Modulators of FPR1 and methods of using same

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

[0002] Restoring body homeostasis after injury or pathogen infection is critical to ensure the survival of the organism. Physiological wound healing and innate immune responses are initiated by the release of soluble mediators from invading pathogens or damaged lesions. Temporally regulated interactive repair processes include, for example, many chemokines, cytokines, acute phase proteins, infiltrating and tissue-resident cells, fibroblasts, neurons, and the vasculature. If the injury is persistent or extensive, physiological wound repair or anti-infection responses 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. Thus, effective regulation of the magnitude and duration of inflammation and resolution responses is critical to the homeostasis of the organism. Following tissue injury or pathogen infection (by bacteria, viruses, fungi, and / or microorganisms), a series 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) serve as the primary 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 chemically active molecules and acute proteins to FPRs recruits leukocytes, stimulates the production of superoxide and cytokines, activates microglia and astrocytes, and triggers other inflammatory and resolution responses critical for injury repair and host defense.

[0003] On the other hand, unbalanced FPR receptor-mediated signaling can lead to pathological inflammatory responses and cause a number of diseases after 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, with limited treatment options. FPR1 is highly expressed in microglia, astrocytes, and cerebral vasculature. After the onset of intracerebral hemorrhage (ICH), dying brain cells, activated platelets, microglia, and astrocytes release a series of pro-inflammatory mediators, 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 first wave of the inflammatory response after ICH and contribute to the development of perihematomal edema and exacerbated mass effect in stroke.

[0005] TBI is the number one cause of disability worldwide. The global incidence of TBI is estimated at 200 per 100,000 people per year. Severe TBI often results in behavioral disorders, brain atrophy, dementia, permanent brain damage, and ultimately death. TBI has limited treatment options, and FPR1 activation has been implicated in mediating the initial inflammatory process in TBI.

[0006] Glioblastoma and malignant glioma are the most common primary brain tumors. The annual incidence is approximately 6 per 100,000 population. There is currently no effective treatment for malignant glioma. FPR1 is highly expressed in glial cells, astrocytes, and cerebral vasculature. Its interaction with chemotactic ligands produced by injury, stress, and pathogens is involved in the pathophysiology of brain cancer.

[0007] ARDS is a life-threatening lung injury that causes leakage of fluid into the lungs and poor blood oxygenation. With an annual incidence of about 70 per 100,000 population, ARDS commonly occurs in patients hospitalized with previous infection or trauma, has few treatment options, and has a mortality rate of over 40% for severe cases. Mitochondrial formylated peptides are elevated in lung fluid and serum of ARDS patients, and activation of FPR1 signaling has been implicated as a major driver of acute lung injury.

[0008] Allergic conjunctivitis (AC) and dry eye syndrome (DES) are the two most common ocular inflammatory disorders, with a predicted 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 have a strong negative impact on patients' quality of life. FPRs are expressed in the conjunctiva, the mucosal tissue layer of the eye, and their expression is elevated in settings of inflammation. Thus, activation of FPR signaling is a potential mediator in the pathogenesis of AC and DES.

[0009] In view of the foregoing, there remains 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 Summary of the Invention [Means for solving the problem]

[0012] One aspect of the present disclosure provides a compound selected from the compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, which can be utilized in the treatment of 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 are independently O, S, N, and NR 4 , C(R 4 )2, and CR 4Selected from Z 1 and Z 2 At least one of is O, S, N, or NR 4 and R 4 is selected from hydrogen, straight chain, 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 is selected from R 5 is selected from hydrogen, straight chain, 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, a heterocyclic group, an aryl group, or a heteroaryl group; (iv) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups

[0033] optionally substituted with at least one group selected from, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing is disclosed herein.

[0015] In one aspect of the disclosure, the compound of formula I is selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0016] In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. These compositions may further comprise an additional pharma- ceutical active agent.

[0017] Another aspect of the disclosure provides a method of 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, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a compound selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0018] In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof an additional pharmacoactive agent either in the same pharmaceutical composition as a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmacologic acceptable salt of the foregoing, or as a separate composition. In some embodiments disclosed herein, the method of treatment comprises administering to a subject in need thereof an additional pharmacoactive agent either in the same composition as a compound selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmacologic acceptable salt of the foregoing, or as a separate composition.

[0019] Also disclosed herein is a method of modulating FPR1 activity, comprising administering to a subject a therapeutically effective amount of a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method of modulating FPR1 comprises administering to a subject a compound selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of modulating FPR1 activity comprises contacting said FPR1 with a compound of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method of modulating FPR1 comprises contacting FPR1 with a compound selected from compounds 1-44 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] I. Definition The terms "a" or "an," when used herein in reference to a noun, encompass "at least one," and thus encompass both the singular and plural units of the noun. For example, "an additional agent" means a single or two or more additional agents.

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

[0022] The term "FPR1 modulator" as used herein refers to an organic chemical small molecule compound (≦10 kDa) that has the ability to change any one or more immune responses or signaling events mediated by FPR1 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 any one or more immune responses or signaling events mediated by FPR1 from their natural state, for example, by binding to and activating the receptor. When an FPR1 modulator is an antagonist, the compound has the ability to reduce or inhibit any one or more immune responses or signaling events mediated by FPR1 from their natural state, for example, by blocking an agonist binding site or an allosteric binding site on the receptor to achieve a reduction or inhibition of the action.

[0023] The term "compound", when referring to a compound of the present disclosure, refers to a group of molecules having the same chemical structure unless otherwise indicated as a group of stereoisomers (e.g., a group of racemates, a group of cis / trans stereoisomers, or a group of (E) and (Z) stereoisomers). However, it is understood that isotopic variations may exist among the constituent atoms of the molecule. Thus, it is clear to one skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains lower amounts of isotopologues having hydrogen atoms at one or more of the deuterium positions designated in the structure. The relative amount of such isotopologues in the compounds of the present disclosure depends on several factors, including, for example, the isotopic purity of the reagents used to generate the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as described above, the relative amount of such isotopologues 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 compounds overall.

[0024] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with a group of the specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and more than one position in any given structure may be substituted with more than one substituent selected from the specified groups, and the substituents may be the same or different at all positions. Combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0025] The term "isotopologues" refers to species that differ in chemical structure only in their isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen is replaced by deuterium or tritium, or a carbon is replaced by 13 C or 14 Compounds having the structures of the present invention except for the replacement by C are within the scope of this disclosure.

[0026] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present invention are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0027] The term "tautomer," as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the movement of an atom, e.g., a hydrogen atom, or a group within a molecule.

[0028] "Stereoisomers" as used herein refers to enantiomers and diastereomers.

[0029] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as the reference compound, except that one or more hydrogen atoms have been replaced with a deuterium atom ("D" or 「2It is recognized that some variation in natural isotopic abundance will occur in the synthesized compound depending on the source of the chemicals used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is low and insignificant, despite this variation, compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise stated, when a "deuterated derivative" of a compound of the present disclosure is referred to, at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 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 bonded at each designated deuterium), at least 4500 (67.5% deuterium bonded at each designated deuterium), at least 5000 (75% deuterium bonded at each designated deuterium), at least 5500 (82.5% deuterium bonded at each designated deuterium), at least 6000 (90% deuterium bonded at each designated deuterium), at least 6333.3 (95% deuterium bonded at each designated deuterium), at least 6466.7 (97% deuterium bonded at each designated deuterium), or at least 6600 (99% deuterium bonded at each designated deuterium).

[0030] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0031] The term "alkyl," as used herein, means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1-30 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1-3 alkyl carbon atoms. And in still other embodiments, an alkyl group contains 1-2 alkyl carbon atoms. In some embodiments, an alkyl group is substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is straight or linear or unbranched. In some embodiments, an alkyl group is branched.

[0032] The term "cycloalkyl" refers to a fully saturated, monocyclic C 3~8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8~14 In some embodiments, the cycloalkyl group is a C3-C6 alkyl group, and any individual ring in said bicyclic ring 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 a C3-C6 alkyl group. 12 In some embodiments, the cycloalkyl is a C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0033] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to monocyclic C alkyl groups that are fully saturated or that contain one or more units of unsaturation and thus are partially saturated, but are not aromatic. 3~8Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8~14 It refers to a hydrocarbon, where any individual ring of said bicyclic ring system has 3-7 members. Bicyclic carbocyclyl includes, for example, a combination of a monocyclic carbocycle fused to a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is a C3-C 12 In some embodiments, the carbocyclyl is a C3-C 10 In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexyl, and cyclopentenyl, cyclohexenyl.

[0034] The term "alkenyl," as used herein, refers to a straight or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is straight chain, linear, or unbranched. In some embodiments, an alkenyl group is branched. In some embodiments, an alkenyl group is cyclic. In some embodiments, an alkenyl group is a C3-C6 alkyl group. 12 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, but not aromatic, as it contains one or more units of unsaturation), monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system in which one or more ring members are independently selected from heteroatoms. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members in which one or more ring members are independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus, heteroatoms. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3-7 ring members. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocyclic ring has one heteroatom that is a nitrogen atom. In some embodiments, the heterocyclic ring has one heteroatom that is an oxygen atom. In some embodiments, the heterocyclic ring has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclic ring has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclic ring is substituted. In some embodiments, the heterocyclic ring is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl.In some embodiments, the 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, tetrahydropyranyl, azetidinyl, oxetanyl, tetrahydrothiophenyl, dihyropyranyl, and tetrahydropyridinyl.

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

[0037] The term "unsaturated," as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a condition in which not all available valence bonds in a compound are filled by substituents, such that the compound contains double or triple bonds.

[0038] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, in which one carbon of the alkyl group is replaced with an oxygen ("alkoxy") atom, provided that 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 iodo, respectively.

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

[0041] As used herein, "aromatic ring" refers to a conjugated, carbocyclic or heterocyclic ring containing a planar ring system having a delocalized pi orbital made up of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring and may be fully saturated or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, further defined below.

[0042] The term "aryl" used alone or as part of a larger moiety, such as in "arylalkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, in which all rings in the system are aromatic rings containing only carbon atoms, and in which each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C7). 10 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 5-14 ring members, where at least one ring in the system is aromatic, where at least one ring in the system contains one or more heteroatoms, and where each ring in the bicyclic or tricyclic ring system contains 3-7 ring members. Bicyclic heteroaryls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected, for example, from 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 3-12 membered heteroaryl. In some embodiments, the heteroaryl is a 3-10 membered heteroaryl. In some embodiments, the heteroaryl is a 3-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-8 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] "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, where every two rings share only one common atom.

[0045] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

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

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

[0048] The term "pharmaceutically acceptable" as used herein refers to a component that is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / loss ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present disclosure upon administration to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19.

[0049] Acids commonly utilized to form pharma-ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as 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. Thus, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-diate, hexyne-2,7-diate, hexyne-1,7-diate, hexyne-2,7-diate, hexyne-1,8-diate, hexyne-2,9 ... -dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharma- ceutically 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] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4Examples of suitable pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

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

[0052] The term "therapeutically effective amount" refers to the amount of a compound for which the compound is administered to produce the desired effect (e.g., ameliorating the symptoms of diseases, disorders, and conditions mediated by FPR1 signaling, reducing the severity of diseases, disorders, and conditions or symptoms thereof, and / or reducing the progression of diseases, disorders, and conditions mediated by FPR1 signaling or symptoms thereof). The exact amount of the therapeutically effective amount depends on the purpose of the treatment and can be ascertained by the skilled artisan 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 cognates refer to slowing or stopping disease progression. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, reduction in risk of complications associated with FPR1 signaling-mediated diseases, disorders, and conditions, and diseases. Improvement or reduction in the severity of any of these symptoms can be easily assessed or subsequently developed according to methods and techniques known in the art.

[0054] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the specified dose, amount, or weight percent value or range of doses, amounts, or weight percent that is recognized by one of skill in the art to result in a pharmacological effect equivalent to that resulting from the specified dose, amount, or weight percent.

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

[0056] [ka]

[0057] [In the formula, (i) Each Z 1 and Z 2 are independently O, S, N, and NR 4 , C(R 4 )2, and CR 4 Selected from Z 1 and Z 2 At least one of is O, S, N, or NR 4 and R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) Y 1 is absent or O, S, and NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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 together with the atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; (iv) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; The 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 selected from the group: Halogen groups, Hydroxy, Thiol, amino, Cyano, -OC(O)C1-C6 straight chain, branched and cyclic alkyl groups; -C(O)OC1-C6 straight chain, branched and cyclic alkyl groups; -NHC1-C6 straight chain, branched and cyclic alkyl groups; -N(C1-C6 straight chain, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 straight chain, branched and cyclic alkyl groups; -C(O)NHC1-C6 straight chain, branched and cyclic alkyl groups; -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl groups, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

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

[0059] [ka]

[0060] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, all other variables not specifically defined herein are as defined in the first embodiment.

[0061] In a third embodiment, the compound of the present disclosure has one of the following structural formulas IIIA or IIIB:

[0062] [ka]

[0063] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, all other variables not specifically defined herein are as defined in the first embodiment.

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

[0065] [ka]

[0066] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, all other variables not specifically defined herein are as defined in the first embodiment.

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

[0068] [ka]

[0069] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, all other variables not specifically defined herein are as defined in the first embodiment.

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

[0071] [ka]

[0072] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, all other variables not specifically defined herein are as defined in the first embodiment.

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

[0074] In an eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from optionally substituted 5- and 6-membered aryl groups, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0075] In a ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R1 is selected from 5- and 6-membered aryl groups substituted with at least one halogen group, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0076] In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from 5- and 6-membered aryl groups substituted with at least one fluoro, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0077] In an eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from 5- and 6-membered aryl groups substituted with at least one chloro, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

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

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

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

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

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

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

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

[0085] In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is selected from an optionally substituted 3- to 6-membered heterocyclic group, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0086] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 is selected from optionally substituted 5- and 6-membered heteroaryl groups, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

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

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

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

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

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

[0092] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 3 is optionally substituted C1-C 10 Straight chain and C2-C 10All other variables 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 a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0094] In a twenty-eighth embodiment, all other variables not specifically defined herein in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0095] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4 is optionally substituted C1-C 10 Straight chain, C2~C 10 All other variables selected from branched alkyl groups, and C3-C6 cyclic alkyl groups not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0096] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 4is 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 variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0097] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R' is hydrogen, and all other variables not specifically defined herein are as defined in any one of the first, second, third, fourth, fifth, or sixth embodiments.

[0098] In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R" is hydrogen, and all other variables 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 1-44 shown in Table 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[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 formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0103] In some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant, hi some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0104] It is also recognized that the pharmaceutical compositions of the present disclosure can be utilized in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise an additional pharma- ceutical active agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutical acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered as a separate composition, either in parallel with, before, or after a composition comprising an additional pharma- ceutical active agent.

[0105] As described above, the pharmaceutical compositions disclosed herein include a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier can be selected from adjuvants and vehicles. As used herein, the pharma- ceutically acceptable carrier can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants, as appropriate for a particular 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, disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by causing any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and 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, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose, cellulose esters ... Ingredients include, for example, sodium cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0106] III. Methods of Treatment and Use In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of the compounds or tautomers described herein, including compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating a disease, disorder, or condition mediated by FPR1 signaling. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, as described herein, including compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease, disorder, or condition mediated by FPR1 signaling. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by FPR1 signaling in a subject, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt described herein, including compounds of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof.

[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 stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizure disorders, amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, or other conditions. diseases), familial spastic paraplegia, spinocerebellar degeneration (SCA), Friedreich's ataxia, Wilson's disease, Menkes syndrome, cerebral autosomal dominant arteriopathy with subcortical infarctions (CADASIL), spinal muscular atrophy, muscular dystrophies, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau disease, fragile X syndrome, spastic paraplesia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette's syndrome, ataxic syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degenration, Guillain-Barre syndrome, causalgia, complex regional pain syndrome type I and II, diabetic neuropathy, and alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal harangela neuralgia, dysphagia, dysphonia, cranial nerve palsies, myelopethies, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, post-meningitis syndrome, prion diseases, myelitis, radiculitis, dysproteinemia associated with diabetes, transthyretin-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, shingles-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

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

[0109] In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts thereof described herein, including compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, are for use in modulating FPR1 activity. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts thereof described herein, including compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the manufacture of a medicament for modulating FPR1 activity. In yet another aspect, disclosed herein is a method of modulating FPR1 activity comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, as described herein, including compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of modulating FPR1 activity comprising contacting said FPR1 in a subject with a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt described herein, including a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof.

[0110] Compounds of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-8, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, may be administered once daily, twice daily, or three times daily, for example, for the treatment of a disease, disorder, or condition mediated by FPR1 signaling.

[0111] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, is administered once daily, twice daily, or three times daily.

[0112] The compounds of formula I, IIA, IIB, IIIA, IIIB, IVA, IVB, VA, VB, VIA, and VIB, compounds 1-18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, buccally, vaginally, transdermally, by patch, pump administration, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time. Other forms of administration contemplated in the present disclosure are described in International Patent Application WO2013 / 075083, International Patent Application WO2013 / 075084, International Patent Application WO2013 / 078320, International Patent Application WO2013 / 120104, International Patent Application WO2014 / 124418, International Patent Application WO2014 / 151142, and International Patent Application WO2015 / 023915.

[0113] The useful dose or therapeutically effective amount of the compounds described herein or their pharma- ceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models.Methods for extrapolating effective doses in mice and other animals to humans are known in the art.See, for example, U.S. Patent No. 4,938,949.

[0114] Those skilled in the art will recognize that when a compound amount is disclosed, the relevant amount of the pharma- ceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharma- ceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the compounds of formula I and its pharma- ceutically acceptable salts" includes 1000 mg of the compound of formula I) and the concentration of the pharma- ceutically acceptable salt of the compound of formula I equivalent to 1000 mg of the compound of formula I.

[0115] Non-Limiting Exemplary Embodiments 1. Compound of formula (I):

[0116] [ka]

[0117] [In the formula, (i) Each Z 1 and Z 2 are independently O, S, N, and NR 4 , C(R 4 )2, and CR 4 Selected from Z 1 and Z 2 At least one of is O, S, N, or NR 4 and R 4 is selected from hydrogen, straight chain, 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 5is selected from R 5 is selected from hydrogen, straight chain, 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, a heterocyclic group, an aryl group, or a heteroaryl group; (iv) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: Figure imgf000012_0001 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 2.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1, wherein is selected from straight chain and branched alkyl groups. 3.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1 or 2, wherein is selected from optionally substituted 5- and 6-membered aryl groups. 4.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 3, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 5.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 4, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 6.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 4, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 7.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1 or 2, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 8.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 7, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 9.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 10.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 11.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 1 or 2, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 12.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 11. 13.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. 14.R 1 is selected from an optionally substituted 3-6 membered carbocyclic group, an optionally substituted alkenyl group, and an optionally substituted heterocyclic group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt of embodiment 1 or 2. 15.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-14, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 16.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-15, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 17.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 16, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 18.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 16, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 19.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-15, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 20.R 2 is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups, or tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of any one of embodiments 1-19. 21.R 3 , optionally substituted C2~C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-20, wherein the compound is selected from a branched alkyl group. 22.R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 21, wherein is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 23. Compound of formula (IIA):

[0118] [ka]

[0119] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 24. Compound of formula (IIB):

[0120] [ka]

[0121] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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 N.R. 4 together with the atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 25.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 25. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 23 or 24, wherein is selected from straight chain and branched alkyl groups. 26.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 23 or 24, wherein is selected from optionally substituted 5- and 6-membered aryl groups. 27.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 26, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 28.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 27, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 29.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 27, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 30.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 23 or 24, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 31.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 30, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 32.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 31, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 33.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 31, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 34.R 1 25. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 23 or 24, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 35.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 34. 36.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof. 37.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 23 or 24, wherein is selected from an optionally substituted 3- to 6-membered heterocyclic group. 38.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-37, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 39.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-38, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 40.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 40, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 41.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 40, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 42.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-38, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 43.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-38, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups. 44.R 3 , optionally substituted C1-C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-43, wherein the compound is selected from a branched alkyl group. 45.R 3The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 44, wherein is 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 , optionally substituted C1-C 10 Straight chain, C2~C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 23-45, wherein the alkyl group is selected from branched alkyl groups, and C3-C6 cyclic alkyl groups. 47.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 45, wherein 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. 48. Compound of formula (IIIA):

[0122] [ka]

[0123] [In the formula, (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 49. Compound of formula (IIIB):

[0124] [ka]

[0125] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR5 is selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 50.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 50. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 48 or 49, wherein is selected from straight chain and branched alkyl groups. 51.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 48 or 49, wherein is selected from optionally substituted 5- and 6-membered aryl groups. 52.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 51, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 53.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 52, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 54.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 52, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 55.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 48 or 49, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 56.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 55, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 57.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 58.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 56, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 59.R 1 50. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 48 or 49, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 60.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. 61.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 60, wherein is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group. 62.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 48 or 49, wherein is selected from an optionally substituted 3- to 6-membered heterocyclic group. 63.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-62, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 64.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-63, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 65.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 64, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 66.R 2The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 64, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 67.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-62, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 68.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-62, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups. 69.R 3 , optionally substituted C1-C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-68, wherein the compound is selected from a branched alkyl group. 70.R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 69, wherein is 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 , optionally substituted C1-C 10 Straight chain, C2~C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 48-70, wherein the alkyl group is selected from branched alkyl groups, and C3-C6 cyclic alkyl groups. 72.R 4The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 71, wherein 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. 73. Compound of formula (IVA):

[0126] [ka]

[0127] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 74. Compound of formula (IVB):

[0128] [ka]

[0129] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R" are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 75.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 75. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73 or 74, wherein is selected from straight chain and branched alkyl groups. 76.R 175. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73 or 74, wherein is selected from optionally substituted 5- and 6-membered aryl groups. 77.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 76, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 78.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 77, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 79.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 77, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 80.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73 or 74, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 81.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 80, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 82.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 81, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 83.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 81, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 84.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73 or 74, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 85.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 84, wherein is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group. 86.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. 87.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 73 or 74, wherein is selected from an optionally substituted 3- to 6-membered heterocyclic group. 88.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 73-87, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 89.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 73-88, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 90.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 89, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 91.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 89, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 92.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 73-87, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 93.R 2The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 73-87, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups. 94.R 3 , optionally substituted C1-C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 73-93, wherein the compound is selected from a branched alkyl group. 95.R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 94, wherein is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl. 96. Compound of formula (VA):

[0130] [ka]

[0131] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R "are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 97. Compound of formula (VB):

[0132] [ka]

[0133] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 98.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 98. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 96 or 97, wherein is selected from straight chain or branched alkyl groups. 99.R 1 98. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 96 or 97, wherein is optionally substituted selected from 5- and 6-membered aryl groups. 100.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 99, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 101.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 102.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 100, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 103.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 96 or 97, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 104.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 103, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 105.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 104, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 106.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 104, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 107.R 1 98. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 96 or 97, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 108.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. 109.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 108, wherein is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group. 110.R 1 98. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 96 or 97, wherein is selected from an optionally substituted 3- to 6-membered heterocyclic group. 111.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-110, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 112.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-111, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 113.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 112, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 114.R2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 112, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 115.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-110, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 116.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-110, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups. 117.R 3 , optionally substituted C1-C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-116, wherein the compound is selected from a branched alkyl group. 118.R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 117, wherein is 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 , optionally substituted C1-C 10 Straight chain, C2~C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 96-118, wherein the alkyl group is selected from branched alkyl groups, and C3-C6 cyclic alkyl groups. 120.R 4The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 119, wherein is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, cycloputyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2,2-trimethylpropyl, cyclopentyl, and cyclohexyl. 121. Compound of formula (VIA):

[0134] [ka]

[0135] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R5 is 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

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

[0137] [ka]

[0138] [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 Selected from R 5 is selected from hydrogen, straight chain, 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; The straight chain, branched and cyclic alkyl groups, heterocyclic groups, aryl groups and heteroaryl groups include the following groups: Halogen groups, 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 straight chain, branched and cyclic thioalkyl groups; C1-C6 straight chain, branched and cyclic haloalkyl groups; C1-C6 straight chain, branched and cyclic haloaminoalkyl groups; C1-C6 straight chain, branched and cyclic halothioalkyl groups, C1-C6 straight chain, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups; 3 to 6 membered heterocycloalkenyl group, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 123.R 1 is selected from cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 123. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121 or 122, wherein is selected from straight chain and branched alkyl groups. 124.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121 or 122, wherein is selected from optionally substituted 5- and 6-membered aryl groups. 125.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 124, wherein is selected from 5- and 6-membered aryl groups substituted with at least one halogen group. 126.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 125, wherein is selected from 5- and 6-membered aryl groups substituted with at least one fluoro. 127.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 125, wherein is selected from 5- and 6-membered aryl groups substituted with at least one chloro. 128.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121 or 122, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 129.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 128, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 130.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 129, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 131.R 1 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 129, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 132.R 1 123. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121 or 122, wherein is selected from optionally substituted 3- to 6-membered cyclic alkyl groups. 133.R 1The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 132, wherein is selected from 3-6 membered cyclic alkyl groups substituted with at least one alkoxy group. 134.R 1 is selected from 3-6 membered cyclic alkyl groups substituted with at least one methoxy group, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. 135.R 1 123. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 121 or 122, wherein is selected from an optionally substituted 3- to 6-membered heterocyclic group. 136.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-135, wherein is selected from optionally substituted 5- and 6-membered heteroaryl groups. 137.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-136, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one halogen group. 138.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 137, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one fluoro. 139.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 137, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one chloro. 140.R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-136, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one cyano. 141.R 2The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-135, wherein is selected from 5- and 6-membered heteroaryl groups substituted with at least one group selected from C1-C6 straight chain, C3-C6 branched, and C3-C6 cyclic alkyl groups. 142.R 3 , optionally substituted C1-C 10 Straight chain and C2-C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-141, wherein the compound is selected from a branched alkyl group. 143.R 3 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 142, wherein is 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 , optionally substituted C1-C 10 Straight chain, C2~C 10 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 121-143, wherein the alkyl group is selected from branched alkyl groups, and C3-C6 cyclic alkyl groups. 145.R 4 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 144, wherein 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. 146. A compound selected from the 44 listed compounds described above, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing. 147. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-146, and at least one pharma- ceutically acceptable carrier. 148. A method for treating or alleviating a disease, disorder or condition mediated by formyl peptide receptor 1 (FPR1) signaling, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 146, or a pharmaceutical composition according to embodiment 147. 149. The disease, disorder, or condition involves the CNS and includes stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizure 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 arteriopathy with subcortical infarction (CAD) ASIL), spinal muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau disease, fragile X syndrome, spastic paraplegia, tuberous sclerosis, Waardenburg syndrome, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, Tourette syndrome, ataxic syndrome, Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Guillain-Barre syndrome, causalgia, complex regional pain syndrome I, and II, diabetic neuropathy, as well as alcoholic neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsies, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitis syndrome, prion disease, myelitis, radiculitis, diabetes-associated dysproteinemia, transthyretin-induced neuropathy, HIV-associated neuropathy, and Lyme disease. 149. The method of embodiment 148, wherein the neuropathy is selected from neuropathy associated with rheumatoid arthritis, neuropathy associated with herpes zoster, neuropathy associated with shingles, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis induced neuropathy, polyneuritis, heavy metal induced neuropathy, transition metal induced neuropathy, drug induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma. 150. The method of embodiment 148 or 149, wherein the disease, disorder, or condition is stroke (thrombotic, embolic, thromboembolic, hemorrhagic, venoconstrictive, 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 oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma. 154. The method of embodiment 153, wherein the malignant glioma is 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 In order to provide a more complete understanding of the present disclosure, the following examples are disclosed. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any manner.

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

[0141] The compounds of the present disclosure can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the synthetic schemes below and in the descriptions for preparing the compounds of formulas (I), (II), (IIIa), (IIIb), and (IIIc), compounds 1-135, pharma- ceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing: Abbreviation Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = Dimethylacetamide DME = dimethoxyethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = ethyl acetate EtOH = ethanol HOAc = acetic acid KOAc = Potassium Acetate LiHMDS = lithium bis(trimethylsilyl)amide MeMgBr = methylmagnesium bromide MeOH = methanol NaOAc = Sodium Acetate NBS = N-bromosuccinimide Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PTSA = p-toluenesulfonic acid monohydrate rt = room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TsCl = p-toluenesulfonyl chloride

[0142] Compound 1: (S)-4-((4-cyanophenyl)sulfonamido)-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) under N2, NBS (1.37 g, 7.7 mmol) was added at 0 °C. The resulting solution was stirred at 0 °C for 1 h. The solvent was removed under reduced pressure and the residue was purified by CombiFlash (PE / EA=1:3) to give 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: To a solution of 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) in a mixture of dioxane and H2O (33 mL, 10 / 1 (v / v)) under N2, Pd(dppf)Cl2 (312 mg, 0.42 mmol) was added. The resulting mixture was stirred at 100 °C for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (PE / EA=1:1) to give 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)sulfonamido)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate: 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, LiHMDS (1.2 mL, 1N solution in THF, 1.2 mmol) was added dropwise. The resulting solution was stirred at -78 °C for 1 h before 4-cyanobenzenesulfonyl chloride (182 mg, 0.90 mmol) was added. The mixture was further stirred at -78 °C for 3 h before the reaction was quenched with saturated aqueous NH4Cl (20 mL). The aqueous medium was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash column chromatography (PE / EA=1:1) to give the product methyl 4-((4-cyanophenyl)sulfonamido)-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)sulfonamido)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid: To a solution of 4-((4-cyanophenyl)sulfonamido)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate (100 mg, 0.24 mmol) in a mixed solvent of MeOH and HO (8 mL, 3:1 (v / v)), NaOH (96 mg, 2.4 mmol) was added. The resulting mixture was stirred at 60 °C under N for 16 h. The organic solvent was removed under reduced pressure. The aqueous medium was acidified to pH 5-6 with 1 N HCl aqueous solution and then extracted with EA (15 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over NaSO, and then filtered. The filtrate was concentrated to dryness to give the product 4-((4-cyanophenyl)sulfonamido)-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 1): To a solution of 4-((4-cyanophenyl)sulfonamido)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (73 mg, 0.18 mmol) in DCM (10 mL) was added (S)-3,3-dimethylbutan-2-amine (27 mg, 0.27 mmol), DIEA (117 mg, 0.91 mmol) and T3P (173 mg, 0.54 mmol) sequentially. The resulting solution was stirred under N2 at ambient temperature for 3 h 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 Combiflash (DCM / MeOH = 10:1) to give the product (S)-4-((4-cyanophenyl)sulfonamido)-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-(phenylsulfonamido)-N-propyl-1H-pyrazole-5-carboxamide

[0150] [ka]

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

[0152] Step 2. Following general step C, 3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamido)-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-(phenylsulfonamido)-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-(phenylsulfonamido)-1H-pyrazole-5-carboxamide

[0155] [ka]

[0156] Step 1. Following general step D, (S)-N-(sec-butyl)-3-(4-fluorophenyl)-1-methyl-4-(phenylsulfonamido)-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-(phenylsulfonamido)-1H-pyrazole-5-carboxamide

[0158] [ka]

[0159] Step 1. Following general step D, 3-(4-fluorophenyl)-N-(2-hydroxyethyl)-1-methyl-4-(phenylsulfonamido)-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0161] [ka]

[0162] Step 1. Following general step A, methyl 4-amino-1-methyl-3-(pyridin-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)sulfonamido)-1-methyl-3-(pyridin-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)sulfonamido)-1-methyl-3-(pyridin-4-yl)-1H-pyrazole-5-carboxylic acid: To a solution of methyl 4-((4-chloro-N-((4-chlorophenyl)sulfonyl)phenyl)sulfonamido)-1-methyl-3-(pyridin-4-yl)-1H-pyrazole-5-carboxylate (400 mg, 0.68 mmol) in EtOH (10 mL) was added KOH (77 mg, 1.37 mmol). The resulting mixture was stirred at 95 °C under N2 for 12 h 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 in HO (0.1% TFA)] to give the product 4-((4-chlorophenyl)sulfonamido)-1-methyl-3-(pyridin-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(pyridin-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)sulfonamido)-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 oil (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) was added NaH (60% dispersion in mineral oil, 2.95 g, 73 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature under N2 for 30 min, then MeI (10.5 g, 73 mmol) was added. The reaction mixture was further stirred at ambient temperature under N2 for 16 h, then diluted with water (200 mL). The aqueous solution was extracted with EA (150 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give 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. Preparation of 1-((1s,4s)-4-methoxycyclohexyl)ethan-1-one: To a solution of (1s,4s)-N,4-dimethoxy-N-methylcyclohexane-1-carboxamide (3.1 g, 15 mmol) in THF (20 mL) was added MeMgBr (7.7 mL, 3N solution in 2-methylTHF, 23 mmol) dropwise under N2 at 0 °C. The resulting solution was stirred under N2 at ambient temperature for 3 h and then diluted with saturated aqueous NH4Cl (30 mL). The aqueous medium was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 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 give the product 1-((1s,4s)-4-methoxycyclohexyl)ethan-1-one as a yellow oil (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: To a solution of 1-((1s,4s)-4-methoxycyclohexyl)ethan-1-one (2.41 g, 15.4 mmol) and diethyl oxalate (2.25 g, 15.4 mmol) in THF (30 mL) was added LiHMDS (15.4 mL, 1N solution in THF, 15.4 mmol) dropwise under N2 at -78 °C. The resulting solution was stirred under N2 at -78 °C for 1 h 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 to dryness to give the product ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxobutanoate as a yellow oil (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: To a stirred solution of aniline (4.91 g, 52.8 mmol) in 5N aqueous hydrochloric acid (10 mL) was added dropwise an ice-cooled solution of sodium nitrite (3.64 g, 52.8 mmol) in water (10 mL) at 0° C. The resulting solution was stirred at 0° C. for 1 h and then added dropwise to an ice-cooled suspension of ethyl 4-((1s,4s)-4-methoxycyclohexyl)-2,4-dioxobutanoate (4.5 g, 18 mmol) and sodium acetate (2.89 g, 35.2 mmol) in a mixture of ethanol and water (30 mL, 1:1 (v / v)). The mixture was further stirred at 0-5°C for 16 h and 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 to dryness to give 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 basified with 5N aqueous NaOH to pH 8-9 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 h and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=5:1 to 2:1) to give 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 regioisomer 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) was added Na2S2O4 (2.8 g, 16 mmol). The resulting solution was stirred at 100 °C for 16 h, then the organic solvent was removed under vacuum. The aqueous solution was diluted with water (30 mL) and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=2:1) ​​to give 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)sulfonamido)-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 h and then filtered. The precipitate was rinsed with 10% EA / PE and dried to give the product ethyl 3-((1s,4s)-4-methoxycyclohexyl)-1-methyl-4-((4-methylphenyl)sulfonamido)-1H-pyrazole-5-carboxylate as a brown solid (330 mg, purity 60%, 76%), which 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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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, 60% purity, 86%), which was used in the next step without further purification. 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: 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) was added BocO (596 mg, 2.7 mmol). The resulting solution was stirred at ambient temperature for 3 h and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=5:1) to give 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-ethyl 4-amino-5-((1s,4s)-4-methoxycyclohexyl)-1H-pyrazole-1,3-dicarboxylate: To a solution of 1-(tert-butyl) 3-ethyl 5-((1s,4s)-4-methoxycyclohexyl)-4-((E)-phenyldiazenyl)-1H-pyrazole-1,3-dicarboxylate (700 mg, 1.53 mmol) in MeOH (7 mL) was added 10% Pd / C (140 mg, 20% wt / wt) under N2. The reaction flask was evacuated under vacuum and then backfilled with H2 (1 atm). The resulting mixture was stirred under H2 atmosphere at ambient temperature for 16 h and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the product 1-(tert-butyl) 3-ethyl 4-amino-5-((1s,4s)-4-methoxycyclohexyl)-1H-pyrazole-1,3-dicarboxylate as a colorless oil (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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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 oil (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 as a brown solid (630 mg, 32%) together with its regioisomer ethyl (E)-1-methyl-4-(phenyldiazenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate 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)sulfonamido)-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate was prepared as a brown solid (450 mg, 60% purity, 60%), which was used in the next step without further purification. Mass (m / z): 427.7 [M+H] + .

[0193] Step 6. Following general step C, 4-((4-chlorophenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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 oil (100 mg, 42%). Mass (m / z): 254.1 [M+H] + .

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

[0199] Step 3. Following general step C, 4-((4-chlorophenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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 oil (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)sulfonamido)-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)sulfonamido)-1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylic acid was prepared as a yellow oil (200 mg, 100%). Mass (m / z): 425.6 [M+H] + .

[0207] Step 5. Following general step D, (S)-4-((4-chlorophenyl)sulfonamido)-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)sulfonamido)-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 at 90° C. under N2 for 5 h 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×2). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, and then filtered. The filtrate was concentrated to dryness to give the product ethyl 5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxylate as a brown oil (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: To a solution of (S)-N-(3,3-dimethylbutan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)isoxazole-3-carboxamide (145 mg, 0.52 mmol) in concentrated H2SO4 (6 mL) was added 100% HNO3 (2 mL). The resulting solution was stirred at ambient temperature for 16 h 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 give 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: 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) was added Zn powder (50 mg, 0.77 mmol). The resulting mixture was stirred at 70° C. for 3 h 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×2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and then filtered. The filtrate was concentrated to dryness to give 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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-1H-pyrazole-3-carboxylate was prepared as a brown solid (330 mg, 60% purity, 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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-1H-pyrazole-5-carboxamide

[0226] [ka]

[0227] Step 1. Following general step B1, methyl 5-bromo-2-methyl-4-[(4-methylbenzene)sulfonamido]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)sulfonamido]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)sulfonamido]-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)sulfonamido)-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)sulfonamido)-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) under N2, bis(pinacolato)diboron (947 mg, 3.7 mmol), KOAc (1.21 g, 12.4 mmol) and Pd(dppf)Cl2 (182 mg, 0.25 mmol) were added. The resulting mixture was stirred at 90 °C under N2 for 16 h and then concentrated under vacuum. The residue was purified by flash column chromatography (PE / EA=10:1) to give the product 2-(3-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-1H-pyrazol-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)sulfonamido)-1H-pyrazol-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-dimethylcyclohex-1-en-1-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-1H-pyrazole-5-carboxamide

[0242] [ka]

[0243] Step 1. Following general step A, (S)-N-(3,3-dimethylbutan-2-yl)-3-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-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)sulfonamido)-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-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate: To a stirred solution of 4-methoxycyclohexan-1-one (2 g, 15.6 mmol) in THF (20 mL) was added a solution of LiHMDS in THF (23.4 mL, 1N, 23.4 mmol) at -78 °C. The resulting solution was stirred at -78 °C for 30 min, 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 further stirred at -78 °C for 1 h and then diluted with saturated aqueous 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 give the product 4-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate as a brown oil (2.4 g, 60%).

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

[0248] Step 3. Following general step A, methyl 4-amino-3-(4-methoxycyclohex-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-methoxycyclohex-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 under H2 atmosphere at ambient temperature for 16 h. 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 give 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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-N-((S)-3,3-dimethylbutan-2-yl)-3-(4-methoxycyclohex-1-en-1-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0264] [ka]

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

[0266] Step 2. Following general step C, 4-((4-chlorophenyl)sulfonamido)-3-(4-methoxycyclohex-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)sulfonamido)-N-((S)-3,3-dimethylbutan-2-yl)-3-(4-methoxycyclohex-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]decan-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]dec-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 general step I, methyl 4-amino-1-methyl-3-(1,4-dioxaspiro[4.5]decan-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)sulfonamido)-1-methyl-3-(1,4-dioxaspiro[4.5]decan-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)sulfonamido)-1-methyl-3-(1,4-dioxaspiro[4.5]decan-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]decan-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazole-5-carboxamide

[0276] [ka]

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

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

[0279] Step 3. Following general step D, (S)-4-((4-chlorophenyl)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-1-methyl-3-(1,4-dioxaspiro[4.5]dec-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)sulfonamido)-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 general step I, methyl 4-amino-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate was prepared as a yellow oil (1.19 g, 96%). Mass (m / z): 240.0 [M+H] + .

[0284] Step 3. Following general step B2, methyl 4-((4-cyanophenyl)sulfonamido)-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)sulfonamido)-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylic acid was prepared as a yellow oil (250 mg, 78%). Mass (m / z): 391.2 [M+H] + .

[0286] Step 5. Following general step D, (S)-4-((4-cyanophenyl)sulfonamido)-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide

[0288] [ka]

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

[0290] Step 2. Following general step C, 4-((4-cyclopropylphenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-1-methyl-1H-pyrazole-5-carboxamide

[0293] [ka]

[0294] Step 1. Following general step B1, methyl 3-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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-difluorocyclohex-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-1H-pyrazole-5-carboxamide

[0303] [ka]

[0304] Step 1. Following general step A, (S)-3-(4,4-difluorocyclohex-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-1H-pyrazole-5-carboxamide (compound 31): To a solution of (S)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-1H-pyrazole-5-carboxamide (30.0 mg, 0.065 mmol) in a mixture of i-PrOH and DCM (5 mL, 9:1 (v / v)) was added Mn(dpm) (0.870 mg, 0.0014 mmol) and phenylsilane (14.1 mg, 0.130 mmol) at 0° C. The resulting solution was stirred at ambient temperature under N for 16 h and then concentrated in vacuo. The crude residue was purified by preparative TLC (PE / EA=1:1) to give the product (S)-N-(3,3-dimethylbutan-2-yl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-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-cyanocyclohex-1-en-1-yl)-N-((S)-3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-1H-pyrazole-5-carboxamide

[0310] [ka]

[0311] Step 1. Following general step A, 3-(4-cyanocyclohex-1-en-1-yl)-N-((S)-3,3-dimethylbutan-2-yl)-1-methyl-4-((4-methylphenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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) was added K2CO3 (1.87 g, 13.5 mmol) and 1-bromo-2-methylpropane (0.740 g, 5.4 mmol). The resulting mixture was stirred at 100 °C for 16 h 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 give the product 4,4,5,5-tetramethyl-2-[3-(2-methylpropoxy)phenyl]-1,3,2-dioxaborolane as a colorless oil (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)sulfonamido)-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)sulfonamido)-3-(4,4-difluorocyclohex-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide & Compound 37: (S)-4-((4-chlorophenyl)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-3-(4,4-difluorocyclohex-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(5-(methoxymethyl)pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0336] [ka]

[0337] Step 1. Following general step A, (S)-4-((4-chlorophenyl)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(5-(methoxymethyl)pyridin-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-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)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0345] [ka]

[0346] Step 1. Preparation of 3-bromo-2-(methoxymethyl)pyridine: To a solution of (3-bromopyridin-2-yl)methanol (500 mg, 2.7 mmol) in THF (10 mL) was added NaH (60% in mineral oil, 128 mg, 3.2 mmol) under N2 at 0°C. The resulting mixture was stirred at 0°C for 30 min before MeI (417 mg, 2.9 mmol) was added. The solution was further stirred at ambient temperature under N2 for 16 h 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 give the product 3-bromo-2-(methoxymethyl)pyridine as a colorless oil (504 mg, 93%). Mass (m / z): 202.0 [M+H] + .

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

[0348] Step 3. Following general step A, (S)-4-((4-cyanophenyl)sulfonamido)-N-(3,3-dimethylbutan-2-yl)-3-(2-(methoxymethyl)pyridin-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)sulfonamido)-3-(4,4-difluorocyclohex-1-en-1-yl)-N-(3,3-dimethylbutan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide and Compound 44: (S)-4-((4-cyanophenyl)sulfonamido)-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)sulfonamido)-3-(4,4-difluorocyclohex-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)sulfonamido)-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 Assays for Detecting and Measuring Modulation of hFPR1 by Compounds

[0354] Cyclic adenosine monophosphate (cAMP) assay CHO-K1 cells stably overexpressing hFPR1 were plated in 384-well cell culture plates (2,000 / 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 plate was briefly centrifuged and the cells were incubated for 10 min at 37° C. in 5% CO2. 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 working 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 centrifuged briefly and the cells were incubated for 1 hour at room temperature. Fluorescence emission from the samples at 665 nm and 620 nm was measured on a Perkin Elmer Envision instrument.

[0355] Reactive oxygen species (ROS) assay Human whole blood was collected and ACK lysis buffer (ThermoFisher, A1049201) was added at 3 times the volume of the blood sample to lyse red blood cells. The sample was incubated on ice for 15 minutes and gently mixed twice during the 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 using FACS analysis with APC-labeled CD11b antibody (Biolegend, 101211) and FITC-labeled CD66b antibody (Biolegend, 305104). Neutrophils were then plated in 96-well plates (300,000 / well). The plates were centrifuged and the supernatant removed. The cells were resuspended in 80 μL of compound solution (prepared in RPMI1640 medium containing 3% FBS) and then incubated at room temperature for 15 minutes. Then 20 μL of a solution containing DCFH-DA (at the concentration recommended by the 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 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 the present disclosure on regulating FPR1-mediated cell signaling were measured by monitoring changes in cellular cAMP levels and formation of reactive oxygen species in human neutrophils in the presence of FPR1 agonists.

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

[0358] [Table 1]

[0359] Other embodiments The present disclosure provides only exemplary embodiments, and those skilled in the art will readily recognize that from this disclosure and the claims, various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure, as defined in the following claims.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In formula: (i) Each Z 1 and Z 2 are independently O, S, N, and NR 4 , C(R 4 ) 2 , and C.R. 4 Selected from Z 1 and Z 2 At least one of is O, S, N, or NR 4 and R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) Y 1 is absent or O, S, and NR 5 is selected from R 5 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic 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 together with the atoms to which they are attached form a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; (iv) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; The linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, carbocyclic groups, linear and branched heteroalkenyl groups, heterocyclic groups, aryl groups and heteroaryl groups are selected from the following groups: Halogen groups, Hydroxy, Thiol, amino, Cyano, -O.C.(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -N(C 1 ~C 6 Straight-chain, branched, and cyclic alkyl groups 2 , -NHC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NH aryl group, -N(aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl groups, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; C 2 ~C 6 Straight-chain, 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 Straight chain, 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 Straight chain, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups; 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

2. R 1 is selected from cyclic alkyl groups, carbocyclic groups, heterocyclic groups, alkenyl groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 2. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 1, wherein is selected from straight chain and branched alkyl groups.

3. R 1 is selected from 5- and 6-membered aryl groups optionally substituted with at least one halogen group, 5- and 6-membered heteroaryl groups optionally substituted with at least one halogen group, 3- to 6-membered alkyl groups optionally substituted with at least one alkoxy group, optionally substituted 3- to 6-membered carbocyclic groups, optionally substituted alkenyl groups, and optionally substituted heterocyclic groups.

4. R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 3, wherein is selected from 5- and 6-membered heteroaryl groups optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 straight chain alkyl groups, C3-C6 branched alkyl groups, and C3-C6 cyclic alkyl groups.

5. R 3 but possibly substituted C 2 ~C 10 Straight chain alkyl groups and C 2 ~C 10 5. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 4, wherein the compound is selected from the group consisting of branched alkyl groups.

6. R 3 6. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 5, wherein is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl.

7. Compound of formula (IIA): 【Chemistry 2】 [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii)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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; The 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 selected from the group: Halogen groups, Hydroxy, Thiol, amino, Cyano, -OC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -N(C 1 ~C 6 Straight-chain, branched, and cyclic alkyl groups 2 , -NHC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NH aryl group, -N(aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl groups, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; C 2 ~C 6 Straight-chain, 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 Straight chain, 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 Straight chain, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups; 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

8. Compound of formula (IIB): 【Chemistry 3】 [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii)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 N.R. 4 together with the atoms to which they are attached form a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) R 4 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v)Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; The 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 selected from the group: Halogen groups, Hydroxy, Thiol, amino, Cyano, -OC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -N(C 1 ~C 6 Straight-chain, branched, and cyclic alkyl groups 2 , -NHC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NH aryl group, -N(aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl groups, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; C 2 ~C 6 Straight-chain, 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 Straight chain, 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 Straight chain, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups; 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

9. R 1 is selected from cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 9. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 7 or 8, wherein is selected from straight chain and branched alkyl groups.

10. R 1 is selected from 5- and 6-membered aryl groups optionally substituted with at least one halogen group, 5- and 6-membered heteroaryl groups optionally substituted with at least one halogen group, 3- to 6-membered alkyl groups optionally substituted with at least one alkoxy group, optionally substituted 3- to 6-membered carbocyclic groups, optionally substituted alkenyl groups, and optionally substituted heterocyclic groups.

11. R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 7 to 10, wherein is selected from 5- and 6-membered heteroaryl groups optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 straight chain alkyl groups, C3-C6 branched alkyl groups, and C3-C6 cyclic alkyl groups.

12. R 3 but possibly substituted C 1 ~C 10 Straight chain alkyl groups and C 2 ~C 10 12. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 7 to 11, wherein the compound is selected from the group consisting of branched alkyl groups.

13. R 3 13. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 12, wherein is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl.

14. R 4 but possibly substituted C 1 ~C 10 Straight chain alkyl group, C 2 ~C 10 Branched alkyl groups and C 3 ~C 6 14. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 7 to 13, wherein the compound is selected from cyclic alkyl groups.

15. R 4 15. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 14, wherein 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.

16. A compound selected from compounds of formula (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), and (VIB): 【Chemistry 4】 [In formula: (i)Y 1 is absent or is a bond, O, S, or NR 5 is selected from R 5 is selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) R1 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; (iii) Each R 2 and R 3 are independently selected from linear, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iv) Each R ' and R " are independently selected from hydrogen, straight chain, branched, and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; The 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 selected from the group: Halogen groups, Hydroxy, Thiol, amino, Cyano, -O.C.(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -N(C 1 ~C 6 Straight-chain, branched, and cyclic alkyl groups 2 , -NHC(O)C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 Straight chain, branched and cyclic alkyl groups; -NH aryl group, -N(aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl groups, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl groups, C 1 ~C 6 Straight chain, branched and cyclic alkyl groups; C 2 ~C 6 Straight-chain, 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 Straight chain, 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- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups and optionally substituted with at least one group selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

17. R 1 is selected from cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; R 2 is an aryl group, and R 3 17. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 16, wherein is selected from straight chain and branched alkyl groups.

18. R 1 is selected from 5- and 6-membered aryl groups optionally substituted with at least one halogen group, 5- and 6-membered heteroaryl groups optionally substituted with at least one halogen group, 3- to 6-membered alkyl groups optionally substituted with at least one alkoxy group, optionally substituted 3- to 6-membered carbocyclic groups, optionally substituted alkenyl groups, and optionally substituted heterocyclic groups.

19. R 2 The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 16 to 18, wherein is selected from 5- and 6-membered heteroaryl groups optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 straight chain alkyl groups, C3-C6 branched alkyl groups, and C3-C6 cyclic alkyl groups.

20. R 3 but possibly substituted C 1 ~C 10 Straight chain alkyl groups and C 2 ~C 10 20. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 16 to 19, wherein the compound is selected from the group consisting of branched alkyl groups.

21. R 3 21. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 20, wherein is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, iso-pentyl, sec-pentyl, neo-pentyl, and 1,2,2-trimethylpropyl.

22. R 4 but possibly substituted C 1 ~C 10 Straight chain alkyl group, C 2 ~C 10 Branched alkyl groups and C 3 ~C 6 22. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 16 to 21, wherein the compound is selected from cyclic alkyl groups.

23. R 4 23. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 22, wherein 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.

24. A compound selected from the following: 【Chemistry 12A】 【Chemistry 12B】 【Chemistry 12C】 【Chemistry 12D】 【Chemistry 12E】 a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing.

25. 25. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1 to 24 and at least one pharma- ceutically acceptable carrier.

26. 26. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 24, or a pharmaceutical composition of claim 25, for use in the treatment or alleviation of a disease, disorder, or condition mediated by formyl peptide receptor 1 (FPR1) signaling.

27. The disease, disorder, or condition involves the CNS and includes stroke, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, epilepsy, seizure 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, cerebral autosomal dominant arteriopathy with subcortical infarctions (CADASIL), spinal muscular atrophy, myopathy, myel ... Dystrophies, Charcot-Marie-Tooth disease, Neurofibromatosis, Von Hippel-Lindau disease, Fragile X syndrome, Spastic paraplegia, Tuberous sclerosis, Waardenburg syndrome, Dystonia, Benign essential tremor, Tardive dystonia, Tardive dyskinesia, Tourette syndrome, Ataxic syndrome, Shy-Drager syndrome, Olivopontocerebellar degeneration, Striatonigral degeneration, Guillain-Barre syndrome, Causalgia, Complex regional pain syndrome types I and II, Diabetic neuropathy, and Alcohol Neuropathy, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsies, myelopathy, traumatic brain injury, traumatic spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitic syndrome, prion disease, myelitis, radiculitis, diabetes mellitus-associated dysproteinemia, transthyretin-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, shingles-associated neuropathy, carpal tunnel 27. The compound, tautomer, deuterated derivative, or pharmacologic acceptable salt, or pharmaceutical composition of claim 26, wherein the compound is selected from chronic neuropathy, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, axonal brain injury, encephalopathy, chronic fatigue syndrome, and malignant glioma.

28. 28. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt, or pharmaceutical composition of claim 27, wherein the malignant glioma is selected from glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma, and anaplastic ganglioglioma.

29. 27. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt, or pharmaceutical composition of claim 26, wherein the disease, disorder, or condition is selected from acute respiratory distress syndrome, dry eye syndrome, and allergic conjunctivitis.

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