FPR1 modulator and how to use it

Abstract

Compounds of formula I, compositions comprising same, and methods of using same, including for use in the treatment of diseases, disorders, and conditions mediated by formyl peptide receptor 1 (FPR1) signaling. JPEG2024510132000083.jpg59170

Description

[Technical Field]

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

[0002] The restoration of bodily homeostasis after injury or pathogen infection is critical to ensuring the survival of the organism. Physiological wound healing and the innate immune response are initiated by the release of soluble signaling molecules from the invading pathogen or damaged lesion. Temporarily regulated, interactive repair processes involve, for example, many chemokines, cytokines, acute-phase proteins, invasive and tissue-resident cells, fibroblasts, nerve cells, and the vascular system. If the injury is persistent or extensive, the physiological trauma repair or anti-infective response can become pathological, leading to excessive inflammation, edema, excessive fibrosis and scarring, 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 resolving response is critical to the homeostasis of the organism. Following tissue injury or pathogen infection (by bacteria, viruses, fungi, and / or microorganisms), a range of formyl peptides, damage-associated molecular pattern (DAMP) molecules, inflammatory lipid mediators (e.g., leukotrienes and lipoxins), and acute-phase proteins (e.g., annexins) are released from invading pathogens, damaged cells, and tissue lesions. Three formyl peptide receptors (FPR1, FPR2, and FPR3) function as major sensors for these chemotactic and activating molecules in humans. FPRs are highly expressed on neutrophils, macrophages, T lymphocytes, dendritic cells, epithelial cells, fibroblasts, microglia, and astrocytes. Binding of chemoactive molecules and acute proteins to FPRs recruits leukocytes, stimulates superoxide and cytokine production, activates microglia and astrocytes, and triggers other significant inflammatory and resolution responses for damage repair and host defense.

[0003] On the other hand, imbalanced FPR receptor-mediated signaling can lead to pathological inflammatory responses and cause numerous diseases following injury or infection, including cerebral edema, dysfunction, and organ failure after stroke or traumatic brain injury (TBI). In addition, chronic activation of FPR-mediated signaling induced by pathogens, tissue stress, and tissue injury is involved in the pathogenesis of brain cancer, gastric cancer, and Parkinson's disease.

[0004] Stroke is the leading cause of death worldwide, and treatment options are limited. FPR is highly expressed in microglia, astrocytes, and the cerebrovascular system. Following the onset of intracerebral hemorrhage (ICH), dying brain cells, activated platelets, microglia, and astrocytes release a range of pro-inflammatory neurotransmitters, acute-phase proteins, and DAMPs, which in turn activate FPR1. FPR1 activation induces leukocyte infiltration, reactive oxygen species (ROS) production, and cytokine release, which constitute the initial wave of the post-ICH inflammatory response and contribute to the development of perihematoma edema and the aggravated mass effect in stroke.

[0005] TBI is the leading cause of disability worldwide. The global incidence of TBI is estimated at 200 cases per 100,000 people per year. Severe TBI often leads to behavioral problems, brain atrophy, dementia, permanent brain damage, and ultimately death. Treatment options for TBI are limited, and FPR1 activation is involved in mediating the initial inflammatory process of TBI.

[0006] Glioblastoma and malignant glioma are the most common primary brain tumors. The annual incidence rate is approximately 6 per 100,000 people. Currently, there is no effective treatment for malignant glioma. FPR1 is highly expressed in glial cells, astrocytes, and the cerebral vascular system. Its interaction with chemotactic ligands resulting from injury, stress, and pathogens is involved in the pathophysiology of brain cancer.

[0007] ARDS is a life-threatening lung injury that causes fluid leakage into the lungs and poor blood oxygenation. With an annual incidence of approximately 70 cases per 100,000 individuals, ARDS commonly occurs in patients hospitalized due to a prior infection or trauma, with limited treatment options and a mortality rate exceeding 40% for severe cases. Mitochondrial formylated peptides are elevated in the lung fluid and serum of ARDS patients, and activation of FPR1 signaling is involved as a major driving force behind acute lung injury.

[0008] Allergic conjunctivitis (AC) and dry eye syndrome (DES) are two of the most common inflammatory disorders of the eye, with a projected incidence of up to 40% of the adult population. Current treatment options for AC and DES only partially alleviate symptoms, and these disorders continue to severely impact the quality of life of patients. FPR is expressed in the conjunctiva, i.e., the mucous membrane layer of the eye, and its expression increases in the context of inflammation. Therefore, activation of FPR signaling is a potential neurotransmitter in the pathogenesis of AC and DES.

[0009] Considering the foregoing, there is still a need for novel therapeutic agents and alternative mechanisms that can effectively address the limited treatment options currently available for stroke, TBI, glioblastoma, glioma, ARDS, AC, and DES. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] International patent application WO2013 / 075083 [Patent Document 2] International patent application WO2013 / 075084 [Patent Document 3] International patent application WO2013 / 078320 [Patent Document 4] International patent application WO2013 / 120104 [Patent Document 5] International patent application WO2014 / 124418 [Patent Document 6] International patent application WO2014 / 151142 [Patent Document 7] International patent application WO2015 / 023915 [Patent Document 8] U.S. Patent No. 4,938,949 [Non-patent literature]

[0011] [Non-Patent Document 1] S.M. Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19. [Non-Patent Document 2] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-Patent Document 3] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia. [Non-Patent Document 4] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York [Overview of the Initiative] [Means for solving the problem]

[0012] One aspect of this disclosure provides compounds selected from the compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof, which can be used to treat diseases mediated by formyl peptide receptor 1 (FPR1) signaling. For example, a compound of the following structural formula I:

[0013] [ka]

[0014] [In the formula, (i) Each Z 1 and Z 2 These are independently O, S, N, NR 4 , C(R 4 )2, and CR 4selected from, Z 1 and Z 2 at least one of which is O, S, N, or NR 4 is, R 4 is selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, (ii) Y 1 is absent or is a bond, O, S, or NR 5 selected from, R 5 is selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, (iii) R 1 is selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups or R 1 and Z 2 together with the atom to which they are attached form a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group, (iv) each R 2 and R 3 is independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, (v) each R ' and R " is independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, hydroxy, thiol, amino, cyano, [[ID=****]]C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups Disclosed herein are tautomers thereof, deuterated derivatives of the compound or tautomer thereof, or pharmaceutically acceptable salts thereof, which are optionally substituted with at least one group selected from the above.

[0015] In one aspect of this disclosure, the compound of formula I is selected from the compounds 1 to 44 shown below, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof.

[0016] In some embodiments, the disclosure provides pharmaceutical compositions comprising compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical compositions may comprise compounds selected from the following compounds 1 to 44, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof. These compositions may further comprise additional pharmaceutically active agents.

[0017] Another aspect of the present disclosure provides a method for treating a disease, disorder, or condition mediated by formyl peptide receptor 1 (FPR1) signaling in a subject, comprising administering a therapeutically effective amount of a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to a subject a compound selected from the following compounds 1 to 44, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0018] In some embodiments disclosed herein, the treatment method involves administering an additional pharmaceutically active agent to a subject requiring it, either as the same pharmaceutical composition as the compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or as a separate composition. In some embodiments disclosed herein, the treatment method involves administering an additional pharmaceutically active agent, either as the same composition as the compounds selected from compounds 1 to 44 listed below, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or as a separate composition.

[0019] Also disclosed herein are methods for modulating FPR1 activity, which include administering a therapeutically effective amount of compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing any of the foregoing. In some embodiments disclosed herein, the method for modulating FPR1 includes administering a compound selected from the following compounds 1 to 44, their tautomers, deuterated derivatives of the compounds or tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing. In some embodiments, a method for modulating FPR1 activity includes contacting FPR1 with a compound of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition containing any of the foregoing. In some embodiments disclosed herein, a method for modulating FPR1 includes contacting FPR1 with a compound selected from the following compounds 1 to 44, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition containing any of the foregoing. [Modes for carrying out the invention]

[0020] I. Definition When used herein to refer to a noun, the terms "a" or "an" encompass the expression "at least one" and therefore include both singular and plural units of the noun. For example, "additional drugs" means one or more additional drugs.

[0021] The terms "FPR1" or "formyl peptide receptor 1," as used herein, refer to the cell surface receptor protein encoded by the FPR1 gene in humans. FPR1 modulates a wide variety of neutrophil functional responses and plays a crucial role in the pathogenesis of various diseases, including, for example, those described above.

[0022] The term "FPR1 modulator," as used herein, refers to an organic small molecule compound (≤10 kDa) that has the ability to alter one or more FPR1-mediated immune responses or signaling events and can be either an FPR1 agonist or an FPR1 antagonist. When an FPR1 modulator is an agonist, the compound has the ability to increase one or more FPR1-mediated immune responses or signaling events from their native state, for example, by binding to and activating the receptor. When an FPR1 modulator is an antagonist, the compound has the ability to decrease or inhibit one or more FPR1-mediated immune responses or signaling events from their native state, for example, by blocking agonist binding sites or allosteric binding sites on the receptor to achieve a reduction or inhibition of their action.

[0023] The term “compound” in the context of the compounds of this disclosure refers to a group of molecules having the same chemical structure, unless otherwise noted as a group of stereoisomers (e.g., a group of racemates, a group of cis / trans stereoisomers, or a group of (E) and (Z) stereoisomers), provided that isotopic variations may exist between the constituent atoms of the molecules. It will also be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom may contain a lower amount of isotopologes having a hydrogen atom at one or more of the designated deuterium positions within its structure. The relative amount of such isotopologes in the compounds of this disclosure depends on several factors, including, for example, the purity of the isotopes in the reagents used to produce the compound and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopologes is less than 49.9% of the compound overall. In other embodiments, the relative amount of such isotopologues is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound overall.

[0024] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” Generally, the term “substituted” refers to replacing a hydrogen group in a given structure with a group of a specified substituent. Unless otherwise noted, an “optionally substituted” group may have substituents at each substitutedable position of the group, and more than one position in any given structure may be substituted with more than one substituent selected from the specified group, and the substituents may be the same or different at all positions. The substituent combinations envisioned herein are combinations that result in the formation of stable or chemically possible compounds.

[0025] The term "isotopologie" refers to species that differ only in their chemical structure in terms of their isotopic composition. Furthermore, unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen being replaced by deuterium or tritium, or carbon being 13 C or 14 Compounds having the structure of the present invention are within the scope of this disclosure, except that they are replaced by C.

[0026] Unless otherwise noted, the structures shown herein are also intended to include all isomeric forms, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise noted, all tautomeral forms of the compounds of this disclosure are within the scope of this disclosure.

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

[0028] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0029] As used herein, “deuterated derivative” means having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or 「2This refers to compounds in which hydrogen is replaced by deuterium. Depending on the origin of the chemicals used in the synthesis, it is recognized that some variations of the natural isotopic abundance may occur in the synthesized compounds. The concentrations of naturally abundant and stable hydrogen isotopes are low and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein, despite these variations. Therefore, unless otherwise stated, when a “deuterated derivative” of a compound in this disclosure is referred to, at least one hydrogen atom is replaced by deuterium at a level well above its natural isotopic abundance of approximately 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium bonding at each designated deuterium), at least 4500 (67.5% deuterium bonding at each designated deuterium), at least 5000 (75% deuterium bonding at each designated deuterium), at least 5500 (82.5% deuterium bonding at each designated deuterium), at least 6000 (90% deuterium bonding at each designated deuterium), at least 6333.3 (95% deuterium bonding at each designated deuterium), at least 6466.7 (97% deuterium bonding at each designated deuterium), or at least 6600 (99% deuterium bonding at each designated deuterium).

[0030] As used herein, the term "isotope enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a given isotope.

[0031] As used herein, the term "alkyl" means a fully saturated, linear or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, alkyl groups contain 1 to 30 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms. In other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms. And in yet another embodiment, alkyl groups contain 1 to 2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are linear or linear or unbranched. In some embodiments, alkyl groups are branched.

[0032] The term "cycloalkyl" refers to a completely saturated, monocyclic C11 molecule. 3~8 Hydrocarbons or spirocyclic, condensed, or cross-linked bicyclic or tricyclic carbons 8~14 This refers to hydrocarbons, where any individual ring in the bicyclic system has 3 to 7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is C3-C 12 It is a cycloalkyl compound. In some embodiments, the cycloalkyl compound is a C3-C8 cycloalkyl compound. In some embodiments, the cycloalkyl compound is a C3-C6 cycloalkyl compound. Non-limiting examples of monocyclic cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0033] The term "carbocyryl" encompasses the term "cycloalkyl" and refers to a monocyclic C molecule that is either fully saturated or partially saturated by containing one or more unsaturated units, but is not aromatic. 3~8Hydrocarbons or spirocyclic, condensed, or cross-linked bicyclic or tricyclic carbons 8~14 This refers to hydrocarbons, where any individual ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclyls include, for example, combinations of monocyclic carbocyclics condensed with phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is C3-C 12 It is carbocyclyl. In some embodiments, carbocyclyl is C3-C 10 These are carbocyclyls. In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexyl, and cyclopentenyl and cyclohexenyl.

[0034] As used herein, the term "alkenyl" means a linear or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear, linear, or unbranched. In some embodiments, the alkenyl group is branched. In some embodiments, the alkenyl group is cyclic. In some embodiments, the alkenyl group is C3-C 12 The alkenyl group is an alkenyl group. In some embodiments, the alkenyl group is a C3-C8 alkenyl group. In some embodiments, the alkenyl group is a C3-C6 alkenyl group. Non-limiting examples of alkenyl groups include allyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, and heptenyl.

[0035] The term “heterocyclyl,” as used herein, means a non-aromatic (i.e., fully saturated or partially saturated, containing one or more unsaturated units, but not aromatic), monocyclic, spirocyclic, condensed, or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected from heteroatoms. Examples of bicyclic heterocyclyls include the following combinations of monocyclic rings: a monocyclic heteroaryl condensed onto a monocyclic heterocyclyl; a monocyclic heterocyclyl condensed onto another monocyclic heterocyclyl; a monocyclic heterocyclyl condensed onto phenyl; a monocyclic heterocyclyl condensed onto a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl condensed onto a monocyclic carbocyclyl / cycloalkyl. In some embodiments, the “heterocyclyl” group contains 3 to 14 ring members, one or more of which are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle independently has one heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle independently has two heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycle independently has three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocycle is a 3 to 12-membered heterocycle. In some embodiments, the heterocycle is a 4 to 10-membered heterocycle. In some embodiments, the heterocycle is a 3 to 8-membered heterocycle. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl.In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranil, azetidinyl, oxetanil, tetrahydrothiophenyl, dihydropyranyl, and tetrahydropyridinyl.

[0036] The term "heteroatom" refers to nitrogen or sulfur in any oxidized form, or silicon; any basic nitrogen in a quaternized form; or a substituteable nitrogen in a heterocyclic ring, e.g., N (in the case of 3,4-dihydro-2H-pyrrolyl, etc.), NH (in the case of pyrrolidinyl, etc.), or NR + This refers to one or more of oxygen, sulfur, and nitrogen, including (in the case of N-substituted pyrrolidinyl, etc.).

[0037] As used herein, the term "unsaturated" means that a part has one or more unsaturated units or degrees of unsaturation. Unsaturated means that not all available valence bonds in a compound are filled with substituents, and therefore the compound contains double or triple bonds.

[0038] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, but the oxygen atom is linked between two carbon atoms.

[0039] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodine, respectively.

[0040] As used herein, the "cyano" or "nitrile" group refers to -C≡N.

[0041] As used herein, “aromatic ring” refers to a carbocyclic or heterocyclic ring containing a conjugated, planar ring system having a delocalized pi electron orbital composed of [4n+2]p orbital electrons (wherein n is an integer from 0 to 6). A “non-aromatic” ring refers to a carbocyclic or heterocyclic ring that does not satisfy the requirements set forth above for aromatic rings and may be fully saturated or partially saturated. Non-restrictive examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows:

[0042] The term "aryl," used alone or as part of a larger term such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or spirocyclic, condensed, or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, where all rings in the system are aromatic rings containing only carbon atoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C6). 10 Examples include rings. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0043] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Examples of bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5 or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, and isoxazolyl.

[0044] A "spirocyclic ring system" refers to a ring system having two or more cyclic rings, where every pair of rings shares only one common atom.

[0045] Suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (SiO), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0046] Non-limiting examples of suitable bases that can be used in this disclosure include 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N;TEA), diisopropylethylamine (i-Pr2EtN;DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe;NaOCH3).

[0047] A pharmaceutically acceptable salt of the disclosed compound is disclosed herein. The salt of the compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0048] As used herein, the term "pharmaceutically acceptable" refers to a component that is within the bounds of sound medical judgment, suitable for use in contact with human and other mammalian tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable profit-benefit ratio. "pharmaceutically acceptable salt" means any non-toxic salt that can be directly or indirectly provided to a recipient by administration. A suitable pharmaceutically acceptable salt is, for example, the salt disclosed in S.M. Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19.

[0049] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, vitaltric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexin-1,6 Examples of salts include dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include salts formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and salts formed with organic acids, such as maleic acid.

[0050] Examples of pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4Examples include alkyl)4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0051] The term "subject" refers to animals, including humans, but is not limited to these.

[0052] The term "therapeutic dose" refers to the amount of compound administered to produce the desired effect (e.g., improving the symptoms of a disease, disorder, or condition mediated by FPR1 signaling, reducing the severity of a disease, disorder, or condition or its symptoms mediated by FPR1 signaling, and / or reducing the progression of a disease, disorder, or condition or its symptoms mediated by FPR1 signaling). The exact amount of the therapeutic dose depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0053] As used herein, the term “treatment” and its related terms mean slowing or halting disease progression. “Treatment” and its related terms, as used herein, include, but are not limited to, complete or partial remission, a reduction in the risk of diseases, disorders, and conditions mediated by FPR1 signaling, and disease-related complications. Improving or reducing the severity of any of these symptoms can be readily assessed or subsequently developed according to methods and techniques known in the art.

[0054] When used in relation to the dose, volume, or mass percentage of an ingredient in a composition or dosage form, the terms "about" and "approximately" include a specified dose, volume, or mass percentage value or range of dose, volume, or mass percentage that is recognized by those skilled in the art as producing a pharmacological effect equivalent to that obtained from a specified dose, volume, or mass percentage.

[0055] II. Compounds and Compositions In the first embodiment, the compound of the present disclosure is a compound having the following structural formula I:

[0056] [ka]

[0057] [In the formula, (i) Each Z 1 and Z 2 These are independently O, S, N, NR 4 , C(R 4 )2, and CR 4 Selected from, Z 1 and Z 2 At least one of them is O, S, N, or NR 4 And, R 4 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)Y 1 It does not exist, or O, S, and NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii)R 1 is selected from linear, branched, and cyclic alkyl groups, alkenyl groups, carbocyclic groups, heterocyclic groups, linear, branched, and cyclic alkenyl groups, linear and branched heteroalkenyl groups, aryl groups, and heteroaryl groups, or R 1 and Z 2 These, together with the atoms to which they are bonded, form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group. (iv) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. (v)Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, linear, branched, and cyclic alkenyl groups, linear and branched heteroalkenyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, -OC(O)C1~C6 linear, branched, and cyclic alkyl groups, -C(O)OC1~C6 linear, branched, and cyclic alkyl groups, -NHC1~C6 linear, branched, and cyclic alkyl groups, -N(C1~C6 linear, branched, and cyclic alkyl groups)2, -NHC(O)C1~C6 linear, branched, and cyclic alkyl groups, -C(O)NHC1~C6 linear, branched, and cyclic alkyl groups, -NHaryl group, -N (aryl group) 2, -NHC(O)aryl group, -C(O)NH aryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above.

[0058] In a second embodiment, the compound of the present disclosure is one of the following compounds with structural formulas IIA or IIB:

[0059] [ka]

[0060] The tautomers thereof, the compounds thereof or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts thereof, and all other variable elements not specifically defined herein are as defined in the First Embodiment.

[0061] In a third embodiment, the compound of the present disclosure is one of the following compounds with structural formula IIIA or IIIB:

[0062] [ka]

[0063] The tautomers thereof, the compounds thereof or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts thereof, and all other variable elements not specifically defined herein are as defined in the First Embodiment.

[0064] In the fourth embodiment, the compound of the present disclosure is one of the following compounds with structural formulas IVA or IVB:

[0065] [ka]

[0066] The tautomers thereof, the compounds thereof or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts thereof, and all other variable elements not specifically defined herein are as defined in the First Embodiment.

[0067] In the fifth embodiment, the compound of the present disclosure is one of the following compounds with structural formulas VA or VB:

[0068] [ka]

[0069] The tautomers thereof, the compounds thereof or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts thereof, and all other variable elements not specifically defined herein are as defined in the First Embodiment.

[0070] In the sixth embodiment, the compound of the present disclosure is one of the following compounds with structural formulas VIA or VIB:

[0071] [ka]

[0072] The tautomers thereof, the compounds thereof or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts thereof, and all other variable elements not specifically defined herein are as defined in the First Embodiment.

[0073] In the seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R 1 R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 R is an aryl group, 3 These are selected from linear and branched alkyl groups, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0074] In the eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R 1 These are selected from 5- and 6-membered aryl groups which may be substituted as applicable, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0075] In the ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R1 This is selected from five- and six-membered aryl groups substituted with at least one halogen group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0076] In the tenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R 1 This is selected from five- and six-membered aryl groups substituted with at least one fluoro, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0077] In the eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 This is selected from five- and six-membered aryl groups substituted with at least one chloro group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0078] In the twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 The 5- and 6-membered heteroaryl groups are selected as may be substituted, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0079] In the 13th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1These are selected from 5- and 6-membered heteroaryls substituted with at least one halogen group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0080] In the fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R 1 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0081] In the 15th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0082] In the sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R 1 This is selected from 3- to 6-membered cyclic alkyl groups which may be substituted as applicable, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0083] In the 17th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 This is selected from a 3- to 6-membered cyclic alkyl group substituted with at least one alkoxy group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0084] In the 18th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 This is selected from a 3- to 6-membered cyclic alkyl group substituted with at least one methoxy group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0085] In the 19th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 The 3- to 6-membered heterocyclic groups are selected as may be substituted, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0086] In the 20th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 The 5- and 6-membered heteroaryl groups are selected as may be substituted, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0087] In the 21st embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0088] In the 22nd embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2This is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0089] In the 23rd embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0090] In the 24th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0091] In the 25th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 This is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0092] In the 26th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 C1~C are substituted depending on the case. 10 Linear chain and C2~C 10All other variable elements selected from branched alkyl groups and not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0093] In the 27th embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, and 1,2,2-trimethylpropyl, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0094] In the 28th embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0095] In the 29th embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4 is optionally substituted C1-C 10 straight-chain, C2-C <x 10 branched alkyl group, and C3-C6 cycloalkyl group, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0096] In the 30th embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4This is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0097] In the 31st embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R' is hydrogen, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0098] In the 32nd embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R'' is hydrogen, and all other variable elements not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0099] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 44 shown in Table 1, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts thereof.

[0100] [ka]

[0101] [ka] [ka] [ka] [ka]

[0102] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1 to 18, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts thereof, or any of the foregoing, and a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.

[0103] 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.

[0104] It should also be recognized that the pharmaceutical compositions of this disclosure can be used in combination therapy, that is, the pharmaceutical compositions described herein may further contain additional pharmaceutically active agents. Alternatively, a pharmaceutical composition comprising compounds selected from the compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1 to 18, their tautomers, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any of the foregoing, may be administered as a separate composition, in parallel with, before or after, a composition containing additional pharmaceutically active agents.

[0105] As described above, the pharmaceutical compositions disclosed herein include pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. When used herein, the pharmaceutically acceptable carriers can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersants, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, adapted to a specific desired dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, discloses various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, for example, by producing any undesirable biological effect or by interacting with any other component of the pharmaceutical composition in a detrimental manner, its use is assumed to be within the scope of this disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering 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, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethyl Examples of excipients include sodium cellulose, ethylcellulose, 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), colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0106] III. Procedures and Methods of Use In another aspect of this disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof described herein, including compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1 to 18, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are intended for use in treating diseases, disorders, or conditions mediated by FPR1 signaling. In another embodiment, the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof described herein, including compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, is disclosed herein for the manufacture of pharmaceuticals for treating diseases, disorders, or conditions mediated by FPR1 signaling. In yet another embodiment, a method for treating a disease, disorder, or condition mediated by FPR1 signaling in a subject is disclosed herein, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, comprising a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compound 1 to 18, its tautomers, deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt thereof, as described herein.

[0107] In some embodiments, the disease, disorder, or condition is of the central nervous system (CNS). In some embodiments, the disease, disorder, or condition is of the stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, paroxysmal disorder, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Taysachs disease, Sandhoff disease. Diseases, familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, autosomal dominant cerebral arteriovenous disease with subcortical infarction (CADASIL), spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hipper-Lindau disease, fragile X syndrome, paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex focal pain syndromes type I and II, diabetic neuropathy, and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal The following conditions are selected: harangela neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, post-meningitis syndrome, prion disease, myelitis, radiculitis, diabetes-related protein abnormalities, trans tyretin-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

[0108] In one embodiment, the disease, disorder, or condition is a stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, and venous). In one embodiment, the disease, disorder, or condition is traumatic brain injury. In one embodiment, the disease, disorder, or condition is a malignant glioma. In one embodiment, the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma. In one embodiment, the malignant glioma is a glioblastoma.

[0109] In another aspect of the present disclosure, a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, Compounds 1-18, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, or a pharmaceutical composition thereof, is for use in modulating FPR1 activity. In another aspect, the use of a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, Compounds 1-18, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, or a pharmaceutical composition 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, which comprises administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, or a pharmaceutical composition thereof, comprising a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, Compounds 1-18, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing. In yet another aspect, a method of modulating FPR1 activity is disclosed herein, which comprises contacting the FPR1 with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, or a pharmaceutical composition thereof, comprising a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, Compounds 1-18, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing, in a subject.

[0110] Compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-8, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof may be administered once, twice, or three times daily, for example, the treatment of diseases, disorders, or conditions mediated by FPR1 signaling.

[0111] In some embodiments, compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB in amounts of 2 mg to 1500 mg or 5 mg to 1000 mg, compounds 1 to 18, their tautomers, deuterated derivatives of the compounds or tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are administered once, twice, or three times daily.

[0112] Compounds of formulas I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, their tautomers, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, intraoral buccally, vaginally, percutaneously, by patch, pump, or via implanted reservoir, and pharmaceutical compositions are formulated accordingly. Parenteral administration modes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration may also be performed by continuous infusion over a selected period. Other forms of administration envisioned in this disclosure are described in international patent applications WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142, and WO2015 / 023915.

[0113] The useful dosage or therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof described in this specification 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.

[0114] One of ordinary skill in the art will recognize that when the amount of a compound is disclosed, the related 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 1000 mg of its pharmaceutically acceptable salt" 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.

[0115] Non-limiting exemplary embodiments 1. Compounds of formula (I):

[0116]

Chemical formula

[0117] [Wherein, (i) Each Z 1 and Z 2 is independently selected from O, S, N, NR 4 , C(R 4 )2, and CR 4 , and at least one of Z <​​​​​​​​​​​​​​selected from R 5 is selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, (iii) R 1 is selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, or R 1 and Z 2 together with the atom to which they are attached form a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group, (iv) each R 2 and R 3 is independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, (v) each R ' and R " is independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, The linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, hydroxy, thiol, amino, cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, [[ID=5)}C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer, compound, or deuterated derivative of a tautomer, or a pharmaceutically acceptable salt thereof, optionally substituted with at least one group selected from the above. 2.R 1 However, R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 1, wherein is selected from linear and branched alkyl groups. 3.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 1 or 2, selected from optionally substituted 5- and 6-membered aryl groups. 4.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 3, wherein the compound is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 5.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 4, wherein the compound is selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 6.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 4, wherein the compound is selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 7.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 1 or 2, selected from optionally substituted 5- and 6-membered heteroaryl groups. 8.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 7 are selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 9.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 8 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 10.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 8 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 11.R 1 However, the compounds of Embodiment 1 or 2, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from substituted 3- to 6-membered cyclic alkyl groups. 12.R 1 However, the compounds of Embodiment 11, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 13.R 1 However, the compounds of Embodiment 12, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 14.R 1 The compounds of Embodiment 1 or 2, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, selected from optionally substituted 3- to 6-membered carbocyclic groups, optionally substituted alkenyl groups, and optionally substituted heterocyclic groups. 15.R 2 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1 to 14, selected from optionally substituted 5- and 6-membered heteroaryl groups. 16.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 1 to 15, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 17.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 16 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 18.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 16 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 19.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 1 to 15, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 20.R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1 to 19, selected from 5 and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups. 21.R 3 However, C2~C is substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 20, comprising branched alkyl groups. 22.R 3 The compounds of Embodiment 21, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 23. Compounds of formula (IIA):

[0118] [ka]

[0119] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv)R 4 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (v)Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 24. Compounds of formula (IIB):

[0120] [ka]

[0121] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 is selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, or R 1 and NR 4 These, together with the atoms to which they are bonded, form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv)R 4 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (v)Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 25.R 1 However, R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 23 or 24, wherein is selected from linear and branched alkyl groups. 26.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 23 or 24, selected from the substituted 5- and 6-membered aryl groups, depending on the circumstances. 27.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 26 are selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 28.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 27 are selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 29.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 27 are selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 30.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 23 or 24, selected from the substituted 5- and 6-membered heteroaryl groups, depending on the circumstances. 31.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 30 are selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 32.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 31 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 33.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 31 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 34.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 23 or 24 are selected from substituted 3- to 6-membered cyclic alkyl groups. 35.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 34 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 36.R 1 However, the compounds of Embodiment 35, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 37.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 23 or 24 are selected from the substituted 3- to 6-membered heterocyclic groups. 38.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 23 to 37, selected from the substituted 5- and 6-membered heteroaryl groups. 39.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 23 to 38, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 40.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 40 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 41.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 40 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 42.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 23 to 38, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 43.R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of the embodiments 23 to 38, selected from 5 and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups. 44.R 3 However, C1~C are substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 23 to 43, comprising branched alkyl groups. 45.R 3The compounds of Embodiment 44, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 46.R 4 However, C1~C are substituted in some cases. 10 Linear chain, C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from branched alkyl groups and C3-C6 cyclic alkyl groups, from any one of embodiments 23-45. 47.R 4 The compounds of Embodiment 45, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl. 48. Compounds of formula (IIIA):

[0122] [ka]

[0123] [In the formula, (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 49. Compounds of formula (IIIB):

[0124] [ka]

[0125] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 50.R 1 R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 48 or 49, wherein is selected from linear and branched alkyl groups. 51.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 48 or 49, selected from the substituted 5- and 6-membered aryl groups, as may be the case. 52.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 51 are selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 53.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 52 are selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 54.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 52 are selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 55.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 48 or 49, selected from the optionally substituted 5- and 6-membered heteroaryl groups. 56.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 55 are selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 57.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 56 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 58.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 56 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 59.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 48 or 49 are selected from substituted 3- to 6-membered cyclic alkyl groups. 60.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 59 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 61.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 60 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 62.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 48 or 49 are selected from the substituted 3- to 6-membered heterocyclic groups. 63.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 48 to 62, selected from the substituted 5- and 6-membered heteroaryl groups. 64.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 48 to 63, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 65.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 64 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 66.R 2However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 64 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 67.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 48 to 62, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 68.R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 48 to 62, wherein the compound is selected from a 5- and 6-membered heteroaryl group substituted with at least one group selected from a C1-C6 linear chain, a C3-C6 branched chain, and a C3-C6 cyclic alkyl group. 69.R 3 However, C1~C are substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 48 to 68, comprising branched alkyl groups. 70.R 3 The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 69, selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 71.R 4 However, C1~C are substituted in some cases. 10 Linear chain, C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from branched alkyl groups and C3-C6 cyclic alkyl groups, from any one of the compounds of Embodiments 48-70. 72.R 4The compounds of Embodiment 71, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl. 73. Compounds of formula (IVA):

[0126] [ka]

[0127] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 74. Compounds of formula (IVB):

[0128] [ka]

[0129] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R" These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 75.R 1 R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 73 or 74, wherein is selected from linear and branched alkyl groups. 76.R 1Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 73 or 74, selected from 5- and 6-membered aryl groups which may be substituted in some cases. 77.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 76, wherein the compound is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 78.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 77, wherein the compound is selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 79.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 77, wherein the compound is selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 80.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 73 or 74, selected from 5- and 6-membered heteroaryl groups which may be substituted in some cases. 81.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 80, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 82.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 81 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 83.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 81 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 84.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 73 or 74 are selected from substituted 3- to 6-membered cyclic alkyl groups. 85.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 84 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 86.R 1 However, the compounds of Embodiment 85, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 87.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 73 or 74, selected from a substituted 3- to 6-membered heterocyclic group. 88.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 73 to 87, selected from the substituted 5- and 6-membered heteroaryl groups. 89.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of embodiments 73 to 88, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 90.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 89 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 91.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 89 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 92.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 73 to 87, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 93.R 2A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 73 to 87, selected from 5 and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups. 94.R 3 However, C1~C are substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of embodiments 73 to 93, comprising branched alkyl groups. 95.R 3 The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 94, selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 96. Compounds of formula (VA):

[0130] [ka]

[0131] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R "These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 97. Compounds of formula (VB):

[0132] [ka]

[0133] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 98.R 1 However, R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 96 or 97, wherein is selected from a linear or branched alkyl group. 99.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 96 or 97, which is substituted by a group selected from 5- and 6-membered aryl groups. 100.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 99, selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 101.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 100, wherein the compound is selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 102.R 1 Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 100, wherein the compound is selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 103.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 96 or 97, selected from the optionally substituted 5- and 6-membered heteroaryl groups. 104.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 103 are selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 105.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 104 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 106.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 104 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 107.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 96 or 97, selected from a 3- to 6-membered cyclic alkyl group which may be substituted in some cases. 108.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 107 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 109.R 1 However, the compounds of Embodiment 108, tautomers, deuterated derivatives, or pharmaceutically acceptable salts are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 110.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 96 or 97, selected from a substituted 3- to 6-membered heterocyclic group. 111.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 96 to 110, selected from the substituted 5- and 6-membered heteroaryl groups. 112.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of embodiments 96 to 111, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 113.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 112 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 114.R2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 112 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 115.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 96 to 110, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 116.R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of the embodiments 96 to 110, selected from 5 and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups. 117.R 3 However, C1~C are substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from branched alkyl groups of any one of embodiments 96 to 116. 118.R 3 The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 117, selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 119.R 4 However, C1~C are substituted in some cases. 10 Linear chain, C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from branched alkyl groups and C3-C6 cyclic alkyl groups, from any one of embodiments 96-118. 120.R 4The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 119, selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl (cycloputyl), pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl. 121. Compounds of formula (VIA):

[0134] [ka]

[0135] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from, R5 is selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above.

[0136] 122. Compounds of formula (VIB):

[0137] [ka]

[0138] [In formula: (i)Y 1 It does not exist, or it is bound, O, S, or NR 5 Selected from R 5 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (ii)R 1 These are selected from linear, branched, and cyclic alkyl groups, alkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iii) Each R 2 and R 3 These are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. (iv) Each R ' and R " These are independently selected from hydrogen, linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. Linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, C1-C6 linear, branched, and cyclic alkyl groups, C2-C6 linear, branched, and cyclic alkenyl groups, C1-C6 linear, branched, and cyclic hydroxyalkyl groups, C1-C6 linear, branched, and cyclic alkoxy groups, C1-C6 linear, branched, and cyclic thioalkyl groups, C1-C6 linear, branched, and cyclic haloalkyl groups, C1-C6 linear, branched, and cyclic haloaminoalkyl groups, C1-C6 linear, branched, and cyclic halothioalkyl groups, C1-C6 linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3-6 membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above. 123.R 1 However, R is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 121 or 122, wherein is selected from linear and branched alkyl groups. 124.R 1A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 121 or 122, selected from the optionally substituted 5- and 6-membered aryl groups. 125.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 124 are selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 126.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 125 are selected from 5- and 6-membered aryl groups that are substituted with at least one fluoropolymer. 127.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 125 are selected from 5- and 6-membered aryl groups substituted with at least one chloro group. 128.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 121 or 122, selected from the optionally substituted 5- and 6-membered heteroaryl groups. 129.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 128 are selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 130.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 129 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 131.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 129 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 132.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 121 or 122 are selected from substituted 3- to 6-membered cyclic alkyl groups. 133.R 1However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 132 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one alkoxy group. 134.R 1 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 133 are selected from 3- to 6-membered cyclic alkyl groups substituted with at least one methoxy group. 135.R 1 However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 121 or 122, selected from a substituted 3- to 6-membered heterocyclic group. 136.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 121 to 135, selected from the optionally substituted 5- and 6-membered heteroaryl groups. 137.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 121 to 136, selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 138.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 137 are selected from 5- and 6-membered heteroaryl groups that are substituted with at least one fluoropolymer. 139.R 2 However, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 137 are selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro group. 140.R 2 However, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiments 121 to 136, selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 141.R 2A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 121 to 135, selected from 5 and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups. 142.R 3 However, C1~C are substituted in some cases. 10 Linear chain and C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 121 to 141, comprising a branched alkyl group. 143.R 3 The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Embodiment 142, selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 144.R 4 However, C1~C are substituted in some cases. 10 Linear chain, C2~C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from branched alkyl groups and C3-C6 cyclic alkyl groups, from any one of embodiments 121-143. 145.R 4 The compounds of Embodiment 144, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl. 146. Compounds selected from the 44 listed compounds described above, their tautomers, deuterated derivatives of those compounds or their tautomers, or pharmaceutically acceptable salts thereof. 147. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 146, and at least one pharmaceutically acceptable carrier. 148. A method for treating or alleviating a disease, disorder or condition mediated by signaling of formyl peptide receptor 1 (FPR1), comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt or pharmaceutical composition according to Embodiment 147 of any one of Embodiments 1 to 146 to a subject in need thereof. 149. A disease, disorder, or condition related to the CNS, including stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, paroxysmal disorders, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, and autosomal dominant cerebral artery disease with subcortical infarction (CAD). ASIL, spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hipper-Lindau disease, fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex focal pain syndrome I, and Diabetic neuropathy (Type II), diabetic neuropathy, alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitis syndrome, prion disease, myelitis, radiculitis, diabetes-related protein abnormalities, trans tyretin-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy. The method of Embodiment 148, selected from related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma. 150. The method of Embodiment 148 or 149, wherein the disease, disorder, or condition is a stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venous constrictive, and venous). 151. The method of Embodiment 148 or 149, wherein the disease, disorder, or condition is traumatic brain injury. 152. The method of Embodiment 148 or 149, wherein the disease, disorder, or condition is malignant glioma. 153. The method of Embodiment 152, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic ependymoma, and anaplastic ganglioglioma. 154. The method of Embodiment 153, wherein the malignant glioma is a glioblastoma. 155. The method of Embodiment 148 or 149, wherein the disease, disorder, or condition is selected from acute respiratory distress syndrome (ARDS), allergic conjunctivitis (AC), and dry eye syndrome (DES). [Examples]

[0139] (Example 1) Compound synthesis To fully understand this disclosure, the following examples are disclosed. These examples are for illustrative purposes only and should not be construed as limiting this disclosure in any way.

[0140] All specific and general compounds, as well as the intermediates disclosed for the preparation of those compounds, are considered to be part of this disclosure.

[0141] The compounds of this disclosure can be prepared according to standard chemical practices or as described herein. Throughout the following synthesis schemes, and in the descriptions for preparing the compounds of formulas (I), (II), (IIIa), (IIIb), and (IIIc), compounds 1-135, any pharmaceutically acceptable salts of those compounds, any of the aforementioned solvates, and any of the aforementioned deuterated derivatives, the following abbreviations are used: Abbreviation Boc2O = Di-tert-butyl dicarbonate DCM = Dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine DMAP = dimethylaminopyridine DMA = Dimethylacetamide DME = Dimethoxyethane DMF = Dimethylformamide DMSO = Dimethyl sulfoxide methoxy / EA = ethyl acetate EtOH = Ethanol HOAc = Acetic Acid KOAc = potassium acetate LiHMDS = Lithium bis(trimethylsilyl)amide MeMgBr = Methylmagnesium bromide MeOH = methanol NaOAc = Sodium Acetate NBS = N-bromosuccinimide Pd(dppf)2Cl2=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) PTSA = p-toluenesulfonic acid monohydrate rt = Room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospholinane-2,4,6-trioxide TEA = Triethylamine TFA = Trifluoroacetic Acid THF = Tetrahydrofuran TsCl=p-toluenesulfonyl chloride

[0142] Compound 1: (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide

[0143] [ka]

[0144] Step 1. Preparation of methyl 4-amino-3-bromo-1-methyl-1H-pyrazole-5-carboxylate: To a solution of methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (1.0 g, 6.4 mmol) in DCM (20 mL), NBS (1.37 g, 7.7 mmol) was added at 0°C under N2. The resulting solution was stirred at 0°C for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by combiflush (PE / EA = 1:3) to obtain the product methyl 4-amino-3-bromo-1-methyl-1H-pyrazole-5-carboxylate as a brown solid (0.96 g, 64%). Mass (m / z): 234.1, 236.1 [M+H] + .

[0145] General Step A. Preparation of Methyl 4-amino-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate: Methyl 4-amino-3-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.0 g, 4.3 mmol), (4-fluorophenyl)boronic acid (896 mg, 6.4 mmol), and Na2CO3 (1.35 g, 12.8 mmol) were dissolved in a mixed solvent of dioxane and H2O (33 mL, 10 / 1 (v / v)), to which Pd(dppf)Cl2 (312 mg, 0.42 mmol) was added under N2. The resulting mixture was stirred at 100°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by combiflush (PE / EA = 1:1) to obtain the product methyl 4-amino-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate as a yellow solid (856 mg, 80%). Mass (m / z): 250.1 [M+H] + .

[0146] General Step B1. Preparation of Methyl 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate: LiHMDS (1.2 mL, 1.2 mmol, 1N solution in THF) was added dropwise to a solution of 4-amino-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate (150 mg, 0.60 mmol) in THF (10 mL) under N2 at -78°C. The resulting solution was stirred at -78°C for 1 hour, and then 4-cyanobenzenesulfonyl chloride (182 mg, 0.90 mmol) was added. The mixture was stirred further at -78°C for 3 hours, and then the reaction product was quenched with saturated aqueous solution of NH4Cl (20 mL). The aqueous medium was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium 2SO4, and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash column chromatography (PE / EA = 1:1) to obtain the product methyl 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate as a white solid (164 mg, 65%). Mass (m / z): 437.0 [M + Na] + .

[0147] General Step C. Preparation of 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid: 100 mg, 0.24 mmol of 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate was added to a solution of MeOH and H2O (8 mL, 3:1 (v / v)) with NaOH (96 mg, 2.4 mmol). The resulting mixture was stirred under N2 at 60°C for 16 hours. The organic solvent was removed under reduced pressure. The aqueous medium was acidified to pH 5-6 with 1N HCl aqueous solution and then extracted with EA (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated and dried to obtain the product 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid as a white solid (73 mg, 75%). Mass (m / z): 401.0 [M+H] + .

[0148] General Step D. Preparation of (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 1): To a solution of 4-((4-cyanophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (73 mg, 0.18 mmol) in DCM (10 mL), (S)-3,3-dimethylbutan-2-amine (27 mg, 0.27 mmol), DIEA (117 mg, 0.91 mmol), and T3P (173 mg, 0.54 mmol) were added sequentially. The resulting solution was stirred under N2 at ambient temperature for 3 hours, and then partitioned with H2O (50 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under vacuum, and the crude residue was purified by combiflush (DCM / MeOH = 10:1) to obtain the product (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 1) as a white solid (54 mg, 61%). Mass (m / z): 484.0 [M+H] + .

[0149] Compound 2: 3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-N-propyl-1H-pyrazole-5-carboxamide

[0150] [ka]

[0151] Step 1. Methyl 3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxylate was prepared as a yellow solid (600 mg, 85%) according to general step B1. Mass (m / z): 390.1 [M+H] + .

[0152] Step 2. Following general Step C, 3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxylic acid was prepared as a white solid (605 mg, 99%). Mass (m / z): 376.1 [M+H] + .

[0153] Step 3. Following general Step D, 3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-N-propyl-1H-pyrazole-5-carboxamide (Compound 2) was prepared as a white solid (57 mg, 51%). Mass (m / z): 417.0 [M+H] + .

[0154] Compound 3: (S)-N-(sec-butyl)-3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxamide

[0155] [ka]

[0156] Step 1. Following general Step D, (S)-N-(sec-butyl)-3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxamide (compound 3) was prepared as a white solid (39 mg, 35%). Mass (m / z): 431.0 [M+H] + .

[0157] Compound 4: 3-(4-fluorophenyl)-N-(2-hydroxyethyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxamide

[0158] [ka]

[0159] Step 1. Following general Step D, 3-(4-fluorophenyl)-N-(2-hydroxyethyl)-1-methyl-4-(phenylsulfonamide)-1H-pyrazole-5-carboxamide (compound 4) was prepared as a white solid (27 mg, 24%). Mass (m / z): 418.9 [M+H] + .

[0160] Compound 5: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxamide

[0161] [ka]

[0162] Step 1. Following general Step A, methyl 4-amino-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxylate was prepared as a brown solid (456 mg, 85%). Mass (m / z): 233.1 [M+H] + .

[0163] Step 2. Following general step B1, methyl 4-((4-chloro-N-((4-chlorophenyl)sulfonyl)phenyl)sulfonamide)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxylate was prepared as a brown solid (400 mg, 79%). Mass (m / z): 580.8 [M+H] + .

[0164] Step 3. Preparation of 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxylic acid: To a solution of methyl 4-((4-chloro-N-((4-chlorophenyl)sulfonyl)phenyl)sulfonamide)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxylate (400 mg, 0.68 mmol) in EtOH (10 mL), KOH (77 mg, 1.37 mmol) was added. The resulting mixture was stirred under N2 at 95°C for 12 hours and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC [column: Gemini-C18, 150 × 21.2 mm, 5 μm; eluent: 10-50% MeCN (0.1% TFA) in H2O] to obtain the product 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxylic acid as a white solid (50 mg, 18%). Mass (m / z): 392.8 [M+H] + .

[0165] Step 4. Following general Step D, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(pyridine-4-yl)-1H-pyrazole-5-carboxamide (compound 5) was prepared as a white solid (55 mg, 90%). Mass (m / z): 475.6 [M+H] + .

[0166] Compound 6: N-((S)-3,3-dimethylbutan-2-yl)-3-((1s,4R)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0167] [ka]

[0168] Step 1. Following general Step D, (1s,4s)-4-hydroxy-N-methoxy-N-methylcyclohexane-1-carboxamide was prepared as a yellow oily substance (9.2 g, 71%). Mass (m / z): 188.1 [M+H] + .

[0169] Step 2. Preparation of (1s,4s)-N,4-dimethoxy-N-methylcyclohexane-1-carboxamide: To a solution of (1s,4s)-4-hydroxy-N-methoxy-N-methylcyclohexane-1-carboxamide (9.2 g, 49 mmol) in DMF (100 mL), NaH (60% dispersion in mineral oil, 2.95 g, 73 mmol) was added at 0°C. The resulting mixture was stirred under N2 at ambient temperature for 30 minutes, and then MeI (10.5 g, 73 mmol) was added. The reaction mixture was further stirred under N2 at ambient temperature for 16 hours, and then diluted with water (200 mL). The aqueous solution was extracted with EA (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated and dried to obtain the product (1s,4s)-N,4-dimethoxy-N-methylcyclohexane-1-carboxamide as a brown solid (4.1 g, 40%). Mass (m / z): 202.0 [M+H] + .

[0170] Step 3.1 Preparation of ((1s,4s)-4-methoxycyclohexyl)ethane-1-one: (1s,4s)-N,4-dimethoxy-N-methylcyclohexane-1-carboxamide (3.1 g, 15 mmol) was added dropwise to a solution of (1s,4s)-N,4-dimethoxy-N-methylcyclohexane-1-carboxamide (20 mL) in THF (20 mL) under N2 conditions at 0°C. The resulting solution was stirred under N2 conditions at ambient temperature for 3 hours and then diluted with saturated aqueous solution of NH4Cl (30 mL). The aqueous medium was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA = 5:1) to obtain the product 1-((1s,4s)-4-methoxycyclohexyl)ethane-1-one as a yellow oily substance (2.4 g, 100%). Mass (m / z): 157.1 [M+H] + .

[0171] Step 4. (General Step E) Preparation of ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxobutanoate: LiHMDS (15.4 mL, 1N solution in THF, 15.4 mmol) was added dropwise to a solution of 1-((1s,4s)-4-methoxycyclohexyl)ethane-1-one (2.41 g, 15.4 mmol) and diethyl oxalate (2.25 g, 15.4 mmol) in THF (30 mL) under N2 at -78°C. The resulting solution was stirred under N2 at -78°C for 1 hour and then diluted with water (40 mL). The aqueous solution was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated and dried to obtain the product ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxobutanoate as a yellow oily substance (3.9 g, 100%). Mass (m / z): 257.1 [M+H] + .

[0172] Step 5. (General Step F) Preparation of rac-ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxo-3-((E)-phenyldiazenyl)butanoate: A stirring solution of aniline (4.91 g, 52.8 mmol) in 10 mL of 5N hydrochloric acid aqueous solution was added dropwise at 0°C to a solution of sodium nitrite (3.64 g, 52.8 mmol) in 10 mL of water (ice-cooled). The resulting solution was stirred at 0°C for 1 hour, and then ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxobutanoate (4.5 g, 18 mmol) and sodium acetate (2.89 g, 35.2 mmol) were added dropwise to an ice-cooled suspension in a mixed solvent of ethanol and water (30 mL, 1:1 (v / v)). The mixture was further stirred at 0-5°C for 16 hours, then diluted with water (50 mL). The aqueous solution was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated and dried to obtain the product rac-ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxo-3-((E)-phenyldiazenyl)butanoate as a yellow solid (3.7 g, 58%). Mass (m / z): 361.0 [M+H] + .

[0173] Step 6. (General Step G) Preparation of ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-5-carboxylate: A solution of methylhydrazine sulfate (1.19 g, 8.25 mmol) in EtOH (5 mL) was basicized to pH 8-9 with 5N NaOH aqueous solution, and then added to a solution of rac-ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxo-3-((E)-phenyldiazenyl)butanoate (2.0 g, 5.5 mmol) in HOAc (15 mL). The resulting solution was stirred at 60°C for 3 hours and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA = 5:1 to 2:1) to obtain the product ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-5-carboxylate as a brown solid (600 mg, 29%), and its positional isomer ethyl 5-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-3-carboxylate as a brown solid (750 mg, 37%). Ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-5-carboxylate: Mass (m / z): 371.1 [M+H] + , Rt=1.489 minutes (2.0 minutes); Ethyl 5-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-3-carboxylate: Mass (m / z): 371.1 [M+H] + , Rt=1.369 minutes (2.0 minutes)

[0174] Step 7. (General Step H) Preparation of ethyl 4-amino-3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate: To a solution of ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((E)-phenyldiazenyl)-1H-pyrazole-5-carboxylate (600 mg, 1.6 mmol) in a mixed solvent of EtOH (16 mL) and water (2 mL), Na2S2O4 (2.8 g, 16 mmol) was added. The resulting solution was stirred at 100 °C for 16 hours, and then the organic solvent was removed under vacuum. The aqueous solution was diluted with water (30 mL) and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA = 2:1) to obtain the product ethyl 4-amino-3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate as a brown solid (170 mg, 37%). Mass (m / z): 282.2 [M+H] + .

[0175] Step 8. (General Step B2) Preparation of ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxylate: A solution of ethyl 4-amino-3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate (170 mg, 0.60 mmol), TsCl (172 mg, 0.90 mmol), and DMAP (74 mg, 0.60 mmol) in pyridine (10 mL) was stirred at ambient temperature for 3 hours and then filtered. The precipitate was rinsed with 10% EA / PE and dried to obtain the product ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxylate as a brown solid (330 mg, purity 60%, 76%). This was used in the next step without further purification. Mass (m / z): 436.0 [M+H] + .

[0176] Step 9. Following general step C, 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxylic acid was prepared as a brown solid (150 mg, 64%). Mass (m / z): 408.1 [M+H] + .

[0177] Step 10. Following general step D, N-((S)-3,3-dimethylbutan-2-yl)-3-((1s,4R)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 6) was prepared as a yellow solid (100 mg, 55%). Mass (m / z): 491.2 [M+H] + .

[0178] Compound 7: N-((S)-3,3-dimethylbutan-2-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxamide

[0179] [ka]

[0180] Step 1. Following general Step G, ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-3-carboxylate was prepared as a brown solid (700 mg, purity 60%, 86%). This was used without further purification in the next step. Mass (m / z): 357.1 [M+H] + .

[0181] Step 2. Preparation of 1-(tert-butyl)3-ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-1,3-dicarboxylate: Boc2O (596 mg, 2.7 mmol) was added to a solution of ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-3-carboxylate (650 mg, 60% purity, 1.1 mmol), TEA (368 mg, 3.6 mmol), and DMAP (22 mg, 0.18 mmol) in DCM (15 mL). The resulting solution was stirred at ambient temperature for 3 hours and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=5:1) to obtain the product 1-(tert-butyl)3-ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-1,3-dicarboxylate as a yellow solid (110 mg, 22%). Mass (m / z): 457.1 [M+H] + .

[0182] Step 3. Preparation of 1-(tert-butyl)3-ethyl4-amino-5-((1s,4s)-4-methoxycyclohexyl)-1H-pyrazole-1,3-dicarboxylate: 10% Pd / C (140 mg, 20% wt / wt) was added to a solution of 1-(tert-butyl)3-ethyl5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-1,3-dicarboxylate (700 mg, 1.53 mmol) in MeOH (7 mL) under N2. The reaction flask was evacuated under vacuum and then refilled with H2 (1 atm). The resulting mixture was stirred under an H2 atmosphere at ambient temperature for 16 hours and then filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the product 1-(tert-butyl)3-ethyl4-amino-5-((1s,4s)-4-methoxycyclohexyl)-1H-pyrazole-1,3-dicarboxylate as a colorless oily substance (610 mg, 86%). Mass (m / z): 268.1[M-C5H8O2+H] + .

[0183] Step 4. Following general step B2, ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxylate was prepared as a yellow solid (137 mg, 23%). Mass (m / z): 422.0 [M+H] + .

[0184] Step 5. Following general Step C, 5-((1s,4s)-4-methoxycyclohexyl)-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxylic acid was prepared as a yellow solid (87 mg, 62%). Mass (m / z): 393.8 [M+H] + .

[0185] Step 6. Following general Step D, N-((S)-3,3-dimethylbutan-2-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxamide (compound 7) was prepared as a white solid (17 mg, 15%). Mass (m / z): 477.8 [M+H] + .

[0186] Compound 8: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxamide

[0187] [ka]

[0188] Step 1. Following general step E, ethyl 2,4-dioxo-4-(tetrahydro-2H-pyran-4-yl)butanoate was prepared as a brown oily substance (900 mg, 50%). Mass (m / z): 229.0 [M+H] + .

[0189] Step 2. Following general step F, rac-ethyl(E)-2,4-dioxo-3-(phenyldiazenyl)-4-(tetrahydro-2H-pyran-4-yl)butanoate was prepared as a brown solid (1.38 g, 100%). Mass (m / z): 332.8 [M+H] + .

[0190] Step 3. Following general Step G, ethyl(E)-1-methyl-4-(phenyldiazenyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate was prepared together as a brown solid (630 mg, 32%), and its positional isomer, ethyl(E)-1-methyl-4-(phenyldiazenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate, was prepared as a brown solid (350 mg, 17%). Ethyl(E)-1-methyl-4-(phenyldiazenyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate: Mass (m / z): 342.9 [M+H] + , Rt=1.417 minutes (2.0 minutes) Ethyl(E)-1-methyl-4-(phenyldiazenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate: Mass (m / z): 342.9 [M+H] + , Rt=1.530 minutes (2.0 minutes)

[0191] Step 4. Following general step H, ethyl 4-amino-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate was prepared as a yellow solid (230 mg, 39%). Mass (m / z): 254.1 [M+H] + .

[0192] Step 5. Following general step B2, ethyl 4-((4-chlorophenyl)sulfonamide)-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate was prepared as a brown solid (450 mg, purity 60%, 60%), which was used without further purification in the next step. Mass (m / z): 427.7 [M+H] + .

[0193] Step 6. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylic acid was prepared as a brown solid (300 mg, 71%). Mass (m / z): 399.7 [M+H] + .

[0194] Step 7. Following general step D, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxamide (compound 8) was prepared as a white solid (20 mg, 41%). Mass (m / z): 482.8 [M+H] + .

[0195] Compound 9: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide

[0196] [ka]

[0197] Step 1. Following general step H, ethyl 4-amino-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a colorless oily substance (100 mg, 42%). Mass (m / z): 254.1 [M+H] + .

[0198] Step 2. Following general step B2, ethyl 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a colorless oily substance (75 mg, 42%). Mass (m / z): 428.0 [M+H] + .

[0199] Step 3. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylic acid was prepared as a colorless solid (80 mg, 82%). Mass (m / z): 400.1 [M+H] + .

[0200] Step 4. Following general Step D, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide (compound 9) was prepared as a white solid (30 mg, 31%). Mass (m / z): 482.7 [M+H] + .

[0201] Compound 10: (S)-4-((4-chlorophenyl)sulfonamide)-1-cyclopropyl-N-(3,3-dimethylbutan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide

[0202] [ka]

[0203] Step 1. Following general Step G, ethyl(E)-1-cyclopropyl-4-(phenyldiazenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow oily substance (600 mg, 23%). Mass (m / z): 368.9 [M+H] + .

[0204] Step 2. Following general step H, ethyl 4-amino-1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow solid (220 mg, 42%). Mass (m / z): 280.0 [M+H] + .

[0205] Step 3. Following general step B2, ethyl 4-((4-chlorophenyl)sulfonamide)-1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow solid (200 mg, 58%). Mass (m / z): 453.7 [M+H] + .

[0206] Step 4. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylic acid was prepared as a yellow oily substance (200 mg, 100%). Mass (m / z): 425.6 [M+H] + .

[0207] Step 5. Following general Step D, (S)-4-((4-chlorophenyl)sulfonamide)-1-cyclopropyl-N-(3,3-dimethylbutan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide (compound 10) was prepared as a white solid (97 mg, 31%). Mass (m / z): 508.7 [M+H] + .

[0208] Compound 11: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide

[0209] [ka]

[0210] Step 1. Preparation of ethyl 5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxylate: A solution of ethyl 2,4-dioxo-4-(tetrahydro-2H-pyran-4-yl)butanoate (500 mg, 2.2 mmol) and hydroxylamine hydrochloride (181 mg, 2.6 mmol) in EtOH (15 mL) was stirred under N2 at 90°C for 5 hours and then concentrated under vacuum. The residue was partitioned between water (20 mL) and EA (30 mL), and the aqueous medium was further extracted with EA (30 mL x 2). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated and dried to obtain the product ethyl 5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxylate as a brown oily substance (425 mg, 86%). Mass (m / z):226.0[M+H] + .

[0211] Step 2. Following general Step C, 5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxylic acid was prepared as a yellow solid (160 mg, 81%). Mass (m / z): 219.9 [M+Na] + .

[0212] Step 3. Following general Step D, (S)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide was prepared as a yellow solid (145 mg, 91%). Mass (m / z): 281.0 [M+H] + .

[0213] Step 4. Preparation of (S)-N-(3,3-dimethylbutan-2-yl)-4-nitro-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide: (S)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide (145 mg, 0.52 mmol) was dissolved in concentrated H2SO4 (6 mL) and 100% HNO3 (2 mL) was added. The resulting solution was stirred at ambient temperature for 16 hours and then slowly diluted with ice-cold water (20 mL). The aqueous solution was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to obtain the product (S)-N-(3,3-dimethylbutan-2-yl)-4-nitro-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide as a yellow solid (120 mg, 71%). Mass (m / z): 325.9 [M+H] + .

[0214] Step 5. Preparation of (S)-4-amino-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide: Zn powder (50 mg, 0.77 mmol) was added to a solution of (S)-N-(3,3-dimethylbutan-2-yl)-4-nitro-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide (50 mg, 0.15 mmol) and NH4Cl (41 mg, 0.77 mmol) in a mixed solvent of EtOH (4 mL) and water (1 mL). The resulting mixture was stirred at 70°C for 3 hours and then filtered. The filtrate was concentrated under vacuum. The residue was partitioned between water (15 mL) and EA (10 mL), and the aqueous medium was further extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then filtered. The filtrate was concentrated and dried to obtain the product (S)-4-amino-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide as a yellow solid (33 mg, 72%). Mass (m / z): 296.0 [M+H] + .

[0215] Step 6. Following general step B2, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide (Example 11) was prepared as a white solid (14 mg, 26%). Mass (m / z): 469.9 [M+H] + .

[0216] Compound 12: (S)-4-((4-cyclopropylphenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide

[0217] [ka]

[0218] Step 1. Following general step B2, (S)-4-((4-cyclopropylphenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide (compound 12) was prepared as a white solid (16 mg, 9%). Mass (m / z): 475.8 [M+H] + .

[0219] Compound 13: N-((S)-3,3-dimethylbutan-2-yl)-5-((1s,4R)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxamide

[0220] [ka]

[0221] Step 1. Following general step H, ethyl 4-amino-5-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-3-carboxylate was prepared as a yellow solid (290 mg, 45%). Mass (m / z): 282.1 [M+H] + .

[0222] Step 2. Following general Step B2, ethyl 5-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxylate was prepared as a brown solid (330 mg, purity 60%, 62%). Mass (m / z): 436.0 [M+H] + .

[0223] Step 3. Following general Step C, 5-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxylic acid was prepared as a brown solid (150 mg, 64%). Mass (m / z): 408.0 [M+H] + .

[0224] Step 4. Following general Step D, N-((S)-3,3-dimethylbutan-2-yl)-5-((1s,4R)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-carboxamide (compound 13) was prepared as a yellow solid (200 mg, 52%). Mass (m / z): 491.1 [M+H] + .

[0225] Compound 14: (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0226] [ka]

[0227] Step 1. Following general step B1, methyl 5-bromo-2-methyl-4-[(4-methylbenzene)sulfonamide]pyrazole-3-carboxylate was prepared as a yellow solid (2.6 g, 80%). Mass (m / z): 387.8 [M+H] + .

[0228] Step 2. Following general Step C, 5-bromo-2-methyl-4-[(4-methylbenzene)sulfonamide]pyrazole-3-carboxylic acid was prepared as a yellow solid (2.36 g, 90%). Mass (m / z): 373.8 [M+H] + .

[0229] Step 3. Following general Step D, 5-bromo-4-[(4-methylbenzene)sulfonamide]-N-[(2S)-3,3-dimethylbutan-2-yl]-2-methylpyrazole-3-carboxamide was prepared as a yellow solid (1.3 g, 50%). Mass (m / z): 456.7 [M+H] + .

[0230] Step 4. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 14) was prepared as a white solid (22 mg, 25%). Mass (m / z): 499.0 [M+H] + .

[0231] Compound 15: (S)-N-(3,3-dimethylbutan-2-yl)-3-(3-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0232] [ka]

[0233] Step 1. Preparation of 2-(3-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-bromo-3-(methoxymethyl)benzene (500 mg, 2.5 mmol) in dioxane (20 mL), bis(pinacolato)diborone (947 mg, 3.7 mmol), KOAc (1.21 g, 12.4 mmol), and Pd(dppf)Cl2 (182 mg, 0.25 mmol) were added under N2. The resulting mixture was stirred under N2 at 90°C for 16 hours and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=10:1) to obtain the product 2-(3-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oily substance (404 mg, 65%). Mass (m / z):249.0[M+H] + .

[0234] Step 2. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(3-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 15) was prepared as a white solid (12 mg, 16%). Mass (m / z): 498.8 [M+H] + .

[0235] Compound 16: (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0236] [ka]

[0237] Step 1. Following general Step A, (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 16) was prepared as a yellow solid (15 mg, 21%). Mass (m / z): 460.9 [M+H] + .

[0238] Compound 17: tert-butyl(S)-4-(5-((3,3-dimethylbutan-2-yl)carbamoyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0239] [ka]

[0240] Step 1. Following general Step A, tert-butyl(S)-4-(5-((3,3-dimethylbutan-2-yl)carbamoyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 17) was prepared as a white solid (27 mg, 31%). Mass (m / z): 581.7 [M+Na] + .

[0241] Compound 18: (S)-N-(3,3-dimethylbutan-2-yl)-3-(4,4-dimethylcyclohexa-1-en-1-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0242] [ka]

[0243] Step 1. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(4,4-dimethylcyclohexa-1-en-1-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 18) was prepared as a white solid (20 mg, 31%). Mass (m / z): 486.8 [M+H] + .

[0244] Compound 19: 4-((4-chlorophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1S,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide

[0245] [ka]

[0246] Step 1. Preparation of 4-methoxycyclohexa-1-en-1-yltrifluoromethanesulfonate: A solution of 4-methoxycyclohexane-1-one (2 g, 15.6 mmol) in THF (20 mL) was stirred, and a solution of LiHMDS in THF (23.4 mL, 1 N, 23.4 mmol) was added at -78°C. The resulting solution was stirred at -78°C for 30 minutes, and then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (6.68 g, 18 mmol) in THF (10 mL) was added. The mixture was stirred further at -78°C for 1 hour, and then diluted with saturated aqueous solution of NH4Cl (50 mL). The aqueous solution was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude residue was purified by flash column chromatography (PE:EA=5:1) to obtain the product 4-methoxycyclohexa-1-en-1-yltrifluoromethanesulfonate as a brown oily substance (2.4 g, 60%).

[0247] Step 2.2 Preparation of (4-methoxycyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 4-methoxycyclohexa-1-en-1-yltrifluoromethanesulfonate (1 g, 3.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.16 g, 4.56 mmol), and KOAc (1.12 g, 11.4 mmol) in dioxane (20 mL), Pd(dppf)Cl2 (140 mg, 0.19 mmol) was added. The reaction mixture was stirred under N2 at 100°C for 16 hours and then concentrated under vacuum. The crude residue was purified by flash column chromatography (PE / EA = 10:1) to obtain the product 2-(4-methoxycyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oily substance (500 mg, 58%).

[0248] Step 3. Following general Step A, methyl 4-amino-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a yellow solid (260 mg, 99%). Mass (m / z): 266.1 [M+H] + .

[0249] Step 4. (General Step I) Preparation of methyl 4-amino-3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate: A mixture of methyl 4-amino-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxylate (260 mg, 0.98 mmol) and 10% Pd / C (52 mg, 20% wt / wt) in MeOH (10 mL) was stirred at ambient temperature under an H2 atmosphere for 16 hours. The resulting mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude residue was purified by preparative TLC (PE / EA = 2:1) to obtain the product methyl 4-amino-3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate as a light brown solid (150 mg, 57%). Mass (m / z): 268.1 [M + H] + .

[0250] Step 5. Following general step B2, methyl 4-((4-chlorophenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a light brown solid (230 mg, 92%). Mass (m / z): 442.0 [M+H] + .

[0251] Step 6. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a yellow solid (180 mg, 80%). Mass (m / z): 427.9 [M+H] + .

[0252] Step 7. Following general Step D, 4-((4-chlorophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1S,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 19) was prepared as a yellow solid (160 mg, 74%). Mass (m / z): 511.0 [M+H] + .

[0253] Compound 20: 4-((4-cyclopropylphenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1S,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide

[0254] [ka]

[0255] Step 1. Following general step B2, methyl 4-((4-cyclopropylphenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a brown solid (140 mg, 83%). Mass (m / z): 447.9 [M+H] + .

[0256] Step 2. Following general Step C, 4-((4-cyclopropylphenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a white solid (150 mg, 88%). Mass (m / z): 434.1 [M+H] + .

[0257] Step 3. Following general Step D, 4-((4-cyclopropylphenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1S,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 20) was prepared as a white solid (40 mg, 28%). Mass (m / z): 517.1 [M+H] + .

[0258] Compound 21: 4-((4-cyanophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1S,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide

[0259] [ka]

[0260] Step 1. Following general step B2, methyl 4-((4-cyanophenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a white solid (550 mg, 62%). Mass (m / z): 433.1 [M+H] + .

[0261] Step 2. Following general Step C, 4-((4-cyanophenyl)sulfonamide)-3-((1S,4S)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a yellow solid (470 mg, 78%). Mass (m / z): 418.9 [M+H] + .

[0262] Step 3. Following general Step D, 4-((4-cyanophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-((1s,4R)-4-methoxycyclohexyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 21) was prepared as a white solid (114 mg, 20%). Mass (m / z): 501.9 [M+H] + .

[0263] Compound 22: 4-((4-chlorophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0264] [ka]

[0265] Step 1. Following general step B2, methyl 4-((4-chlorophenyl)sulfonamide)-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a colorless oily substance (66 mg, 39%). Mass (m / z): 462.1 [M+Na] + .

[0266] Step 2. Following general step C, 4-((4-chlorophenyl)sulfonamide)-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a white solid (50 mg, 78%). Mass (m / z): 426.1 [M+H] + .

[0267] Step 3. Following general Step D, 4-((4-chlorophenyl)sulfonamide)-N-((S)-3,3-dimethylbutan-2-yl)-3-(4-methoxycyclohexa-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 22) was prepared as a white solid (38 mg, 63%). Mass (m / z): 509.2 [M+H] + .

[0268] Compound 23: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole-5-carboxamide

[0269] [ka]

[0270] Step 1. Following general Step A, methyl 4-amino-1-methyl-3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow solid (2 g, 80%). Mass (m / z): 294.0 [M+H] + .

[0271] Step 2. Following the general Step I, methyl 4-amino-1-methyl-3-(1,4-dioxaspiro[4.5]decano-8-yl)-1H-pyrazole-5-carboxylate was prepared as a brown solid (2 g, 100%). Mass (m / z): 296.1 [M+H] + .

[0272] Step 3. Following general step B2, methyl 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(1,4-dioxaspiro[4.5]decano-8-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow solid (330 mg, 62%). Mass (m / z): 469.8 [M+H] + .

[0273] Step 4. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole-5-carboxylic acid was prepared as a white solid (320 mg, 90%). Mass (m / z): 455.8 [M+H] + .

[0274] Step 5. Following general Step D, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole-5-carboxamide (compound 23) was prepared as a white solid (206 mg, 53%). Mass (m / z): 539.2 [M+H] + .

[0275] Compound 24: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-pyrazole-5-carboxamide

[0276] [ka]

[0277] Step 1. Following general step B2, methyl 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow oily substance (415 mg, 65%). Mass (m / z): 468.0 [M+H] + .

[0278] Step 2. Following general Step C, 4-((4-chlorophenyl)sulfonamide)-1-methyl-3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-pyrazole-5-carboxylic acid was prepared as a yellow oily substance (400 mg, 82%). Mass (m / z): 454.1 [M+H] + .

[0279] Step 3. Following general Step D, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-pyrazole-5-carboxamide (compound 24) was prepared as a white solid (225 mg, 47%). Mass (m / z): 537.2 [M+H] + .

[0280] Compound 25: (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide

[0281] [ka]

[0282] Step 1. Following general Step A, methyl 4-amino-3-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a yellow solid (1.22 g, 96%). Mass (m / z): 238.1 [M+H] + .

[0283] Step 2. Following the general Step I, methyl 4-amino-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow oily substance (1.19 g, 96%). Mass (m / z): 240.0 [M+H] + .

[0284] Step 3. Following general step B2, methyl 4-((4-cyanophenyl)sulfonamide)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a white solid (1.76 g, 87%). Mass (m / z): 405.0 [M+H] + .

[0285] Step 4. Following general Step C, 4-((4-cyanophenyl)sulfonamide)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylic acid was prepared as a yellow oily substance (250 mg, 78%). Mass (m / z): 391.2 [M+H] + .

[0286] Step 5. Following general Step D, (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide (compound 25) was prepared as a white solid (75 mg, 24%). Mass (m / z): 474.2 [M+H] + .

[0287] Compound 26: (S)-4-((4-cyclopropylphenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide

[0288] [ka]

[0289] Step 1. Methyl 4-((4-cyclopropylphenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a white solid (370 mg, 71%) according to general step B1. Mass (m / z): 430.0 [M+H] + .

[0290] Step 2. Following general Step C, 4-((4-cyclopropylphenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a yellow solid (360 mg, 90%). Mass (m / z): 416.0 [M+H] + .

[0291] Step 3. Following general Step D, (S)-4-((4-cyclopropylphenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 26) was prepared as a white solid (165 mg, 45%). Mass (m / z): 499.0 [M+H] + .

[0292] Compound 27: (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxamide

[0293] [ka]

[0294] Step 1. Following general step B1, methyl 3-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a white solid (230 mg, 43%). Mass (m / z): 420.1 [M+H] + .

[0295] Step 2. Following general Step C, 3-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a white solid (200 mg, 86%). Mass (m / z): 406.1 [M+H] + .

[0296] Step 3. Following general Step D, (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxamide (compound 27) was prepared as a white solid (39 mg, 15%). Mass (m / z): 489.1 [M+H] + .

[0297] Compound 28: (S)-4-((4-cyano-2-fluorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide

[0298] [ka]

[0299] Step 1. Following general step B1, methyl 4-((4-cyano-2-fluorophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a white solid (220 mg, 57%). Mass (m / z): 433.0 [M+H] + .

[0300] Step 2. Following general Step C, 4-((4-cyano-2-fluorophenyl)sulfonamide)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a yellow solid (210 mg, 97%). Mass (m / z): 418.8 [M+H] + .

[0301] Step 3. Following general Step D, (S)-4-((4-cyano-2-fluorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 28) was prepared as a white solid (27 mg, 11%). Mass (m / z): 501.8 [M+H] + .

[0302] Compound 29: (S)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0303] [ka]

[0304] Step 1. Following general Step A, (S)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 29) was prepared as a white solid (28 mg, 42%). Mass (m / z): 494.8 [M+H] + .

[0305] Compound 30: (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide and Compound 31: (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0306] [ka]

[0307] Step 1. Following general Step A, (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 30) was prepared as a yellow solid (15 mg, 21%). Mass (m / z): 460.9 [M+H] + .

[0308] Step 2. Preparation of (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 31): (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (30.0 mg, 0.065 mmol) was dissolved in a mixed solvent of i-PrOH and DCM (5 mL, 9:1 (v / v)), to which Mn(dpm)3 (0.870 mg, 0.0014 mmol) and phenylsilane (14.1 mg, 0.130 mmol) were added at 0°C. The resulting solution was stirred under N2 at ambient temperature for 16 hours and then concentrated under vacuum. The crude residue was purified by preparative TLC (PE / EA=1:1) to obtain the product (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 31) as a white solid (12.6 mg, 36%). Mass (m / z): 460.9 [M-17] + .

[0309] Compound 32: 3-(4-cyanocyclohexa-1-en-1-yl)-N-((S)-3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0310] [ka]

[0311] Step 1. Following general Step A, 3-(4-cyanocyclohexa-1-en-1-yl)-N-((S)-3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 32) was prepared as a white solid (41 mg, 55%). Mass (m / z): 483.9 [M+H] + .

[0312] Compound 33: (S)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0313] [ka]

[0314] Step 1. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)phenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 33) was prepared as a white solid (35 mg, 38%). Mass (m / z): 499.0 [M+H] + .

[0315] Compound 34: (S)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-3-(3-(trifluoromethoxy)phenyl)-1H-pyrazole-5-carboxamide

[0316] [ka]

[0317] Step 1. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamide)-3-(3-(trifluoromethoxy)phenyl)-1H-pyrazole-5-carboxamide (compound 34) was prepared as a white solid (25 mg, 25%). Mass (m / z): 538.9 [M+H] + .

[0318] Compound 35: (S)-N-(3,3-dimethylbutan-2-yl)-3-(3-isobutoxyphenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide

[0319] [ka]

[0320] Step 1. Preparation of 4,4,5,5-tetramethyl-2-[3-(2-methylpropoxy)phenyl]-1,3,2-dioxaborolane: To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.00 g, 4.5 mmol) in DMF (10 mL), K2CO3 (1.87 g, 13.5 mmol) and 1-bromo-2-methylpropane (0.740 g, 5.4 mmol) were added. The resulting mixture was stirred at 100°C for 16 hours and then diluted with H2O (50 mL). The aqueous solution was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (PE:EA = 0-7%) to obtain the product 4,4,5,5-tetramethyl-2-[3-(2-methylpropoxy)phenyl]-1,3,2-dioxaborolane as a colorless oily substance (600 mg, 44%). Mass (m / z): 277.0 [M+H] + .

[0321] Step 2. Following general Step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(3-isobutoxyphenyl)-1-methyl-4-((4-methylphenyl)sulfonamide)-1H-pyrazole-5-carboxamide (compound 35) was prepared as a white solid (38 mg, 29%). Mass (m / z): 526.9 [M+H] + .

[0322] Compound 36: (S)-4-((4-chlorophenyl)sulfonamide)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide & Compound 37: (S)-4-((4-chlorophenyl)sulfonamide)-3-(4,4-difluorocyclohexyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0323] [ka]

[0324] Step 1. Following general step B1, methyl 3-bromo-4-((4-chlorophenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a yellow solid (200 mg, 19%). Mass (m / z): 407.6 [M+H] + .

[0325] Step 2. Following general Step C, 3-bromo-4-((4-chlorophenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a white solid (150 mg, 78%). Mass (m / z): 393.7 [M+H] + .

[0326] Step 3. Following general Step D, (S)-3-bromo-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared as a white solid (150 mg, 74%). Mass (m / z): 476.6 [M+H] + .

[0327] Step 4. Following general Step A, (S)-4-((4-chlorophenyl)sulfonamide)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 36) was prepared as a white solid (30 mg, 25%). Mass (m / z): 514.8 [M+H] + .

[0328] Step 5. Following general Step I, (S)-4-((4-chlorophenyl)sulfonamide)-3-(4,4-difluorocyclohexyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 37) was prepared as a white solid (7 mg, 27%). Mass (m / z): 516.9 [M+H] + .

[0329] Compound 38: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide

[0330] [ka]

[0331] Step 1. Following general Step A, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 38) was prepared as a white solid (20 mg, 19%). Mass (m / z): 493.1 [M+H] + .

[0332] Compound 39: (S)-4-((4-chlorophenyl)sulfonamide)-3-(2-(difluoromethyl)phenyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0333] [ka]

[0334] Step 1. Following general Step A, (S)-4-((4-chlorophenyl)sulfonamide)-3-(2-(difluoromethyl)phenyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 39) was prepared as a yellow solid (5.1 mg, 4%). Mass (m / z): 525.1 [M+H] + .

[0335] Compound 40: (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(5-(methoxymethyl)pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0336] [ka]

[0337] Step 1. Following general Step A, (S)-4-((4-chlorophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(5-(methoxymethyl)pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 40) was prepared as a white solid (34.0 mg, 57%). Mass (m / z): 519.8 [M+H] + .

[0338] Compound 41: (S)-4-((4-cyanophenyl)sulfonamide)-3-(2,4-difluorophenyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0339] [ka]

[0340] Step 1. Following general step B1, methyl 3-bromo-4-((4-cyano-N-((4-cyanophenyl)sulfonyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylate was prepared as a yellow solid (11 g, 82%). Mass (m / z): 585.6 [M+Na] + .

[0341] Step 2. Following general Step C, 3-bromo-4-((4-cyanophenyl)sulfonamide)-1-methyl-1H-pyrazole-5-carboxylic acid was prepared as a yellow solid (8.2 g, 96%). Mass (m / z): 384.8 [M+H] + .

[0342] Step 3. Following general Step D, (S)-3-bromo-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared as a yellow solid (5.3 g, 46%). Mass (m / z): 467.9 [M+H] + .

[0343] Step 4. Following general Step A, (S)-4-((4-cyanophenyl)sulfonamide)-3-(2,4-difluorophenyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 41) was prepared as a white solid (360 mg, 23%). Mass (m / z): 502.1 [M+H] + .

[0344] Compound 42: (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0345] [ka]

[0346] Step 1. Preparation of 3-bromo-2-(methoxymethyl)pyridine: (3-bromopyridine-2-yl)methanol (500 mg, 2.7 mmol) was dissolved in THF (10 mL) and NaH (60% of mineral oil, 128 mg, 3.2 mmol) was added under N2 at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, and then MeI (417 mg, 2.9 mmol) was added. The solution was further stirred under N2 at ambient temperature for 16 hours, and then diluted with H2O (20 mL). The aqueous solution was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under vacuum to obtain the product 3-bromo-2-(methoxymethyl)pyridine as a colorless oily substance (504 mg, 93%). Mass (m / z): 202.0 [M+H] + .

[0347] Step 2. Preparation of (2-(methoxymethyl)pyridine-3-yl)boronic acid: To a solution of 3-bromo-2-(methoxymethyl)pyridine (500 mg, 2.47 mmol) in dioxane (5 mL), B2Pin2 (943 mg, 3.71 mmol), KOAc (1.21 g, 12.4 mmol), and Pd(dppf)Cl2 (181 mg, 0.24 mmol) were added. The resulting mixture was stirred under N2 at 90°C for 1 hour and then concentrated under vacuum. The crude residue was purified by flash column chromatography (PE / EA = 0-50%) to obtain the product (2-(methoxymethyl)pyridine-3-yl)boronic acid as a yellow oily substance (210 mg, 50%). Mass (m / z): 168.1 [M+H] + .

[0348] Step 3. Following general Step A, (S)-4-((4-cyanophenyl)sulfonamide)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 42) was prepared as a white solid (12 mg, 13%). Mass (m / z): 510.8 [M+H] + .

[0349] Compound 43: (S)-4-((4-cyanophenyl)sulfonamide)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide and Compound 44: (S)-4-((4-cyanophenyl)sulfonamide)-3-(4,4-difluorocyclohexyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0350] [ka]

[0351] Step 1. Following general Step A, (S)-4-((4-cyanophenyl)sulfonamide)-3-(4,4-difluorocyclohexa-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 43) was prepared as a white solid (28 mg, 13%). Mass (m / z): 505.8 [M+H] + .

[0352] Step 2. Following general Step I, (S)-4-((4-cyanophenyl)sulfonamide)-3-(4,4-difluorocyclohexyl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 44) ​​was prepared as a white solid (8.5 mg, 11%). Mass (m / z): 507.9 [M+H] + .

[0353] (Example 2) In vitro assay for detecting and measuring hFPR1 modulation by compounds

[0354] Cyclic adenosine monophosphate (cAMP) assay CHO-K1 cells stably overexpressing hFPR1 were plated in 384-well cell culture plates (2,000 cells / well / 5 μL) in 1× Stimulation Buffer (LANCE Ultra cAMP Kit, Perkin Elmer, TRF0263). 1 μL of compound solution (prepared in ddH2O containing 0.2% DMSO) was added to each well. The plates were briefly centrifuged, and the cells were incubated at 37°C in 5% CO2 for 10 minutes. Then, 4 μL of a solution containing 2.5 μM forskolin and 0.25 nM WKYMVm (FPR1 agonist, GLPBIO, GC15140) was added to each well. 5 μL of Eu-cAMP solution (diluted to the manufacturer's recommended concentration in detection buffer, LANCE Ultra cAMP Kit) and 5 μL of ULight anti-cAMP solution (diluted in detection buffer, LANCE Ultra cAMP Kit) were added to each well. The plates were briefly centrifuged, and the cells were incubated at room temperature for 1 hour. Fluorescence emission from the samples at 665 nm and 620 nm was measured using a Perkin Elmer Envision instrument.

[0355] Reactive oxygen species (ROS) assay Human whole blood was collected, and erythrocytes were lysed with ACK lysis buffer (ThermoFisher, A1049201) in an amount equal to three times the volume of the blood sample. The sample was incubated on ice for 15 minutes, gently mixed twice during incubation. Then, 10 mL of DPBS was added, and the sample was centrifuged for 8 minutes. After removing the supernatant, the remaining cells were resuspended in RPMI1640 medium containing 3% FBS and centrifuged again for 10 minutes. After removing the supernatant, the cells were again resuspended in RPMI1640 medium containing 3% FBS. Neutrophil cell counts were determined by FACS analysis using APC-labeled CD11b antibody (Biolegend, 101211) and FITC-labeled CD66b antibody (Biolegend, 305104). Neutrophils were then plated into 96-well plates (300,000 / well). The plates were centrifuged and the supernatant was removed. The cells were resuspended in 80 μL of compound solution (prepared in RPMI1640 medium containing 3% FBS) and incubated at room temperature for 15 minutes. Then, 20 μL of solution containing DCFH-DA (at the concentration recommended by manufacturer Yeasen Biotechnology, 50101ES01) and fMLP (500 nM) was added. The cells were incubated in 5% CO2 at 37°C for 20 minutes, away from light. After incubation, the cells were placed on ice for 5 minutes, washed twice with 200 μL of ice-cold DPBS, and then resuspended at 100 μL / well in ice-cold DPBS. Fluorescence from each sample was measured at 485 nm excitation and 535 nm emission.

[0356] As illustrated in the examples in Table 1, the effects of the compounds of this disclosure on the regulation of FPR1-mediated cell signaling were measured by monitoring changes in cellular cAMP levels and the formation of anti-reactive oxygen species in human neutrophils in the presence of an FPR1 agonist.

[0357] ***:I C 50 <100nM,; **:100nM <IC 50 <1μM; *:1μM <IC 50 <25μM NA: No activity up to 25 μM; ND: Undetermined

[0358] [Table 1]

[0359] Other Embodiments This disclosure provides merely exemplary embodiments. Those skilled in the art will readily recognize that various variations, modifications, and alterations can be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

1. Compounds selected from the compounds of formulas (IIA) and (IIB): 【Chemistry 1】 [In formula: (i)Y 1 It does not exist. (ii)R 1 This is selected from cyclic alkyl groups, carbocyclic groups, heterocyclic groups, cyclic alkenyl groups, aryl groups, and heteroaryl groups. (iii) R2 is selected from aryl groups, and R3 is selected from linear, branched, and cyclic alkyl groups. (iv)R 4 These are selected from hydrogen, linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. (v)Each R ' and R " It is hydrogen, Linear, branched, and cyclic alkyl groups, cyclic alkenyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups are the following groups: halogen group, Hydroxy, Thiol, amino, Cyano, -OC(O)C 1 ~C 6 Linear, branched, and cyclic alkyl groups, -C(O)OC 1 ~C 6 linear, branched, and cyclic alkyl groups -NHC 1 ~C 6 Linear, branched, and cyclic alkyl groups, -N(C 1 ~C 6 (Linear, branched, and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 Linear, branched, and cyclic alkyl groups, -C(O)NHC 1 ~C 6 Linear, branched, and cyclic alkyl groups, -NHaryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NH aryl group, -NH heteroaryl group, -N (heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C 1 ~C 6 Linear, branched, and cyclic alkyl groups, C 2 ~C 6 Linear, branched, and cyclic alkenyl groups, C 1 ~C 6 Linear, branched, and cyclic hydroxyalkyl groups, C 1 ~C 6 Linear, branched, and cyclic alkoxy groups, C 1 ~C 6 Linear, branched, and cyclic thioalkyl groups, C 1 ~C 6 Linear, branched, and cyclic haloalkyl groups, C 1 ~C 6 Linear, branched, and cyclic haloaminoalkyl groups, C 1 ~C 6 Linear, branched, and cyclic halothioalkyl groups, C 1 ~C 6 Linear, branched, and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3-6 member heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups A tautomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with at least one group selected from the above.

2. R 1 However, R is selected from cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. 2 is an aryl group, R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1, selected from linear and branched alkyl groups.

3. R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from a 5- and 6-membered aryl group optionally substituted with at least one halogen group, a 5- and 6-membered heteroaryl group optionally substituted with at least one halogen group, a 3- to 6-membered cyclic alkyl group optionally substituted with at least one alkoxy group, an optionally substituted 3- to 6-membered carbocyclic group, and an optionally substituted heterocyclic group.

4. R 3 However, C is substituted in some cases. 1 ~C 10 Linear alkyl groups and C3-C 10 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, selected from branched alkyl groups.

5. R 3 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 4, selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl.

6. R 4 However, C is substituted in some cases. 1 ~C 10 Linear alkyl groups, C3-C 10 Branched alkyl groups, and C 3 ~C 6 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 5, selected from cyclic alkyl groups.

7. R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 6, selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cyclobutyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl.

8. Compounds selected from the following: 【Chemistry 2A】 【Chemistry 2B】 【Chem.2C】 [Transformation into 2D] 【Transformation 2E】 The tautomer thereof, the compound thereof, or a deuterated derivative of the tautomer thereof, or a pharmaceutically acceptable salt thereof.

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

10. The pharmaceutical composition according to claim 9, for use in the treatment or alleviation of diseases, disorders or conditions mediated by signal transduction of formyl peptide receptor 1 (FPR1).

11. Diseases, disorders, or conditions related to the CNS include stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, paroxysmal disorders, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, autosomal dominant cerebral artery disease with subcortical infarction (CADASIL), Spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hipper-Lindau disease, fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxia syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barré syndrome, causalgia, complex focal pain syndromes type I and II, Diabetic neuropathy, alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitis syndrome, prion disease, myelitis, radiculitis, diabetes-related protein abnormalities, trans tyretin-induced neuropathy, HIV-related neuropathy, Lyme disease-related neuropathy The pharmaceutical composition according to claim 10, selected from neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

12. The pharmaceutical composition according to claim 11, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma.

13. The pharmaceutical composition according to claim 10, wherein the disease, disorder, or condition is selected from acute respiratory distress syndrome, dry eye syndrome, and allergic conjunctivitis.

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