.

Claims

1. A compound of the following structural formula IIa: 【Chemical 1】 [wherein: Z 1 and Z 2 are both each O or N, Ring A is an aromatic or non-aromatic ring, X a and X b each independently is C, N, or a bond, X 1 , X 2 , X 3 , and X 4 is, independently of each other, C or N, Ring B is an aromatic or non-aromatic ring, Y a is C, N, or a bond, Y 1 、 Y 2 、 Y 3 、 Y 4 、 and Y 5 is, independently of one another, C or N, Ring C is C 3 ~C 12 selected from carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl, R 1 、R 2 、and R 3 each occurrence, independently, is halogen, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, 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 carbocyclic, 3- to 12-membered heterocyclic, 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, each optionally substituted with 1 to 3 groups selected therefrom, 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 each optionally substituted with 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 each, upon each occurrence, is independently selected from hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl, R h 、 R i 、 and R j any one of C 1 to C 4 The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH, R k is, for each occurrence, independently of one another, hydrogen, C 1 to C 4 alkyl, and C 3 to C 6 selected from cycloalkyl, R h 、R i 、and R j any one of C 1 to C 4 alkyl 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, 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 deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

2. A compound of the following structural formula III: 【Chemical 2】 [wherein: Ring A and Ring B are each an aromatic ring] is the compound according to Claim 1, its tautomer, its deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

3. A compound of the following structural formula IV: 【Chemical Formula 3】 [wherein: X a 、 X b 、 X 1 、 X 2 、 and X 3 Among them, three or less are N, Y a 、Y 1 、Y 2 、Y 3 、and Y 4 Among them, three or less are N], the compound according to claim 1, its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

4. X a 、 X b 、 X 1 、 X 2 、 and X 3 Two or less of them are N, Y a 、Y 1 、Y 2 、Y 3 、and Y 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein two or less of Y

5. X a and X b are each C or N, Y a The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein Y is C or N.

6. Ring A is pyridinyl or pyrimidinyl substituted with k groups of R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the ring A is pyridinyl or pyrimidinyl substituted with k groups of R.

7. A compound of the following structural formula V: 【Chemical Formula 4】 [wherein X 1 is C or N], the compound according to claim 1, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

8. The following structural formula VI: 【Chemical Formula 5】 is the compound according to Claim 1, its tautomer, its deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

9. Ring C is R 3 substituted with n groups of C 5 ~C 6 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, and 8, which is cycloalkyl or 5- to 6-membered heterocyclyl.

10. Ring C is R 3 substituted with n groups of C 5 to C 6 is cycloalkyl or 5- to 6-membered heterocyclyl, and the 5- to 6-membered heterocyclyl contains 1 or 2 heteroatoms selected from O and N, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, and 8.

11. Ring C is cyclohexyl or 6-membered heterocyclyl having n groups of R 3 and the 6-membered heterocyclyl contains 1 or 2 heteroatoms selected from O and N, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, and 8.

12. Ring C is a tetrahydro-2H-pyranyl substituted with n groups of R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, and 8, wherein the ring C is a tetrahydro-2H-pyranyl substituted with n groups of R.

13. A compound of the following structural formula VII: 【Chemical Formula 6】 [wherein: Ring A and Ring B are each an aromatic ring, X a 、 X b 、 X 1 、 X 2 、 and X 3 Among them, three or less are N, Y a 、Y 1 、Y 2 、Y 3 、and Y 4 wherein three or less of them are N], the compound according to claim 1, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

14. X a 、 X b 、 X 1 、 X 2 、 and X 3 Among them, two or less are N, Y a 、 Y 1 、 Y 2 、 Y 3 、 and Y 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13, wherein no more than two of

15. X a and X b are each C or N, Y a The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13, wherein Y is C or N.

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

17. Ring B is phenyl substituted with m groups of R 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 13 to 15, wherein the ring B is phenyl substituted with m groups of R.

18. R 1 、R 2 、and R 3 each occur independently and is halogen, cyano, C 1 -C 6 -C 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 -cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and 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 alkyl) of C 1 ~C 6 alkyl is each optionally substituted with 1 to 3 groups selected from halogen, cyano, C(=O)OR k 、 and -OR k and is optionally substituted with 1 to 3 groups selected from halogen, cyano, C(=O)OR R 1 、 R 2 、 and R 3 any one of C 3 to C 6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with one to three groups selected from halogen, cyano, C 1 to C 4 alkyl, and -OR k and are optionally substituted with one to three groups selected therefrom, R h and R i each occurrence of which, independently of one another, is selected from hydrogen and C 1 -C 4 -C alkyl R h and R i any one of C 1 ~C 4 the alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH, R k which, for each occurrence, is independently selected from hydrogen and C 1 to C 4 alkyl R h and R i any one of the C 1 to C 4 wherein the alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13.

19. R 1 , R 2 , and R 3 is, for each occurrence, independently halogen, cyano, C 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 to C 4 alkyl and C 1 to C 4 alkoxy, and -C(=O)(C 1 to C 4 alkyl) of C 1 to C 4 alkyl is each optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OR k and R h and R i each, independently for each occurrence, is hydrogen and C 1 -C 2 selected from alkyl, R k which, for each occurrence, is independently selected from hydrogen and C 1 -C 2 alkyl, of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13.

20. R 1 、R 2 、and R 3 each occur independently and is selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, -C(=O)(C 1 -C 4 -alkyl), and -OR k ; R 1 、R 2 、and R 3 Any one of C 1 to C 4 alkyl is optionally substituted with 1 to 3 groups of halogen, R k which, for each occurrence, is independently selected from hydrogen and C 1 -C 2 -alkyl, a compound according to any one of claims 1 to 3, 7, 8, and 13, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof.

21. R 1 wherein, for each occurrence, independently, F, Cl, Br, C 1 to C 2 alkyl, and -OR k is selected from, R 1 of C 1 ~C 2 the alkyl is optionally substituted with one to three groups of halogen, R k which, for each occurrence, is independently selected from hydrogen and C 1 -C 2 -alkyl, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13.

22. R 1 which, for each occurrence, is independently selected from F, -CH 3 , and -OH, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13.

23. R 2 wherein, for each occurrence, independently, F, Cl, Br, and C 1 ~C 2 is selected from alkyl R 1 of C 1 ~C 2 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13, wherein the alkyl is optionally substituted with 1 to 3 halogens.

24. R 2 which, for each occurrence, is independently selected from Cl and -CF 3 and the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, and 13

25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Claims 1 to 3, 7, 8, and 13, wherein k is an integer selected from 0, 1, and 2.

26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Claims 1 to 3, 7, 8, and 13, wherein m is an integer selected from 1 and 2.

27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Claims 1 to 3, 7, 8, and 13, wherein n is 0.

28. 【Fig. 7】 selected from is the compound according to Claim 1, its tautomer, its deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

29. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, 13, and 28, and at least one pharmaceutically acceptable carrier.

30. A pharmaceutical composition for use in a method of treating a disease, disorder, or condition mediated by signal transduction of formyl peptide receptor 1 (FPR1) in a subject, the composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, 13, and 28, wherein the method comprises administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, 7, 8, 13, and 28.

31. The disease, disorder, or condition is related to the CNS and is selected from stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizure disorder, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, familial spastic paraplegia, spinocerebellar ataxia (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, autosomal dominant cerebral arteriopathy with subcortical infarcts (CADASIL), spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau, fragile X, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, essential tremor, late-onset dystonia, late-onset dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager, olivopontocerebellar atrophy, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex regional pain syndrome types I and II, diabetic neuropathy, and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Ménière's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitic syndrome, prion disease, myelitis, neuritis, protein abnormality blood disease related to diabetes, transthyretin-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma, the pharmaceutical composition according to claim 30.

32. The disease, disorder, or condition is stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, and venous), the pharmaceutical composition according to claim 31.

33. The disease, disorder, or condition is traumatic brain injury, the pharmaceutical composition according to claim 31.

34. The disease, disorder, or condition is malignant glioma, the pharmaceutical composition according to claim 31.

35. The pharmaceutical composition according to claim 34, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma.

36. The pharmaceutical composition according to claim 35, wherein the malignant glioma is glioblastoma.

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