Imidazole-containing compounds, their derivatives, and their uses

Abstract

This disclosure relates to novel α2 adrenergic receptor (α2AR) agonists and their uses. In particular, this disclosure relates to imidazole-containing compounds of formula (IA), formula (IB), formula (IC), formula (ID), or formula (II). These compounds may be useful as peripherally selective α2AR agonists for the treatment or prevention of diseases.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Patent Application No. 63 / 498,049 filed on 25 April 2023, U.S. Patent Application No. 63 / 515,229 filed on 24 July 2023, U.S. Patent Application No. 63 / 550,274 filed on 6 February 2024, U.S. Patent Application No. 63 / 550,228 filed on 6 February 2024, and U.S. Patent Application No. 63 / 557,039 filed on 23 February 2024, the disclosures of which are incorporated herein by reference in their entirety.

[0002] This disclosure describes novel α2 adrenergic receptor (α2AR) agonists and their uses. In particular, this disclosure describes novel imidazole-containing compounds and their derivatives. These compounds may be useful as α2AR agonists for the treatment or prevention of diseases. [Background technology]

[0003] The α2-adrenergic receptor (α2AR) family, as part of G protein-coupled receptors, plays a crucial role in the biological functions of many central nervous system (CNS) systems. α2ARs are important in regulating neurotransmitter release and therefore influence a range of central physiological processes. Agonists targeting these receptors, such as clonidine and dexmedetomidine, have been successfully used to treat several conditions, primarily within the CNS. Relevant applications include the treatment of hypertension, sedation in intensive care, and the treatment of issues such as agitation associated with attention deficit hyperactivity disorder (ADHD) and schizophrenia or bipolar disorder.

[0004] Clonidine was initially developed to manage hypertension. Subsequently, it was found that clonidine induces sedation by activating α2ARs in the presynaptic and postsynaptic centers of the locus coeruleus (LC), a nucleus in the dorsomedial pons. Dexmedetomidine was later developed and approved as a sedative, particularly in adult patients who were initially intubated and mechanically ventilated in intensive care settings, due to its superior α2AR selectivity and pharmacokinetic properties more suitable for sedation.

[0005] Clonidine, in addition to its antihypertensive and sedative effects, is also approved for epidural use under the brand name Duraclon, representing a significant advance in the treatment of cancer pain. The analgesic mechanism is broadly attributed to the diffusion of clonidine into the spinal cord and the activation of α2AR in the dorsal horn, thereby attenuating pain transmission to higher CNS centers. Due to this central action, α2AR agonists exert significant analgesic effects and are an important method of pain management.

[0006] However, the application of α2AR agonists to analgesic treatment is fraught with difficulties, primarily due to the range of other biological side effects they can cause in the central nervous system. Duraclon has been shown to induce centrally mediated sedation, hypotension, bradycardia, and suppression of its application, which persist throughout the analgesic treatment process. Such sedative effects significantly limit the doses that can be safely administered. As a result, while α2AR agonists such as clonidine and dexmedetomidine are considered important for pain treatment in both academic research and clinical settings, their sedative effects pose a major obstacle to their widespread use in medical applications.

[0007] Therefore, it is desirable to develop a new class of α2AR agonists that can provide substantial therapeutic benefits in pain management, such as reduced sedative effects, thereby expanding the range of therapeutic alternatives to address broadly unmet medical needs. [Overview of the project] [Means for solving the problem]

[0008] In a general embodiment, the Disclosure relates to a method for treating or preventing a disease in a subject in need thereof, comprising administering a therapeutically effective dose of a peripherally selective α2-adrenergic receptor (α2AR) agonist to the subject.

[0009] In some embodiments, a peripherally selective α2AR agonist activates at least one subtype of α2AR, particularly α2A AR, α2B AR, or α2C AR.

[0010] In some embodiments, peripherally selective α2AR agonists have Kp,uu,brain values ​​of less than 0.05, 0.02, or 0.01.

[0011] In some embodiments, the disease is selected from pain, rosacea, spasticity, and aging.

[0012] In some embodiments, peripherally selective α2AR agonists cause a reduction in CNS-mediated biological effects such as sedation, hypotension, and bradycardia compared to treatment with non-peripherally selective α2AR agonists.

[0013] In another general embodiment, the disclosure provides a peripherally selective α2AR agonist comprising an α2AR activating moiety covalently bound to a peripherally distributed portion, and its use in the treatment of a disease.

[0014] In another general embodiment, the Disclosure relates to a method for treating or preventing a disease in a subject in need thereof, comprising administering a therapeutically effective dose of a peripherally selective α2AR agonist to the subject, wherein the peripherally selective α2AR agonist comprises an α2AR activating moiety covalently bound to a peripherally distributed portion.

[0015] In some embodiments, peripherally selective α2AR agonists have less sedative effect than non-peripherally selective α2AR agonists.

[0016] In another general aspect, the present disclosure provides a compound of formula (I-A): [Chemical formula] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein in the formula,[[]] Y is C(R 1 ), N, -O-C, -C-NH-, -CH2-C(O)-, or -CH=N-; when Y is C(R 1 ), R 1 is selected from H, D, and halogen; when Y is -O-C-, the oxygen atom is bonded to A, the carbon atom is bonded to both R T and B, and when Y is -C-NH-, the carbon atom is bonded to both R T and A, and the nitrogen atom is bonded to B; A is a ring selected from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl, and 2,1,3-benzothiadiazole; B is [Chemical formula] wherein X is NH, O, or S; R a is H and methyl; n is 0, 1, 2, or 3; each R 2 is H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, OR 4 , -CN, N3, NO2, N(R 4 )2, OR4, SR 4 , C(O)R 4SO2N(R 4 )2, CH2SR 4 Independently selected from alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, one or more R 5 It has been replaced with, R 4 The R is selected from H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, and alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, and optionally one or more R 5 Replaced by, R 5 These are selected from halogen, hydroxyl, -CN, -NO2, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Alternatively, A is a phenyl ring, and there are two R 2 If is substituted at an adjacent position to the phenyl ring, then two R 2 The groups, together with the carbon atoms to which they are bonded, condense on ring A to form a ring that forms a bicyclic ring, such as quinolinyl, indolyl, benzothienyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, sinnolinyl, quinoxalinyl, or 1,2,4-benzotriazinyl. m is 0, 1, 2, or 3. Each R 3These are independently selected from H, D, halogens, -OH, -SH, optionally substituted alkyls, optionally substituted heterocycles, and optionally substituted aryls. Alternatively, R 3 R is a group bonded to the -NH of the imidazole ring, 3 The following formula: [ka] And in the formula: R 5 is hydrogen or alkyl, R 6 is hydrogen, alkyl, cycloalkyl, or alkenyl, R 7 is an amino acid residue, and R 8 is alkyl or cycloalkyl, R T is R L -R P And R P R is optional. C It has been replaced with, R L It is a linker, and one end is R P It is connected to one end, and the other end is connected to the Y, R P R L It is a part that connects to one end, and R C It is a cap, R P The part that connects, Regarding compounds.

[0017] In another general embodiment, this disclosure relates to compounds of formula (IB): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y is a bond, CH(R 1), NH, -O-CH-, -C-NH-, -CH2-C(O)-, or -CH=N-, Y is C(R 1 ) If R 1 It is selected from H, D and halogen, If Y is -OC-, then the oxygen atom is bonded to A, and the carbon atom is bonded to B. If Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R 2 , n, R 3 , m and R T In equation (IA), it is defined as described above. Regarding compounds.

[0018] In another general embodiment, this disclosure relates to compounds of formula (IC): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y is a bond, CH(R 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)-, or -CH=N-, Y is C(R 1 ) If R 1 It is selected from H, D and halogen, If Y is -OC-, then the oxygen atom is bonded to A, and the carbon atom is bonded to B. If Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R 2 , n, R 3 , m and R T In equation (IA), it is defined as described above. Regarding compounds.

[0019] In another general embodiment, this disclosure relates to compounds of formula (ID): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y 1 is CH or N, X 1 It is selected from H, D and halogen, R T However, in equation (IA), as defined above, Regarding compounds.

[0020] In another general embodiment, this disclosure relates to compounds of formula (II): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, A is [ka] It was one of the selections, n1 is either 1 or 2. Each R 1 These are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl, and -COOH. B is [ka] It is one of the selected ones, where X is S, O, or NH. R T teeth, [ka] And, Ring M is C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, C 6-12 Aryl, or C 1-12is heteroaryl, C 3-12 cycloalkyl or C 2-12 heterocyclyl is optionally fused with aryl, r is 1 or 2, n2 is 0, 1, or 2, each R 2 is independently selected from hydrogen, halogen, hydroxyl, and alkoxy, R 3 is CN, hydroxyl, alkoxy, -C(O)-C 0-12 alkylene-CN, -C 0-12 alkylene-C 2-12 heterocyclyl, -SO2-alkyl, -C(O)-NR 4 R 4’ 、-SO2-NR 4 R 4’ 、-C 0-12 alkylene-R 3’ 、-O-C 0-12 alkylene-COOH, -C 0-12 alkylene-N(R 4 )-C(O)-R 5 、-C 0-12 alkylene-N(R 4 )-SO2-R 5 、-C 0-12 alkylene-C 1-12 heteroaryl, -C 0-12 alkylene-O-C 0-12 alkylene-N(R 4 )-SO2-R 5 、-C 0-12 alkylene-P(=O)(R 4 )(R 4’ )、

Chemical formula

Chemical formula

[0021] In some embodiments, the compound of formula (II) is formula (II-A): [ka] And in the formula, R 1 , R 2 , R 3 And n1 is defined in equation (II) as described above. It is a compound.

[0022] In some embodiments, the compound of formula (II) is formula (II-B): [ka] And in the formula, R 1 , R 8 n1, n3, and n4 are defined as above in equation (II), It is a compound.

[0023] In some embodiments, the compound of formula (II) is formula (II-C): [ka] And in the formula, n2 is 1 or 2, and R 1 , R 2 , R 3 And n1 is defined in equation (II) as described above. It is a compound.

[0024] In some embodiments, the compound of formula (II) is formula (II-D): [ka] And, During the ceremony, n2 is either 0 or 1. R 3 is -C(O)-NHR 4 -SO2-NHR4 -NH-C(O)-R 5 , and -NH-SO2-R 5 , and -NH-R 7 Selected from, R 4 is -C 0-12 Alkilen-NHR 6a , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a , or an alkyl group substituted with trialkylammonium, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, R 5 is -C 0-12 Alkilen-NHR 6a , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a , or an alkyl group substituted with trialkylammonium, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, Each R 6a is -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, and -C 0-12 Alkylene-C 1-12 Selected independently from heteroaryls, C3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, R 7 C 1-12 Heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(alkoxy) or -C 0-12 Alkylene-N(R) 4 )-C(=S)-R 5 and R 1 , R 2 , R 4a , and n1 and are defined in equation (II) as above, It is a compound.

[0025] In some embodiments, the compound of formula (II) is formula (II-E): [ka] And in the formula: x is either 0 or 1, y is either 0 or 1. X is S, O, or NH, and R 1 , R 2 , R 3 n1 and n2 are defined in equation (II) as described above. It is a compound.

[0026] In some embodiments, the compound of formula (II) is formula (II-F): [ka] And in the formula, R 2 is R 3 It is adjacent to R 2 and R3 Together with the carbon atoms to which they are bonded, one or more R 4a It forms a complex ring that is substituted by any choice, and R 1 , R 4a And n1 is defined in equation (II) as described above. It is a compound.

[0027] In some embodiments, the compound of formula (II) is formula (II-G): [ka] And in the formula, Each R 2 These are independently selected from hydroxyl and alkoxy compounds. R 3 is selected from hydroxyl and alkoxy, and R 1 n1 and r are defined as above in equation (II), It is a compound.

[0028] In some embodiments, the compound of formula (II) is (II-H): [ka] And in the formula, M is C 6-12 Aryl or C 1-12 It is a heteroaryl, R 3 is -C 0-12 Alkylene-COOH, -OC 0-12 Alkylene-COOH, -C 0-12 Alkylene-P(O)(OH)2,-C(O)-NH-SO2-R 5 -C(O)-NH-C 0-12 Alkylene-COOH,-NH-C 0-12 Alkylene-COOH, -SO2-OH, and [ka] Selected from, in the formula, -C 0-12 The alkylene-COOH is optionally substituted with one or more substituents selected from amino and alkylamino, and R 1 , R 2 And n1 is defined in equation (II) as described above. It is a compound.

[0029] In another aspect, the present disclosure relates to pharmaceutical compositions comprising compounds described herein or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable carriers.

[0030] In another aspect, the disclosure relates to the use of the compounds described herein or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates for the treatment or prevention of diseases, including pain, glaucoma, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, and cancer, in subjects where such use is required.

[0031] Other features and advantages of this disclosure are evident from the additional descriptions provided herein, including different examples. The examples provided illustrate different components and methodologies useful for carrying out this disclosure. Such examples do not limit the claimed disclosure. Based on this disclosure, a person skilled in the art can identify and use other components and methodologies useful for carrying out this disclosure.

[0032] The aforementioned and other purposes, aspects, features, and advantages of the exemplary embodiments can be better understood by referring to the following description, which will become more apparent and be interpreted in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0033] [Figure 1-1]Figures 1A-1H show the PWT values ​​of the Siamese mouse model group, SNI mouse model group, solvent group, and drug treatment group one hour after administration. Figure 1A: Oral administration of 3 mg / mL pregabalin. Figure 1B: Subcutaneous administration of 1 mg / mL morphine. Figure 1C: Oral administration of 1 mg / mL compound 1-B and 10 mg / mL compound 1-B. Figure 1D: Oral administration of 1 mg / mL compound 10-B. Figure 1E: Oral administration of 1 mg / mL compound 44-B and 1 mg / mL compound 45-B. Figure 1F: Oral administration of 1 mg / mL compound 46-B and 1 mg / mL compound 47-B. Figure 1G: Oral administration of 2 mg / mL compound 121 and 2 mg / mL compound 136. Figure 1H: Oral administration of 2 mg / mL compound 118 and 2 mg / mL compound 156. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 2-1] Figures 2A-2D show the PWT values ​​of the Siamese mouse model group, bone cancer pain mouse model group, solvent group, and drug treatment group one hour after drug administration. Figure 2A: Oral administration of 3 mg / mL pregabalin. Figure 2B: Subcutaneous administration of 1 mg / mL morphine. Figure 2C: Oral administration of 1 mg / mL compound 44-B. Figure 2D: Oral administration of 20 mg / mL compound 1-B and 20 mg / mL compound 44-B. [Figure 2-2] Same as above. [Figure 3-1] Figures 3A-3C show the PWT values ​​of the Siamese mouse model group, postoperative pain mouse model group, solvent group, and drug treatment group one hour after drug administration. Figure 3A: 10 mg / mL compound 1-B oral administration. Figure 3B: 10 mg / mL compound 44-B oral administration. Figure 3C: 3 mg / mL morphine subcutaneous administration. [Figure 3-2] Same as above. [Figure 4-1]Figures 4A-4C show the body weight curves (Figure 4A), tumor volume growth curves (Figure 4B), and tumor volume at day 17 (Figure 4C) for each group of mice in the MC38 syngeneic model of subcutaneous colorectal cancer, including Group 1 (control group, 0 mg / kg, oral administration, QD* days 0-17), Group 2 (clonidine, 5 mg / kg, oral administration, QD* days 0-3; 2 mg / kg, oral administration, QD* days 4-17), Group 3 (compound 1-B HCl, 5 mg / kg, oral administration, BID* days 0-17), and Group 4 (compound 1-B HCl, 10 mg / kg, oral administration, BID* days 0-3; 5 mg / kg, oral administration, QD* days 4-17). Data are expressed as "mean ± standard error". [Figure 4-2] Same as above. [Figure 5] Figures 5A-5B show the total migration distance over 0-60 minutes for the clonidine and compound 1-B HCl test (Figure 5A) and the clonidine, brimonidine tartrate and compound 44-B HCl test (Figure 5B). Data are expressed as mean ± SEM (n=6). ***p<0.001, comparison with solvent group, one-way ANOVA followed by Dunnutt's multiple comparisons. [Figure 6-1] Figures 6A-6D show the effects of clonidine and compound 44-B HCl on the rotorod test in C57BL / 6 mice 30 minutes after administration (Figure 6A). Latency times at 30 minutes (Figure 6B), 60 minutes (Figure 6C), and 120 minutes (Figure 6D). [Figure 6-2] Same as above. [Modes for carrying out the invention]

[0034] Various publications, articles, and patents are cited or referenced in the background art and throughout this specification. Each of these references is incorporated herein by reference in its entirety. Discussions of documents, acts, materials, apparatus, articles, etc., included herein are intended to provide context for this disclosure. Such discussions do not constitute any and all of the prior art relating to this disclosure.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to whom this disclosure relates. Otherwise, any specific terms used herein have the meanings set forth herein.

[0036] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references (one or more) unless the context clearly indicates otherwise.

[0037] Unless otherwise specified, the term "at least" preceding a set of elements should be understood to refer to all elements of that set. For example, "at least A, B, and C" means that each of A, B, and C exists. The term "at least one" preceding a set of elements should be understood to refer to a single element of the set, or any combination of two or more elements of the set. For example, "at least one of A, B, and C" means that only A exists, only B exists, only C exists, both A and B exist, both A and C exist, both B and C exist, or each of A, B, and C exists. Depending on the context, "at least one of ~" preceding a set of elements can also include situations where one or more of the elements exist in greater than one form. For example, "at least one of A, B, and C" can also include situations where A exists alone, or overlapping with one or more of elements B and C.

[0038] As used herein, the conjunctive term "and / or" between multiple enumerated elements is understood to encompass both individual and conjectural choices. For example, when two elements are joined by "and / or," the first choice refers to the applicability of the first element without the second element. The second choice refers to the applicability of the second element without the first element. The third choice, constitutively, refers to the applicability of the first and second elements together. Any one of these choices is understood to fall within its meaning and therefore satisfy the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more choices is also understood to fall within its meaning and therefore satisfy the requirements of the term "and / or."

[0039] Unless otherwise specified, any numerical values, such as concentrations or concentration ranges, described herein should be understood in all cases to be modified by the term “approximately.” Therefore, numerical values ​​typically include ±10% of the listed values. For example, the description “10 times” includes 9 times and 11 times. Where used herein, the use of numerical ranges explicitly includes all possible substitutions and combinations of subranges, all individual numerical values ​​within that range, integers and values ​​within such ranges, unless the context clearly indicates otherwise.

[0040] As used herein, “Subject” means any animal that is treated or has been treated by the methods described herein, such as mammals, in particular humans. As used herein, the term “mammal” encompasses any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys and apes, and humans.

[0041] The term "pharmaceutically acceptable salt" refers to a salt of a target compound that is safe and effective for topical use in mammals and possesses the desired biological activity. pharmaceutically acceptable salts include salts of acidic or basic groups present in a particular compound. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, carbonates, bicarbonates, acetates, lactates, salicylates, citrates, tartrates, propionates, butyrates, pyruvates, oxalates, malons, pantothenates, bitartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucarons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds used in this disclosure can form pharmaceutically acceptable salts with a variety of amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts. For a review of pharmaceutically acceptable salts, see Berge et al., 66 J.Pharm.Sci.1-19(1977), which is incorporated herein by reference.

[0042] As used herein, the term “alkyl” means a saturated, monovalent, unbranched, or branched hydrocarbon chain. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups may have a specified number of carbon atoms. Where a number appears as a subscript after the symbol “C”, the subscript more specifically defines the number of carbon atoms that a particular alkyl group may contain. For example, “C1-C 10 "Alkyl" or "C 1-10 The term "alkyl" is intended to include alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C1-C8 alkyl" or "C 1-8 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0043] As used herein, the term “alkenyl” refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. The alkenyl group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). Where a number appears as a subscript after the symbol “C”, the subscript more specifically defines the number of carbon atoms that the particular alkenyl may contain. For example, “C2-C 10 "Alkenil" or "C 2-10 The term "alkenyl" is intended to include alkenyl groups having 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C2-C8 alkenyl" or "C 2-8 "Alkenyl" refers to an alkenyl having 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0044] As used herein, the term “alkynyl” refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more suitable substituents. The term “alkynyl” also includes groups having one triple bond and one double bond. Where a number appears as a subscript after the symbol “C”, the subscript more specifically defines the number of carbon atoms that the particular alkynyl may contain. For example, “C2-C 10 "Alkinyl" or "C 2-10 "Alkynyl" is intended to include alkynyl groups having 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C2-C8 alkynyl" or "C 2-8 "Alkynyl" refers to an alkynyl having 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0045] As used herein, the term “cycloalkyl” refers to any stable monocyclic or polycyclic saturated hydrocarbon ring system. Cycloalkyl groups may be unsubstituted or substituted with one or more suitable substituents. Cycloalkyl groups may have a specified number of carbon atoms. For example, “C3-C6 cycloalkyl” or “C 3-6"Cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, or 6 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Polycyclic cycloalkyls include bridging ring structures, fused ring structures, and spiro ring structures, where all ring atoms are carbon atoms. A "spiro ring" is a polycyclic ring system in which two rings share one carbon atom, typically called a "spiro atom," which is a quaternary carbon atom. A "fused ring" is a polycyclic ring system in which two rings share two adjacent atoms called "bridgehead atoms," i.e., the two rings share one covalent bond so that the bridgehead atoms are directly bonded. A "bridging ring" is a polycyclic ring system in which two rings share three or more atoms, with the bridgehead atoms separated by a bridging containing at least one atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0046] As used herein, the term “aryl” refers to any carbon-based aromatic group, including but not limited to phenyl, naphthyl, anthracenyl, and phenanthranil. The aryl portion is well known; see, for example, Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). The aryl group may be substituted or unsubstituted with one or more suitable substituents. The aryl group may have a monocyclic structure (i.e., monocyclic formula) or a polycyclic structure (i.e., polycyclic formula, e.g., bicyclic or tricyclic). For example, the aryl group may be a monocyclic aryl group, e.g., phenyl.

[0047] The term “heterocyclyl” encompasses stable monocyclic and polycyclic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen, whose ring structure is saturated or partially unsaturated, unless the ring system is entirely aromatic. The heterocyclyl group may be unsubstituted or may be substituted with one or more suitable substituents on one or more carbon atoms and / or nitrogen heteroatoms of the heterocyclyl. Heterocyclyls may include monocyclic (i.e., monocyclic) or polycyclic (i.e., polycyclic, e.g., bicyclic) structures. Polycyclic heterocyclyls include bridging ring structures, fused ring structures, and spiro-ring structures, where at least one ring atom of at least one ring of the polycyclic ring system is a heteroatom, e.g., oxygen, nitrogen, or sulfur, as defined above. The heterocyclyl ring can be bonded to the parent molecule at any suitable heteroatom (typically nitrogen) or carbon atom of the ring. The term "4- to 9-membered monocyclic or bicyclic heterocyclil" includes a 4, 5, 6, 7, 8, or 9-membered monocyclic or bicyclic ring structure containing at least one heteroatom ring member selected from oxygen, nitrogen, and sulfur, or independently selected from oxygen and nitrogen, and optionally containing 1 to 3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, or independently selected from oxygen and nitrogen, provided that the ring structure is saturated or partially unsaturated, but not entirely aromatic.

[0048] In certain embodiments, the term “heterocyclyl” refers to 4, 5, 6, or 7-membered monocyclic and 6, 7, 8, or 9-membered bicyclic groups having at least one heteroatom (O, S, or N) in at least one of the rings, where the heteroatom-containing ring typically has one, two, or three heteroatoms, such as one or two heteroatoms independently selected from O, S, and / or N, or independently selected from O and N. Where a number appears as a subscript after the symbol “C”, the subscript more specifically defines the number of carbon atoms that the particular heterocycle may contain, in addition to the heteroatoms that the particular heterocycle may contain. For example, “C1-C 10 "Heterocyclyl" or "C 1-10A "heterocyclyl" is intended to contain a heterocyclyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C1-C8 heterocyclyl" or "C 1-8 "Heterocyclyl" refers to a heterocyclyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0049] Examples of monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranil, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, piperazinyl, dioxanil, morpholinil, azepanil, oxepanil, and oxazepanil (e.g., 1,4-oxazepanil, 1,2-oxazepanil). Examples of bicyclic heterocyclyl groups include, but are not limited to, 2-azabicyclo[2.2.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[3.3]heptanyl, 3-azabicyclo[2.2.2]octanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 7-oxa-2-azabicyclo[3.5]nonanyl, and 5-azabicyclo[2.3]hexanyl.

[0050] As used herein, the term “heteroaryl” includes stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups may be unsubstituted or substituted with one or more suitable substituents. Heteroaryls may have monocyclic (i.e., monocyclic) or multicyclic (i.e., polycyclic, e.g., bicyclic or tricyclic) structures. Each ring of a heteroaryl group containing heteroatoms may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. Heteroaryl groups that are polycyclic, e.g., bicyclic or tricyclic, must contain at least one fully aromatic ring, but the other fused rings may be aromatic or non-aromatic. For example, in the case of a bicyclic heteroaryl, the fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Heteroaryls can be bonded to the parent molecule at any available nitrogen or carbon atom on any ring of the heteroaryl group. In some embodiments, the term “heteroaryl” refers to five or six-membered monocyclic groups and nine or ten-membered bicyclic groups having at least one heteroatom (O, S, or N) on at least one of the rings, and the heteroatom-containing rings typically have one, two, or three heteroatoms, such as one or two heteroatoms selected from O, S, and / or N. Heteroaryl groups may be unsubstituted or may be substituted with one or more suitable substituents on one or more of the carbon and / or nitrogen heteroatoms of the heteroaryl. The nitrogen and sulfur heteroatoms of the heteroaryl may optionally be oxidized (i.e., N → O and S(O)r, where r is 0, 1, or 2).

[0051] When a number appears as a subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular heteroaryl can contain, in addition to the heteroatoms that the particular heteroaryl can contain. For example, "C1-C 10 "heteroaryl" or "C 1-10The term "heteroaryl" is intended to include heteroaryl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C1-C8 heteroaryl" or "C 1-8 "Heteroaryl" refers to a heteroaryl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0052] Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanil, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranil, indolidinyl, benzofuranil, chromonyl, coumalinyl, benzopyranil, sinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, phlopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0053] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. The alkoxy group is bonded to the parent molecule via a bond with an oxygen atom. The alkoxy group may have a specified number of carbon atoms. For example, "C1-C 10 "alkoxy" or "C 1-10 "Alkoxy" is intended to include alkoxy groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Furthermore, for example, "C1-C4 alkoxy" or "C 1-4"Alkoxy" refers to an alkoxy having one, two, three, or four carbon atoms. Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy), butoxy (e.g., n-butoxy, isobutoxy, tert-butoxy), and pentyloxy (e.g., n-pentyloxy, isopentyloxy, neopentyloxy). The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above, such as -S-methyl, -S-ethyl, etc., bonded to the parent molecule via a bond to a sulfur atom. Typical examples of alkylthios include, but are not limited to, -SCH3, -SCH2CH3, etc.

[0054] As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine. Correspondingly, the term "halo" means fluoro, chloro, bromo, and iodine.

[0055] "Haloalkyl" is intended to include both branched and linear saturated aliphatic hydrocarbon groups substituted with one or more halogen atoms. "Fluorinated alkyl" or "fluoroalkyl" refers in particular to any alkyl group as defined above substituted with at least one fluoro atom, e.g., 1 to 3 fluoro atoms, e.g., 1, 2, or 3 fluoro atoms. Examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Preferred examples of fluoroalkyls include, but are not limited to, -CF3, -CHF2, -CH2CF3, and -CF2CF3.

[0056] The terms "hydroxy" and "hydroxyl" can be used interchangeably and refer to the -OH group.

[0057] The terms "carboxy" and "carboxyl" can be used interchangeably and refer to the -COOH group.

[0058] The term "ester" refers to -COOR, where R is an alkyl group as defined above.

[0059] The term "cyano" refers to -CN.

[0060] The term "oxo" refers to a double-bonded oxygen group, i.e., a substituent with the formula =O.

[0061] The term "keto" refers to -C(O)R, where R is an alkyl group as defined above.

[0062] As used herein, the term "amino" refers to -NH2. One or more hydrogen atoms of an amino group may be substituted by substituents such as alkyl groups, referred to as "alkylamino." An alkylamino group has one or both hydrogen atoms of an alkyl-substituted amino group and is bonded to the parent molecule via a bond with the nitrogen atom of the alkylamino group. Examples of alkylaminos include methylamino (-NHCH3), dimethylamino (-N(CH3)2), and -NHCH2CH3.

[0063] As used herein, the term “aminoalkyl” is intended to include both branched and linear saturated aliphatic hydrocarbon groups substituted with one or more amino groups. For example, “C 1-4 The term "aminoalkyl" is intended to include alkyl groups having 1, 2, 3, or 4 carbon atoms substituted with one or more amino groups. The aminoalkyl group is bonded to the parent molecule via a bond between the alkyl portion of the aminoalkyl group and the carbon atoms. Typical examples of aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, and -CH2CH(NH2)CH3.

[0064] As used herein, "amide" refers to -C(O)N(R)2, where each R is independently an alkyl group (including both branched and linear alkyl groups) or a hydrogen atom. Examples of amide groups include, but are not limited to, -C(O)NH2, -C(O)NHCH3, and -C(O)N(CH3)2.

[0065] The terms "hydroxyl-substituted alkyl," "hydroxyl alkyl," and "hydroxyalkyl" are used interchangeably and refer to a branched or linear aliphatic hydrocarbon group substituted with one or more hydroxyl groups. A hydroxyalkyl group is bonded to its parent molecule via a bond to the carbon atoms of the alkyl portion of the hydroxyalkyl group. A hydroxyalkyl group can have a specified number of carbon atoms. For example, "C1-C 10 "Hydroxyalkyl" or "C 1-10 The term "hydroxyalkyl" is intended to include hydroxyalkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. Also, for example, "C1-C4 hydroxyalkyl" or "C 1-4 "Hydroxyalkyl" refers to a hydroxyalkyl group having 1, 2, 3, or 4 carbon atoms. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (-CH2OH) and hydroxyethyl (-CH2CH2OH).

[0066] As used herein, “amide” refers to -N(R')C(O)R, where each R and R' is independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Examples of amide groups include, but are not limited to, -NHC(O)CH3, -NHC(O)CH2CH3, and -N(CH3)C(O)CH3.

[0067] As used herein, "carbamide" refers to -N(R')C(O)N(R)2, where each R and R' is independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Examples of carbamide groups include, but are not limited to, -NHC(O)NH2, -NHC(O)NHCH3 (methylcarbamide), and -NHC(O)NH(Ph).

[0068] As used herein, "sulfonamide" refers to -N(R')SO2-R, where each R and R' is independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl groups. Examples of sulfonamide groups include, but are not limited to, -NHSO2CH3 (methylsulfonamide) and -NHSO2Ph.

[0069] In accordance with the conventions used in this technical field, [ka] In the structural formulas of this specification, is used to represent the bonding site of a group, site, or substituent to the core, backbone, or parent molecule structure.

[0070] If it has been shown that the bond to the substituent intersects with a bond connecting two atoms in the ring, then such a substituent can bond to any atom on the ring.

[0071] As used herein, the term “substituted” with respect to any organic radical (e.g., alkyl, cycloalkyl, heteroaryl, aryl, heterocyclyl, etc.) means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that all normal valencies are maintained and the substitution results in a stable compound. When a particular group is “substituted,” it may have one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 to 2 substituents, independently selected from a list of substituents. The term “independently,” when used with respect to substituents, means that if two or more such substituents are possible, such substituents may be the same or different from one another. Suitable examples of substituents include, but are not limited to, alkyl, halo, haloalkyl, alkoxy, amide, hydroxy, hydroxyalkyl, amino, carboxyl, ester, oxo, and cyano.

[0072] If any variable appears two or more times in any component or formula of a compound, its definition in each appearance is independent of its definition in every other appearance. Therefore, for example, if a group is shown to be substituted with 0 to 3 R groups, this group may be optionally substituted with up to 3 R groups, and in each appearance, R is selected independently of the definition of R.

[0073] The terms "optional" or "optionally" mean that the described event or situation may occur but is not required, and such description includes situations in which the event or situation may or may not occur. For example, "optionally substituted heterocyclyl" means that substituents may or may not be present, and such description includes situations in which the heterocyclyl group is substituted with an appropriate substituent and the heterocyclyl group is not substituted with any substituent.

[0074] Those skilled in the art will recognize that, in certain embodiments, the compounds described herein may have one or more chiral carbon atoms in their structure. Any chemical formula, as used herein, in which a bond is shown only as a solid line and not as a solid wedge bond or hashed wedge bond, or which is shown to have a specific arrangement (e.g., R or S) around one or more atoms, each assumes a possible stereoisomer or a mixture of two or more stereoisomers. Stereoiomers include enantiomers and diastereomers. Enantiomers are stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images, and arise when two or more stereoisomers of a compound have different stereoconfigurations in one or more equivalent stereocenters and are not mirror images of each other. Substituents (e.g., alkyl, heterocyclyl, etc.) may contain stereocenters in either an R configuration or an S configuration.

[0075] Certain examples include chemical structures containing the terms (R) or (S). When (R) or (S) is used in the name or chemical representation of a compound, it is intended to mean that the compound is a single isomer at its stereocenter having an established absolute configuration of either (R) or (S).

[0076] Stereochemically pure isomers can be obtained by techniques known in the art in consideration of this disclosure. For example, diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatography, and enantiomers can be separated from each other by selective crystallization or chiral chromatography of diastereoisomer salts with optically active acids or bases. Pure stereoisomers can also be prepared synthetically from suitable stereochemically pure starting materials or by using stereoselective reactions.

[0077] The compounds described herein can also form tautomers. The term "tautomer" refers to a compound that is an interchangeable form of a particular compound structure, in which the substitution of hydrogen atoms and electrons changes. Tautomers are constituent isomers of chemical compounds that readily interconvert, usually resulting in the rearrangement of protons (hydrogen). Thus, the two structures can reach equilibrium through the movement of π electrons and atoms (usually hydrogen). All tautomers and mixtures of tautomers of the compounds described herein are included in the scope of this disclosure.

[0078] The compounds described herein may exist in solvated and unsolvated forms. The term “solvate” means the physical association of a compound described herein with one or more solvent molecules, for example, by hydrogen bonding. Solvent molecules in a solvate may exist in regular and / or irregular arrangements. A solvate may contain either stoichiometric or unstoichiometric amounts of solvent molecules. “Solvate” encompasses both solution-phase solvates and isolateable solvates. The compounds described herein may form solvates with water (i.e., hydrates) or common organic solvents. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanelates, and isopropanolates. Methods of solvation are generally known in the art.

[0079] All isotopes of atoms present in the compounds described herein, including intermediates and final products, are also included within the scope of this disclosure. Isotopes include atoms with the same atomic number but different mass numbers. Common examples of hydrogen isotopes include, but are not limited to, deuterium and tritium. Carbon isotopes include, 13 C and 14 C is included.

[0080] This disclosure further includes isotope-labeled compounds. An “isotope-labeled” or “radiolabeled” compound is a compound of this disclosure in which one or more atoms are replaced or substituted by atoms having atomic masses or mass numbers different from those typically found in nature (i.e., naturally occurring). Isotope-labeled compounds can generally be prepared by the prior art known to those skilled in the art, or by processes similar to those described herein, using appropriate isotope-labeling reagents instead of unlabeled reagents used in other methods.

[0081] As used herein, the names of compounds are intended to encompass all possible existing isomeric forms of the compound, including stereoisomers (e.g., enantiomers, diastereomers, racemates or racemic mixtures, and any mixtures thereof).

[0082] In a general embodiment, the disclosure relates to a method for treating or preventing a disease in a subject requiring such treatment, comprising administering a therapeutically effective dose of a peripherally selective α2AR agonist to the subject.

[0083] In some embodiments, a peripherally selective α2AR agonist activates at least one subtype of α2AR, particularly α2A AR, α2B AR, or α2C AR.

[0084] In some embodiments, the diseases include glaucoma, pain, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, and cancer.

[0085] In certain embodiments, the disease is selected from pain, rosacea, spasticity, and aging.

[0086] In some embodiments, treatment with a peripherally selective α2AR agonist has less sedative effect than treatment with a non-peripherally selective α2AR agonist, at similar or equivalent dosages.

[0087] In some embodiments, the peripherally selective α2AR agonist includes an α2AR activating moiety covalently bound to the peripherally distributed portion.

[0088] In another general embodiment, the disclosure provides a peripherally selective α2AR agonist comprising an α2AR activating moiety covalently bound to a peripherally distributed portion, and its use in the treatment or prevention of disease.

[0089] In some embodiments, the diseases include glaucoma, pain, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, and cancer.

[0090] In a particular embodiment, the disease is pain.

[0091] Pain, as a complex and multidimensional sensory and emotional experience, presents a significant challenge to human health. It is not only a major symptom of physical illness but also a significant factor affecting quality of life and causing considerable physical and mental distress to patients. The key components of pain are neuropathic pain and nociceptive pain. Neuropathic pain is caused by lesions or diseases of the somatosensory nervous system. Neuropathic pain can be divided into central neuropathic pain and peripheral neuropathic pain. Central neuropathic pain includes spinal cord injury, post-stroke pain, and MS pain, while peripheral neuropathic pain includes diabetic neuropathy, postherpetic neuralgia, HIV-related pain, chemotherapy-induced peripheral neuropathy, and postoperative neuropathic pain. Currently, first-line treatments include gabapentinoids, tricyclic antidepressants, and norepinephrine / serotonin reuptake inhibitors. While these drugs can alleviate pain to some extent, the side effects of long-term use still lead to a decline in patients' quality of life. Second-line therapies such as opioate receptor agonists not only have side effects but also high addiction rates and cause many social impacts, and are not adequately meeting the demand for neuropathic pain treatment.

[0092] Alpha-2-arsenic agonists such as clonidine and dexmedetomidine are considered important methods for treating pain in academic research and clinical applications. Scientists have found that intrathecal administration of alpha-2-arsenic agonists can effectively reduce pain. However, there are limitations to the therapeutic benefits of alpha-2-arsenic agonists. Existing alpha-2-arsenic agonists are often associated with a variety of biological reactions, including sedation, hypotension, bradycardia, drowsiness, dizziness, depression, orthostatic hypotension, constipation, nausea, stomach upset, dry mouth (xerostomia), dry nasal mucosa, impotence, fluid retention, edema, and pupil dilation. These other biological effects, particularly sedation, limit the doses that can be safely administered, thereby limiting the broad usefulness of these drugs in long-term pain management. This not only affects the patient's quality of life but also limits the applicability of these drugs to various types and levels of pain symptoms. These biological effects, particularly sedation, have a serious impact on the application of alpha-2-arsenic agonists in the field of medical use.

[0093] Therefore, there is a need to develop novel α2AR agonist compounds to treat pain by reducing sedation. Our research aims to make a significant contribution to the field of pain management by providing not only more effective but also safer long-term non-opioid alternatives. The compounds and methods described herein may be useful in addressing such unmet needs.

[0094] As used herein, “effective amount” means the amount of a composition or compound that elicits a biological or medical response in a tissue system or subject as sought by a researcher, veterinarian, physician, or other professional, which may include relief of symptoms of the disease, disorder, or condition being treated. The effective amount may vary depending on various factors such as the subject’s physical condition, age, weight, health status, and the specific disease, disorder, or condition being treated. The effective amount can be readily determined by those skilled in the art in consideration of this disclosure.

[0095] In a particular embodiment, the effective amount refers to an amount of the composition or compound described herein that is sufficient to activate α2AR. In another particular embodiment, the effective amount refers to an amount of the composition or compound described herein that is sufficient to treat or prevent a disease or alleviate symptoms associated with a disease.

[0096] In some embodiments, the pain is nociceptive pain, neuropathic pain such as peripheral neuropathic pain, or mixed pain.

[0097] In some embodiments, neuropathic pain includes cancer-related pain, diabetic neuropathy, post-infectious neuralgia, trigeminal neuralgia, peripheral neuropathy, immune-mediated neuropathy, HIV-related pain, post-stroke pain syndrome, phantom limb pain, chemotherapy-induced peripheral neuropathy, complex regional pain syndrome, and metabolic, endocrine, and toxic neuropathy, chronic post-surgical pain, traumatic peripheral nerve injury, locked-in syndrome, and hereditary neuropathy.

[0098] In some embodiments, the pain is postoperative pain.

[0099] In some embodiments, the peripherally selective α2AR agonist includes an α2AR activating moiety covalently bound to the peripherally distributed portion.

[0100] In another general embodiment, the Disclosure relates to a method for treating or preventing a disease in a subject in need thereof, comprising administering a therapeutically effective dose of a peripherally selective α2AR agonist to the subject, wherein the peripherally selective α2AR agonist comprises an α2AR activating moiety covalently bound to a peripherally distributed portion.

[0101] In some embodiments, the diseases include glaucoma, pain, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, and cancer.

[0102] In some embodiments, the disease is glaucoma or cancer.

[0103] In some embodiments, the disease is pain.

[0104] In some embodiments, the pain is nociceptive pain, neuropathic pain such as peripheral neuropathic pain, or mixed pain.

[0105] In some embodiments, neuropathic pain includes cancer-related pain, diabetic neuropathy, post-infectious neuralgia, trigeminal neuralgia, peripheral neuropathy, immune-mediated neuropathy, HIV-related pain, post-stroke pain syndrome, phantom limb pain, chemotherapy-induced peripheral neuropathy, complex regional pain syndrome, and metabolic, endocrine, and toxic neuropathy, chronic post-surgical pain, traumatic peripheral nerve injury, locked-in syndrome, and hereditary neuropathy.

[0106] In some embodiments, the pain is postoperative pain.

[0107] In some embodiments, treatment with a peripherally selective α2AR agonist results in fewer side effects than treatment with a non-peripherally selective α2AR agonist, at similar or equivalent dosages.

[0108] In some embodiments, treatment with peripherally selective α2AR agonists does not cause side effects.

[0109] The following embodiments apply to all of the general embodiments described above.

[0110] In some embodiments, side effects include sedation, decreased heart rate, and decreased blood pressure, with sedation being a particularly significant side effect.

[0111] As used herein, the term "non-peripherally selective α2AR agonist" refers to a compound that readily distributes to the CNS after administration to a subject and binds to and activates α2AR receptors in both the central nervous system (brain and spinal cord) and the peripheral nervous system. Examples of non-peripherally selective α2AR agonists include, but are not limited to, dexmedetomidine and clonidine.

[0112] While not bound by theory, if an α2AR agonist binds to α2AR in the central nervous system and activates α2AR, the α2AR agonist may cause the aforementioned side effects in patients, including sedation, decreased heart rate, blood pressure, depression, bradycardia, orthostatic hypotension, constipation, nausea, stomach upset, dry mouth (xerostomia), nasal dryness, impotence, fluid retention, edema, and pupil dilation.

[0113] As used herein, the term “peripherally selective α2AR agonist” refers to a compound that exerts its effects primarily outside the central nervous system (CNS) because it is typically hindered by the blood-CNS barrier. The blood-CNS barrier, a physical barrier between the blood and the CNS, protects the CNS from both toxic and pathogenic agents in the blood. The blood-CNS barrier includes the blood-brain barrier, the blood-spinal cord barrier, and the blood-CSF (cerebrospinal fluid) barrier. By significantly hindering entry into the CNS, compounds can act on the rest of the body with few or no side effects associated with their effects on the brain or spinal cord. Examples of peripherally selective α2AR agonists include, but are not limited to, the compounds described herein, such as those of formula (IA), (IB), (IC), (ID), or (II) as described herein.

[0114] Peripherally selective α2AR agonists primarily bind to or activate α2AR outside the CNS, and therefore produce fewer or no of the aforementioned side effects compared to non-peripherally selective α2AR agonists. This invention addresses an unmet need and has developed a series of peripherally selective α2AR agonists.

[0115] In some embodiments, peripherally selective α2AR agonists bind to α2AR at Ki values ​​in the ranges of 250 nM to 1000 nM, 50 nM to 250 nM, 10 nM to 50 nM, or less than 10 nM. In some other embodiments, peripherally selective α2AR agonists activate α2AR at EC50 values ​​in the ranges of 250 nM to 1000 nM, 50 nM to 250 nM, 10 nM to 50 nM, or less than 10 nM.

[0116] Non-peripherally selective α2AR agonists and peripherally selective α2AR agonists can be distinguished in terms of their permeability across the blood-brain barrier (BBB). Drugs that specifically target the central nervous system (CNS) must first cross the BBB. In contrast, peripherally selective drugs exert their effects mainly outside the CNS because they are primarily hindered by the blood-brain barrier (BBB). The blood-brain barrier (BBB) ​​substantially limits the entry of these drugs into the CNS, resulting in a dominance of drug concentrations outside the CNS compared to inside. The BBB permeability of a compound can be measured using any method known in the art. For example, one experimental measure of BBB permeability is Kp, which is the concentration of the drug in the brain divided by its concentration in the blood.

[0117] As used herein, “Kp” or “B / P ratio” refers to the ratio of the concentrations of a compound in the brain and blood. Kp is often calculated as “logBB,” which refers to the logarithmic ratio of the concentrations of a compound in the brain and blood. Kp is a common value used to describe permeability across the blood-brain barrier. In some embodiments, a compound is considered “peripherally selective” if, upon administration to a subject, its Kp is less than 0.4, 0.2, 0.1, 0.05, 0.02, or 0.01.

[0118] Kp,uu,brain is another common numerical value used to describe permeability across the blood-brain barrier. As used herein, "Kp,uu,brain" or "Kp,uu" refers to the unbound brain-to-plasma partition coefficient. This represents the ability of a drug to cross the blood-brain barrier (BBB) ​​after systemic administration. Kp,uu provides a more accurate measure of the distribution equilibrium of unbound fractions in the brain and plasma.

[0119] Any method known in the art can be used to measure Kp,uu,brain. One example is the area under the curve (AUC) method, which calculates the AUC of the unbound drug concentration-time profile in both brain and plasma after a single dose. Another example is steady-state concentration, which uses the steady-state unbound concentration of the drug in brain interstitial fluid (C_u,brain,ss) and plasma (C_u,plasma,ss).

[0120] In some embodiments, a compound is considered “peripherally selective” if, at the time of administration to a subject, its Kp,uu,brain is less than 0.4, 0.2, 0.1, 0.05, 0.02, or 0.01. In some further embodiments, a compound is considered “peripherally selective” if, at the time of administration to a subject, its Kp,uu,brain is less than 0.05, 0.02, or 0.01.

[0121] In some embodiments, peripherally selective α2AR agonists include an α2AR activating moiety covalently bound to the peripherally distributed portion.

[0122] In certain embodiments, the α2AR activating moiety is a non-peripherally selective α2AR agonist or another peripherally selective α2AR agonist.

[0123] In certain embodiments, the α2AR activating moiety is (R)-3-nitrobiphenillin, A-193080, ADX-415, AGN192836, AGN-191103, AGN-197075, AGN-201781, AGN-241622, amitraz, apralonidine, AR-08, betanidine, brimonidine, 48962, bromocriptine, tyrazoline, clonidine, detomidine, detomidine carboxylic acid, dexmedetomidine, dipivefrin, DL-methylfedrine, droxidopa, epinephrine, ergotamine, etilephrine, etomidate, fadorumidine, guanabenz, guanethidine, guanfacine, guanxabenz, indanidine, lophenidine The α2AR agonist is selected from the group consisting of medetomidine, mephentermine, metamfetamine, metalaminolmethoxamine, methyldopa, methyldopert, methyldopert hydrochloride, methylnorepinephrine, mibazerol, moxonidine, naphazoline, norepinephrine, norphenephrine, octopamine, ODM-105, oxymetazoline, pergolide, phenylpropanolamine, povafonidine, propylhexedrine, pseudoephedrine, racepinephrine, rezatomidine, lylmenidine, romifidine, synephrine, talipexol, tashipimidine, thiamenidine, tizanidine, xylazine, xylometazoline, and their functional derivatives.

[0124] As used herein, a functional derivative of an α2AR agonist refers to any compound derived from an α2AR agonist by a chemical reaction. Examples of derivatives include, but are not limited to, salts of acids or bases, prodrugs, and compounds containing protected functional groups such as hydroxyl, amino, carboxyl, or carbonyl groups.

[0125] In certain embodiments, the α2AR activating moiety is a non-peripherally selective α2AR agonist, such as dexmedetomidine, brimonidine, and clonidine.

[0126] In certain embodiments, the α2AR activating moiety is dexmedetomidine.

[0127] As used herein, the term “peripheral distribution portion” refers to a portion that can increase or improve the peripheral selectivity of an α2AR agonist. In some embodiments, peripheral selectivity is increased or improved so that the α2AR agonist is a peripherally selective α2AR agonist.

[0128] According to embodiments of this disclosure, the peripheral distribution portion may be the following chemical fragments. • Type A fragments; those that can increase the overall molecular polarity of a compound or decrease its overall lipophilicity; • Type B fragments: those that can increase the overall molecular weight or molecular size of a compound; and • C-type fragments: those containing substrate elements for efflux transporters.

[0129] In some embodiments, the peripheral distribution portion is a type A fragment.

[0130] In certain embodiments, the A-type fragment increases the total number of intermolecular hydrogen bonds (H bonds) within a compound, such as an H-bond donor and an H-bond acceptor. In preferred embodiments, the A-type fragment is an H-bond donor.

[0131] In certain embodiments, the A-type fragment increases the overall molecular polarity of the compound. For example, such an A-type fragment may contain a polar functional group or a charged group. Examples of polar functional groups include, but are not limited to, hydroxyl groups, amine groups, amide groups, sulfonamide groups, carboxyl groups, ether groups, imine groups, hydroxylamine groups, ester groups, aldehyde groups, ketone groups, nitro groups, phosphoric acid groups, thioether groups, and sulfone groups. Examples of charged groups include, but are not limited to, quaternary ammonium compounds, carboxylic acids, and organic acids such as sulfonic acids.

[0132] In certain embodiments, the A-type fragment reduces the overall lipophilicity of the compound. Examples of such A-type fragments include, but are not limited to, alkyl or acyl groups added to functional groups such as hydroxyl and amino.

[0133] In certain embodiments, the A-type fragment is not capable of assisting in the formation of a tertiary amine or an intramolecular H bond.

[0134] In some embodiments, the peripheral distribution portion is a type B fragment.

[0135] In certain embodiments, the B-type fragment is a bulky group that can increase the overall molecular weight and molecular size of the compound. Examples of such B-type fragments include, but are not limited to, long alkyl chains, polyethylene glycol (PEG), large aromatic groups, and extra cyclic or heterocyclic groups.

[0136] In some embodiments, the peripheral distribution portion is a C-type fragment.

[0137] In certain embodiments, the C-type fragment comprises a substrate element of an efflux transporter, and the efflux transporter is a P-glycoprotein (P-gp) transporter, a breast cancer resistance protein (BCRP) transporter, or a multidrug resistance protein 2 (MRP2) transporter. As used herein, the term “efflux transporter substrate element” refers to a fragment that makes the compound a substrate for an efflux transporter. In other words, the term “efflux transporter substrate element” refers to a fragment that is a substrate for an efflux transporter.

[0138] In certain embodiments, the C-type fragment includes a P-gp substrate element.

[0139] While not bound by theory, P-gp efflux is a significant limiting factor for blood-brain barrier (BBB) ​​permeability. Any method known in the art can be used to determine whether a compound is a P-gp substrate. For example, P-gp substrates can be identified using the efflux ratio obtained from an in vitro P-gp assay, MDCK-MDR1. A compound is considered a P-gp substrate if its efflux ratio is greater than 2, 5, 8, 10, 50, or 100.

[0140] Alternatively, there are several rules for determining potential P-gp efflux substrates. • The total number of N atoms and O atoms (N+O) ≥ 8; • Molecular weight (MW) greater than 400; and / or Acids with pKa > 4. In contrast, if a compound is a base with N+O<4, MW<400, and / or pKa<8, it is a non-substrate of P-gp.

[0141] Certain structural modifications can improve P-gp efflux by removing steric hindrance to hydrogen bond donor atoms through the bonding of bulky groups or demethylation of nitrogen atoms, and by improving hydrogen bond potential through the removal of adjacent electron-withdrawing groups or the introduction of hydrogen bond groups such as amides.

[0142] In certain embodiments, the substrate element of P-gp includes one or more of the above-described structural modifications.

[0143] In a particular embodiment, the P-gp substrate element is [ka] Selected from.

[0144] In certain embodiments, the C-type fragment contains a substrate element of the BCPR transporter.

[0145] In certain embodiments, the C-type fragment contains a substrate element of the MPR2 transporter.

[0146] In certain embodiments, the C-type fragment does not contain substrate elements for uptake transporters such as LAT1, GLUT1, MCT1, CAT1, CNT2, OATP, PEPT1, PEPT2, and OCT.

[0147] In some embodiments, the peripheral distribution portion reduces and / or minimizes brain exposure to a peripherally selective α2AR agonist.

[0148] In certain embodiments, the peripheral distribution portion reduces passive intercellular BBB permeability by increasing topological polar surface area (TPSA), increasing molecular weight, increasing polarity, or by adding hydrogen bonds, particularly hydrogen bond donors.

[0149] In a particular embodiment, the peripheral distribution portion involves introducing an acidic group to a peripherally selective α2AR agonist.

[0150] In certain embodiments, the peripheral distribution portion includes a substrate element of P-gp, which increases P-gp efflux by increasing lipophilicity, increasing hydrogen bond receptors, removing steric hindrance around hydrogen bond receptors, or removing electron-withdrawing groups adjacent to hydrogen bond receptors.

[0151] In certain embodiments, the peripheral distribution portion is designed to make the compound a bisubstrate for both P-gp and BCRP.

[0152] compound In a general form, this disclosure is based on formula (IA): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y is C(R 1 ), N, -OC, -C-NH-, -CH2-C(O)-, or -CH=N-, Y is C(R 1 ) If R1 It is selected from H, D and halogen, If Y is -OC-, the oxygen atom is bonded to A and the carbon atom is R T B is bound to both B and; If Y is -C-NH-, then the carbon atom is R T The nitrogen atom is bonded to both A and B, A is a ring selected from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl, and 2,1,3-benzothiadiazole. B is [ka] In the formula, X is NH, O, or S, and R a These are H and methyl, n is 0, 1, 2, or 3. Each R 2 H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, OR 4 -CN, N3, NO2, N(R 4 )2, OR4, SR 4 , C(O)R 4 SO2N(R 4 )2, CH2SR 4 Independently selected from alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, one or more R 5 It has been replaced with, R 4The R is selected from H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, and alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, and optionally one or more R 5 Replaced by, R 5 These are selected from halogen, hydroxyl, -CN, -NO2, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Alternatively, A is a phenyl ring, and there are two R 2 If is substituted at an adjacent position to the phenyl ring, then two R 2 The groups, together with the carbon atoms to which they are bonded, condense on ring A to form a ring that forms a bicyclic ring, such as quinolinyl, indolyl, benzothienyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, sinnolinyl, quinoxalinyl, or 1,2,4-benzotriazinyl. m is 0, 1, 2, or 3. Each R 3 These are independently selected from H, D, halogens, -OH, -SH, optionally substituted alkyls, optionally substituted heterocycles, and optionally substituted aryls. Alternatively, R 3 R is a group bonded to the -NH of the imidazole ring, 3 The following formula: [ka] And in the formula: R 5is hydrogen or alkyl, R 6 is hydrogen, alkyl, cycloalkyl, or alkenyl, R 7 is an amino acid residue, and R 8 is alkyl or cycloalkyl, R T is R L -R P And R P R is optional. C It has been replaced with, R L It is a linker, and one end is R P It is connected to one end, and the other end is connected to the Y, R P R L It is a part that connects to one end, and R C R P This is the cap, which is the part that is joined. Regarding compounds.

[0153] When used in this specification, R L The term refers to a part that covalently bonds two functional groups or parts within a single molecule. L One part is R P Bonded to R L The other end is connected to Y. L This can be any part that performs the binding function, for example, a linker used in proteolytically targeted chimeras (PROTACs) and an uncleavable linker used in antibody-drug conjugates (ADCs). L Examples include, but are not limited to, polyethylene glycol (PEG) and alkyl chains of various lengths, glycols, alkynes, triazoles, saturated heterocycles such as piperazines and piperidines, thioethers, and maleimidocaproyl linkers.

[0154] In some embodiments, R LThe substituent is selected from alkyl, polyethylene glycol, other glycols, cycloalkyl, heterocyclic, aryl, and heteroaryl, and the cycloalkyl, heterocyclic, aryl, or heteroaryl substituent may be substituted with at least one substituent selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, and hydroxyalkyl.

[0155] In a particular embodiment, R L The following: [ka] Or a combination of two or more of those will be selected. L If the result is a combination of two or more of the above fragments, the order in which the fragments are combined is arbitrary.

[0156] According to embodiments of this disclosure, R p The following is the chemical part: • Substances that can increase the overall molecular weight of a compound, such as bulky functional groups and additional molecular structures (including long alkyl chains, large aromatic groups, and extra cyclic structures such as cyclohexane or cyclopentane rings). • Compounds that can increase the overall molecular polarity of compounds such as hydroxyl, amine, amide, sulfonamide, ether, imine, hydroxylamine, ester, aldehyde, ketone, nitro, phosphate, and thioether, and • Functional groups that can impart an electric charge to a compound, such as carboxylic acids, quaternary ammonium compounds, and quaternary phosphonium compounds, which ionize at physiological pH. It is possible.

[0157] In some embodiments, R P R C If not replaced by R P teeth, [ka] That is the case.

[0158] In some embodiments, R P R C If it is replaced with R P teeth, [ka] That is the case.

[0159] When used in this specification, R C The term is R P This refers to the chemical part covalently bonded to the end of a molecule.

[0160] In some embodiments, R C is -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -NH-C 0-12 Alkylene-C 3-12 Cycloalkyl, -NH-C 0-12 Alkylene-C 2-12 Heterocyclyl, -NH-C 0-12 Alkylene-C 1-12 Heteroaryl, -OC 0-12 Alkylene-C 3-12 Selected from cycloalkyl, -OC 0-12 Alkylene-C 2-12 Heterocycline, -OC 0-12 Alkylene-C 1-12 These are alkyl groups substituted with heteroaryl and trialkylammonium compounds, and C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is optionally substituted with one or more substituents selected from hydroxy, alkyl, oxo, and ketone.

[0161] In a particular embodiment, R C teeth, [ka] That is the case.

[0162] In a particular embodiment, R C teeth, [ka] [ka] That is the case.

[0163] In another general embodiment, this disclosure relates to compounds of formula (IB): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y is a bond, CH(R 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)-, or -CH=N-, Y is C(R 1 ) If R 1 It is selected from H, D and halogen, If Y is -OC-, then the oxygen atom is bonded to A, and the carbon atom is bonded to B. If Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R 2 , n, R 3 , m and R T In equation (IA), it is defined as described above. Regarding compounds.

[0164] In another general embodiment, this disclosure relates to compounds of formula (IC): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y is a bond, CH(R 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)-, or -CH=N-, Y is C(R 1 ) If R 1 It is selected from H, D and halogen, If Y is -OC-, then the oxygen atom is bonded to A, and the carbon atom is bonded to B. If Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R 2 , n, R 3 , m and R T In equation (IA), it is defined as described above. Regarding compounds.

[0165] In another general embodiment, this disclosure relates to compounds of formula (ID): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, Y 1 is CH or N, X 1 is selected from H, D and halogen; and R T However, in equation (IA), as defined above, Regarding compounds.

[0166] In some embodiments, the compound of formula (IA) is formula (IA-1): [ka] A compound having, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, R 1 It is selected from H, D and halogen, A is a ring selected from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, 4H-pyran, or 4H-thiopyran. R 2 , n, R 3 , m and R T It is defined in equation (IA) as described above.

[0167] In some embodiments, the compound of formula (IA) is formula (IA-2): [ka] A compound having, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, A is a ring selected from phenyl, 1,2,3,4-tetrahydro-1-naphthyl, quinoxalinyl, pyrimidinyl, and 2,1,3-benzothiadiazole. Y is CH, N, -O-CH- or -C-NH-, If Y is -OC-, the oxygen atom is bonded to A and the carbon atom is R T and [ka] Combine with both, If Y is -C-NH-, then the carbon atom is R T Bonded to both A and the nitrogen atom [ka] Combine, X is NH, O, or S, and R 2 , n and R T It is defined in equation (IA) as described above.

[0168] In a particular embodiment, if the compound of formula (IA) has formula (IA-1) or (IA-2), R T teeth, [ka] And in the formula: Ring M is C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, C 6-12 Aryl, or C 1-12 It is a heteroaryl, C 3-12 Cycloalkyl or C 2-12 Heterocyclines are selectively condensed with aryl groups. r is either 1 or 2. n2 is 0, 1, or 2. Each R 2 This is independently selected from hydrogen, halogen, hydroxyl, and alkoxy. R 3 is CN, hydroxy, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -SO2-alkyl, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ , -C 0-12 Alkilen-R 3’ ,-OC 0-12 Alkylene-COOH, -C 0-12 Alkylene-N(R) 4 )-C(O)-R 5 , -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkylene-OC 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(R 4’ ), [ka] , -NH-R 7 , or [ka] Selected from, -C 0-12 Alkilen-R 3’ One of the -CH2- groups in the middle is optionally an oxygen atom, or [ka] It is replaced with -C 0-12 Alkilen-R 3’ C is optionally substituted with one or more substituents selected from amino and alkylamino compounds. 2-12 Heterocyclyl and C 1-12 Each heteroaryl has one or more R 4a It is replaced by an optional selection, R 3’ is -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ , -C 0-12 Alkylene-COOH, -C 0-12 Alkylene-N(R) 4 )-C(O)-R 5 , -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , C 0-12 Alkylene-C 1-12 Selected from heteroaryls, Each R 4a These include hydroxy, alkyl, oxo, ketone, and -C 2-12 Selected independently from heterocyclines, R 4 and R 4’ Each of these independently consists of hydrogen, alkyl, alkoxy, and -SO2-N(R 6a ) t , -C 0-12Alkylene-COOH, -C 0-12 Alkylene-N(R) 6a ) t , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a , or hydroxyalkyl, where the hydroxyalkyl is optionally substituted with an alkoxy, alkyl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, Or, R4 and R4’ Together with the nitrogen atom to which they are bonded, they form a heterocycle containing one or more heteroatoms selected from O, N, and S. Alternatively, one R 2 R 3 If adjacent to R 2 and R 3 Together with the atoms to which they are bonded, one or more R 4a This forms a ring that is substituted by any choice, R 5 is amino, alkylamino, C 1-12 Haloalkyl, -C 0-12 Alkilen-OR 6a , -C 0-12 Alkylene-N(R) 6a ) t , -C 0-12 Alkilen-SR 6a , -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 2-12Alkenyl, or alkyl optionally substituted with cyano, amide, trialkylammonium, or thiolate, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, Each R 6a is hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Selected independently from heteroaryls, alkyl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, R 6 is an alkyl group optionally substituted with an alkoxy, amino, sulfonamide, carbamide, or cyano. R 7 is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted with C 3-12 Cycloalkyl, C 2-12 Ariel, C 1-12 Heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(R 4’ ), -C 0-12 Alkylene-N(R) 4 )-C(=S)-R 5 -C(=S)-R 5 , or alkyl groups optionally substituted with cyano, R 8These are alkoxy, amino, alkylamino, amide, sulfonamide, or carbamide. n3 is 0, 1, 2, 3, or 4. n4 is 1, 2, 3, 4, 5, or 6. t is 2 or 3, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4. Regarding compounds.

[0169] In another general embodiment, this disclosure relates to compounds of formula (II): [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, During the ceremony, A is [ka] It was one of the selections, n1 is either 1 or 2. Each R 1 These are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl, and -COOH. B is [ka] It is one of the selected ones, where X is S, O, or NH. R T teeth, [ka] And, Ring M is C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, C 6-12 Aryl, or C 1-12 It is a heteroaryl, C3-12 Cycloalkyl or C 2-12 Heterocyclines are selectively condensed with aryl groups. r is either 1 or 2. n2 is 0, 1, or 2. Each R 2 This is independently selected from hydrogen, halogen, hydroxyl, and alkoxy. R 3 is CN, hydroxy, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -SO2-alkyl, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ , -C 0-12 Alkilen-R 3’ ,-OC 0-12 Alkylene-COOH, -C 0-12 Alkylene-N(R) 4 )-C(O)-R 5 , -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkylene-OC 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(R 4’ ), [ka] , -NH-R 7 , or [ka] Selected from, , -C 0-12 Alkilen-R 3’ One of the -CH2- groups in the middle is optionally an oxygen atom, or [ka] It is replaced with -C 0-12 Alkilen-R 3’ C is optionally substituted with one or more substituents selected from amino and alkylamino compounds. 2-12 Heterocyclyl and C 1-12 Each heteroaryl has one or more R 4a It is replaced by an optional selection, R 3’ is -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ , -C 0-12 Alkylene-COOH, -C 0-12 Alkylene-N(R) 4 )-C(O)-R 5 , -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , C 0-12 Alkylene-C 1-12 Selected from heteroaryls, Each R 4a These include hydroxy, alkyl, oxo, ketone, and -C 2-12 Selected independently from heterocyclines, R 4 and R 4’ Each of these independently consists of hydrogen, alkyl, alkoxy, and -SO2-N(R 6a ) t , -C 0-12 Alkylene-COOH, -C 0-12 Alkylene-N(R) 6a ) t , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a, or hydroxyalkyl, where the hydroxyalkyl is optionally substituted with an alkoxy, alkyl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, Or, R4 and R4’ Together with the nitrogen atom to which they are bonded, they form a heterocycle containing one or more heteroatoms selected from O, N, and S. Alternatively, one R 2 R 3 If adjacent to R 2 and R 3 Together with the atoms to which they are bonded, one or more R 4a This forms a ring that is substituted by any choice, R 5 is amino, alkylamino, C 1-12 Haloalkyl, -C 0-12 Alkilen-OR 6a , -C 0-12 Alkylene-N(R) 6a ) t , -C 0-12 Alkilen-SR 6a , -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 2-12 Alkenyl, or alkyl optionally substituted with cyano, amide, trialkylammonium, or thiolate, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, Each R 6a is hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Selected independently from heteroaryls, alkyl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional selection, R 6 is an alkyl group optionally substituted with an alkoxy, amino, sulfonamide, carbamide, or cyano. R 7 is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted with C 3-12 Cycloalkyl, C 2-12 Ariel, C 1-12 Heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(R 4’ ), -C 0-12 Alkylene-N(R) 4 )-C(=S)-R 5 -C(=S)-R 5 , or alkyl groups optionally substituted with cyano, R 8 These are alkoxy, amino, alkylamino, amide, sulfonamide, or carbamide. n3 is 0, 1, 2, 3, or 4. n4 is 1, 2, 3, 4, 5, or 6. t is 2 or 3, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4. Regarding compounds.

[0170] In some embodiments, A is [ka] That is the case.

[0171] In some embodiments, A is [ka] That is the case.

[0172] In some embodiments, R 1 This is an alkyl group, for example, methyl.

[0173] In some embodiments, R 1 These are halogens, such as fluorine or chlorine.

[0174] In some embodiments, R 1 is an alkoxy, for example, -OMe.

[0175] In some embodiments, R 1 The compound is hydroxyl, -COOH, or -CH2OH.

[0176] In some embodiments, R 1 This is a haloalkyl group, for example, trifluoromethyl or -CH2CH2F.

[0177] In some embodiments, B is [ka] That is the case.

[0178] In some embodiments, B is [ka] In this formula, X is S, O, or NH.

[0179] In some embodiments, R T teeth, [ka] That is the case.

[0180] In some embodiments, R T teeth, [ka] That is the case.

[0181] In some embodiments, the ring M is C 6-12 Aryl or C 1-12 It is a heteroaryl compound.

[0182] In some embodiments, the ring M is C 3-12 Cycloalkyl or C 2-12 It is a heterocycline, and its C 3-12 Cycloalkyl or C 2-12 Heterocyclines are selectively condensed with aryl groups.

[0183] In some embodiments, ring M is phenyl, pyridinyl, pyrimidinyl, thiophenyl, cyclopentyl, or cyclohexyl.

[0184] In some embodiments, ring M is [ka] That is the case.

[0185] In some embodiments, R 2 It is hydrogen.

[0186] In some embodiments, R 2 It is a hydroxyl group.

[0187] In some embodiments, R 2 These are halogens, such as fluorine or chlorine.

[0188] In some embodiments, the pharmaceutically acceptable salts of the compound of formula (I) are trifluoroacetate or hydrochloride salts.

[0189] In some embodiments, the compound of formula (II) is formula (II-A): [ka] And in the formula, R 1 , R 2 , R 3 And n1 is defined in equation (II) as described above. It is a compound.

[0190] In some embodiments, R 1 These are halogens, haloalkyls, hydroxyls, alkyls, or -COOH groups.

[0191] In a particular embodiment, R 1 These are methyl, ethyl, hydroxyl, fluorine, chlorine, trifluoromethyl, -CH2CH2F, or -COOH.

[0192] In some embodiments, n1 is 2.

[0193] In some embodiments, R 2 These are hydrogen, hydroxyl, or halogen.

[0194] In a particular embodiment, R 2 It is either fluorine or chlorine.

[0195] In some embodiments, R 3 is -C(O)-NR 4 R 4’ or -SO2-NR 4 R 4’ And R 4 and R 4’ Each of them independently consists of hydrogen, alkyl, alkoxy, and -C. 0-12 Alkylene-N(R) 6a ) t, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a or hydroxyalkyl, where the hydroxyalkyl is optionally substituted with an alkoxy, alkyl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is replaced by an optional choice in R 4a , R 6a And t are defined as described above.

[0196] In a particular embodiment, R 4 and R 4’ Each of these is independently hydrogen, alkyl, alkoxy, or hydroxyalkyl.

[0197] In a particular embodiment, R 4 and R 4’ Each of them is independent, [ka] That is the case.

[0198] In a particular embodiment, R 4 and R 4’ Each of them independently consists of an alkoxy-substituted hydroxyalkyl, for example, [ka] In the equation, p is 0, 1, 2, or 3, and in particular p is 2.

[0199] In some embodiments, R 3 is -C(O)-NR 4 R 4 or -SO2-NR4 R 4’ And in the formula, R 4 and R 4’ Together with the nitrogen atoms to which they are bonded, they form a heterocycle containing one or more heteroatoms selected from O, N, and S, in particular, R 4 R4' and R4', together with the nitrogen atom to which they are bonded, form a six-membered heterocycle.

[0200] In some embodiments, R 3 hydroxyl, -COOH, -CH(CH3)-COOH, -CN, [ka] That is the case.

[0201] In some embodiments, R 3 C 0-12 Alkylene-N(R) 4 )-C(O)-R 5 , -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 or -C 0-12 Alkylene-OC 0-12 Alkylene-N(R) 4 )-SO2-R 5 And R 4 is hydrogen or alkyl, and R 5 is amino, alkylamino, C 1-12 Haloalkyl, -C 0-12 Alkilen-OR 6a , -C 0-12 Alkylene-N(R) 6a ) t , -C 0-12 Alkilen-SR 6a , -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 2-12The alkyl group may be optionally substituted with an alkenyl, cyano, or amide, and C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl has one or more R 4a It is replaced by an optional choice in R 4a , R 6a And t are defined as described above.

[0202] In a particular embodiment, R 5 This includes amino, alkylamino, alkoxy, alkyl, or -C 2-12 It is Alkenil.

[0203] In a particular embodiment, R 5 This is a cyano-substituted alkyl group, for example, -CH2CN.

[0204] In a particular embodiment, R 5 This is an amide-substituted alkyl group, for example, -CH2CH3CONH2.

[0205] In a particular embodiment, R 5 This is an alkyl group substituted with an alkoxy, trialkylammonium, or thiolate.

[0206] In a particular embodiment, R 5 ga-C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, or -C 0-12 Alkylene-C 1-12 If it is a heteroaryl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Heteroaryls are [ka] Selected from.

[0207] In a particular embodiment, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl has one or more R 4a If it is replaced with R 4a The compound is hydroxyl, methyl, oxo, or -C(O)-Me.

[0208] In some embodiments, R 3 teeth, [ka] And in the formula, m is 0, 1, 2, 3, 4 or 5, R 6 This is an alkyl group optionally substituted with a sulfonamide, carbamide, or cyano.

[0209] In a particular embodiment, R 6 is a sulfonamide of the formula -N(R')SO2-R, where each R and R' is independently selected from hydrogen and alkyl, in particular, R 6 It is -NHSO2CH3.

[0210] In a particular embodiment, R 6 is a carbamide of the formula -N(R')C(O)N(R)2, where each R and R' is independently selected from hydrogen, alkyl, and heteroaryl, and in particular R 6 teeth, [ka] That is the case.

[0211] In a particular embodiment, R 6 This refers to alkyl groups optionally substituted with cyano compounds, for example, C compounds optionally substituted with cyano compounds. 1-4 Alkyl, especially cyano-substituted C 1-4 It is alkyl.

[0212] In certain embodiments, m is 1, 2, or 3, particularly 2.

[0213] In some embodiments, R 3 is -NH-R 7 And in the formula, R 7 C is a hydrogen atom, optionally substituted with C. 3-12 Cycloalkyl, C 1-12 Heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(R 4’ ), -C 0-12 Alkylene-N(R) 4 )-C(=S)-R 5 -C(=S)-R 5 , or an alkyl group optionally substituted with cyano, where R 4 , R 4’ and R 5 It is defined as described above.

[0214] In a particular embodiment, R 7 It is hydrogen.

[0215] In a particular embodiment, R 7 teeth, [ka] That is the case.

[0216] In a particular embodiment, R 7 This refers to alkyl groups optionally substituted with cyano compounds, for example, C compounds optionally substituted with cyano compounds. 1-4 Alkyl, especially cyano-substituted C 1-4 It is alkyl.

[0217] In a particular embodiment, R 3 teeth, [ka] Therefore, n is 3 or 4, especially 4.

[0218] In some embodiments, the compound of formula (II) is formula (II-B): [ka] And in the formula, R 1 , R 8 n1, n3, and n4 are defined as above in equation (II), It is a compound.

[0219] In some embodiments, R 1 This is hydrogen or alkyl, for example alkyl, especially methyl.

[0220] In some embodiments, n1 is 2.

[0221] In some embodiments, n3 is 0, 1, or 3.

[0222] In some embodiments, n4 is 2, 3, or 5.

[0223] In some embodiments, R 8 is an alkoxy, for example C 1-4 These are alkoxys, especially methoxy or ethoxy compounds.

[0224] In some embodiments, R 8 It is an amino acid.

[0225] In some embodiments, R 8 This includes alkylaminos, for example, C 1-4 Alkylaminos, especially methylaminos.

[0226] In some embodiments, R 8 is an amide of the formula -N(R')C(O)R, where R and R' are independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.

[0227] In some embodiments, R 8 is an amide of the formula -N(R')C(O)R, and in particular, R 8 It is -NHCOCH3.

[0228] In some embodiments, R 8 This is a sulfonamide of the formula -N(R')SO2-R, where R and R' are independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.

[0229] In a particular embodiment, R 8 It is a sulfonamide of the formula -N(R')SO2-R, where R and R' are hydrogen, -C 0-12 Alkylene-C 2-12 Selected independently from heterocyclyls and alkyls, particularly R 3 It is -NHSO2CH3.

[0230] In some embodiments, R 8 This is a carbamide of the formula -N(R')C(O)N(R)2, where R and R' are independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.

[0231] In a particular embodiment, R 8 is a carbamide of the formula -N(R')C(O)N(R)2, where each R and R' is independently selected from hydrogen, alkyl, and heteroaryl, in particular, R 3 is -NHC(O)NHCH3, or [ka] That is the case.

[0232] In some embodiments, if the compound is a compound of formula (II), R 8 -OCH3, -NH2, -NHCH3, -NHC(O)CH3, [ka] That is the case.

[0233] In some embodiments, the compound of formula (II) is formula (II-C): [ka] And in the formula, n2 is 1 or 2, and R 1 , R 2 , R 3 And n1 is defined in equation (II) as described above. It is a compound.

[0234] In some embodiments, R 1 This is an alkyl group, for example, methyl.

[0235] In some embodiments, n1 is 2.

[0236] In some embodiments, n2 is 1.

[0237] In some embodiments, R 2 It is either hydrogen or a halogen.

[0238] In a particular embodiment, R 2 It is fluorine.

[0239] In some embodiments, R 3 is -C(O)-NR 4 R 4’ And in the formula, R 4 and R 4’ Each of these independently consists of hydrogen, hydroxyl, alkyl, alkoxy, -SO2-NHCH3, -SO2-NH-Ph, -CH2-COOH, -CH2-CH2-COOH, or [ka] That is the case.

[0240] In some embodiments, R3 is -SO2-NR 4 R 4’ And in the formula, R 4 and R 4’ Each of these is independently hydrogen, hydroxyl, or -C 0-12 Alkylene-C 2-12 It is a heterocycline.

[0241] In some embodiments, R 3 is -NH-C(O)-R 5 ,-N(CH3)-C(O)-R 5 or -NH-SO2-R 5 And in the formula, R 5 is alkyl, -C 0-12 Alkylene-alkoxy, -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-NH-C 1-12 Alkyl, -C 0-12 Alkylene-NH-C 2-12 Heterocyclyl or -C 0-12 Alkylene-C 2-12 It is a heterocycline.

[0242] In a particular embodiment, R 5 This is an alkyl group, for example, methyl.

[0243] In a particular embodiment, R 5 is -C 0-12 Alkylene alkoxys, for example, -CH2-OCH3.

[0244] In a particular embodiment, R 5 is -C 0-12 Alkylene-C 3-12 Cycloalkyl, for example, [ka] That is the case.

[0245] In a particular embodiment, R 5 is -C 0-12Alkylene-NH-C 1-12 is alkyl, for example, -NH-CH3.

[0246] In certain embodiments, R 5 is C 0-12 Alkylene-NH-C 2-12 heterocyclyl, for example,

Chemical formula

[0247] In certain embodiments, R 5 is -C 0-12 Alkylene-C 2-12 heterocyclyl, for example,

Chemical formula

[0248] In some embodiments, R 3 is -SO2-alkyl, for example, -SO2-CH3.

[0249] In some embodiments, R 3 is -C 0-12 Alkylene-COOH, for example, -COOH, -CH2-COOH, -C(Me)2-COOH, -CH2-CH2-COOH.

[0250] In some embodiments, R 3 is -C 0-12 Alkylene-P(=O)(R 4 )(R 4’ ), and for example,

Chemical formula

[0251] In some embodiments, R 3 is -C 0-12 Alkylene-C 1-12Heteroaryls, for example, [ka] That is the case.

[0252] In some embodiments, R 3 is -NH-R 7 For example, -NH-CH3, [ka] And -NH-C(=S)-R 5 ,for example, [ka] That is the case.

[0253] In some embodiments, the compound of formula (II) is formula (II-D): [ka] And, During the ceremony, n2 is either 0 or 1. R 3 is -C(O)-NHR 4 -SO2-NHR 4 -NH-C(O)-R 5 , and -NH-SO2-R 5 , and -NH-R 7 Selected from, R 4 is -C 0-12 Alkilen-NHR 6a , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a , or an alkyl group substituted with trialkylammonium, C3-12 Cycloalkyl, C 2-12 heterocyclyl and C 1-12 each of heteroaryl is optionally substituted with one or more R 4a and R 5 is -C 0-12 alkylene-NHR 6a -C 0-12 alkylene-C 3-12 cycloalkyl, -C 0-12 alkylene-C 2-12 heterocyclyl, -C 0-12 alkylene-C 1-12 heteroaryl, -C 0-12 alkylene-OR 6a or alkyl substituted with trialkylammonium, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 1-12 each of heteroaryl is optionally substituted with one or more R 4a and each R 6a is independently selected from -C 0-12 alkylene-C 3-12 cycloalkyl, -C 0-12 alkylene-C 2-12 heterocyclyl, and -C 0-12 alkylene-C 1-12 heteroaryl, C 3-12 cycloalkyl, C 2-12 heterocyclyl and C 1-12 each of heteroaryl is optionally substituted with one or more R 4a and [[ID=6D]] R 7 is C 1-12 heteroaryl, -C 0-12 alkylene-N(R 4 )-SO2-R 5 -C 0-12 alkylene-P(=O)(R 4 )(alkoxy) or -C 0-12 alkylene-N(R 4 )-C(=S)-R 5 and R 1 R2 , R 4a , and n1 and are defined in equation (II) as above, It is a compound.

[0254] In some embodiments, R 1 This is an alkyl group, for example, methyl.

[0255] In some embodiments, R1 is an alkoxy, for example, -OMe.

[0256] In some embodiments, n1 is 1.

[0257] In some embodiments, n1 is 2.

[0258] In some embodiments, n2 is 0.

[0259] In some embodiments, n2 is 1.

[0260] In some embodiments, R 2 It is either hydrogen or a halogen.

[0261] In some embodiments, R 3 is -C(O)-NHR 4 or -SO2-NHR 4 And in the formula, R 4 is -C 0-12 Alkilen-NHR 6a , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a or an alkyl group substituted with trialkylammonium, and C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl is one or more R 4aIt is optionally replaced, and in the formula, R 4a and R 6a It is defined as described above.

[0262] In a particular embodiment, R 4 teeth, [ka] That is the case.

[0263] In some embodiments, R 3 is -NH-C(O)-R 5 or -NH-SO2-R 5 And in the formula, R 5 is -C 0-12 Alkilen-NHR 6a , -C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, -C 0-12 Alkylene-C 1-12 Heteroaryl, -C 0-12 Alkilen-OR 6a or an alkyl group substituted with trialkylammonium, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl and C 1-12 Each heteroaryl is one or more R 4a It is optionally replaced, and in the formula, R 4a and R 6a It is defined as described above.

[0264] In a particular embodiment, R 5 This is an alkyl group substituted with trialkylammonium.

[0265] In a particular embodiment, R 5 ga-C 0-12 Alkylene-C 3-12 Cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclyl, or -C 0-12 Alkylene-C1-12 If it is a heteroaryl, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Heteroaryls are [ka] Selected from.

[0266] In a particular embodiment, C 3-12 Cycloalkyl, C 2-12 Heterocyclyl, and C 1-12 Each heteroaryl has one or more R 4a If it is replaced with R 4a The compound is hydroxyl, methyl, oxo, or -C(O)-Me.

[0267] In some embodiments, R 3 is -NH-R 7 And in the formula, R 7 C 1-12 Heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 , -C 0-12 Alkylene-P(=O)(R) 4 )(alkoxy) or -C 0-12 Alkylene-N(R) 4 )-C(=S)-R 5 And in the formula, R 4 and R 5 It is defined as described above.

[0268] In a particular embodiment, R 7 teeth, [ka] That is the case.

[0269] In some embodiments, the compound of formula (II) is formula (II-E): [ka] And in the formula: x is either 0 or 1, y is either 0 or 1. X is S, O, or NH, and R 1 , R 2 , R 3 n1 and n2 are defined as above in equation (II), It is a compound.

[0270] In some embodiments, x is 0, y is 1, and X is S, O, or NH.

[0271] In some embodiments, x is 0 or 1, y is 0, and X is NH.

[0272] Some implementation methods, each R 1 These are independently selected from hydrogen, halogens, alkoxys, and alkyls.

[0273] In a particular embodiment, R 1 These are methyl, chlorine, or methoxy.

[0274] In some embodiments, n2 is 1.

[0275] In some embodiments, n2 is 2.

[0276] In some embodiments, R 2 It is hydrogen.

[0277] In some embodiments, R 3 is -C(O)-NR 4 R 4’ And in the formula, R 4 and R 4’ Each of them is independently either hydrogen or an alkoxy.

[0278] In some embodiments, R 3 is -SO2-NR 4 R 4’ And in the formula, R4 and R 4’ Each of them is independently either hydrogen or alkyl.

[0279] In some embodiments, R 3 is -NH-C(O)-R 5 or -NH-SO2-R 5 And in the formula, R 5 is alkyl or -C 0-12 Alkylene-C 2-12 It is a heterocycline.

[0280] In a particular embodiment, R 5 This is an alkyl group, for example, methyl.

[0281] In a particular embodiment, R 5 is -C 0-12 Alkylene-C 2-12 Heterocyclines, for example, [ka] That is the case.

[0282] In some embodiments, the compound of formula (II) is formula (II-F): [ka] And in the formula, R 2 is R 3 It is adjacent to R 2 and R 3 Together with the carbon atoms to which they are bonded, one or more R 4a It forms a complex ring that is substituted by any choice, and R 1 , R 4a And n1 is defined in equation (II) as described above. It is a compound.

[0283] In some embodiments, R 2 and R 3Together with the carbon atoms to which they are bonded, one or more R 4a This forms a 5- or 6-membered complex ring, which may be optionally substituted.

[0284] In some embodiments, the compound of formula (II-F) is (II-F-1): [ka] In the formula, M1 is one or more R 4a It is a complex ring that may be substituted by any choice. It is a compound.

[0285] In some embodiments, the compound of formula (II) is formula (II-G): [ka] And in the formula, Each R 2 These are independently selected from hydroxyl and alkoxy compounds. R 3 is selected from hydroxyl and alkoxy, and R 1 n1 and r are defined as above in equation (II), It is a compound.

[0286] In some embodiments, one R 2 R 3 It is adjacent to.

[0287] Some implementation methods, each R 2 This is selected independently from hydroxyl and methoxy.

[0288] In some embodiments, R 3 The compound is selected from hydroxyl and methoxy.

[0289] In some embodiments, the compound of formula (II-G) is the compound of formula (II-G-1) as (II-G-2): [ka] That is the case.

[0290] In some embodiments, the compound of formula (II) is (II-H): [ka] And in the formula, M is C 6-12 Aryl or C 1-12 It is a heteroaryl, R 3 is -C 0-12 Alkylene-COOH, -OC 0-12 Alkylene-COOH, -C 0-12 Alkylene-P(O)(OH)2,-C(O)-NH-SO2-R 5 -C(O)-NH-C 0-12 Alkylene-COOH,-NH-C 0-12 Alkylene-COOH, -SO2-OH, and [ka] And in the formula, -C 0-12 The alkylene-COOH is optionally substituted with one or more substituents selected from amino and alkylamino, and R 1 , R 2 And n1 is defined in equation (II) as described above. It is a compound.

[0291] In some embodiments, M is phenyl.

[0292] In some embodiments, M is pyridinyl.

[0293] Exemplary compounds of formula (IA), (IB), (IC), (ID), or (II) include, but are not limited to, the compounds described herein, and any tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof.

[0294] In certain embodiments, compounds selected from compounds 1-251, 401-403, 501-509, 601 and 602, or their tautomers, stereoisomers, pharmaceutically acceptable salts or solvates are provided.

[0295] All possible combinations of the above embodiments of compounds of formula (IA), (IB), (IC), (ID), or (II), as well as their tautomers, stereoisomers, pharmaceutically acceptable salts, and solvates, are considered to be within the scope of this disclosure.

[0296] Exemplary compounds of formula (IA), (IB), (IC), (ID), or (II) include, but are not limited to, the following compounds, and their tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates.

[0297] [Table 1]

[0298] [Table 2]

[0299] [Table 3]

[0300] [Table 4]

[0301] [Table 5]

[0302] [Table 6]

[0303] [Table 7]

[0304] [Table 8]

[0305] [Table 9]

[0306] [Table 10]

[0307] [Table 11]

[0308] [Table 12]

[0309] Exemplary R of formulas (IA), (IB), (IC), (ID), or (II) T Examples include, but are not limited to, the following.

[0310] [Table 13]

[0311] [Table 14]

[0312] [Table 15]

[0313] [Table 16]

[0314] [Table 17]

[0315] [Table 18]

[0316] [Table 19]

[0317] Preparation method The compounds described herein can be prepared by any number of methods generally described below and more specifically illustrated by the exemplary compounds that follow the Examples section herein. The compounds provided herein, prepared by the processes described below, can be synthesized in the form of a mixture of stereoisomers (e.g., enantiomers, diastereomers), including a racemic mixture of enantiomers, which can be separated from each other using separation procedures known in the art, such as liquid chromatography using a chiral stationary phase. Additionally or alternatively, stereochemically pure isomers of the compounds described herein can be derived from the corresponding stereochemically pure isomers of suitable starting materials, intermediates, or reagents. For example, if a particular stereoisomer is desired, the compound can be synthesized by a stereospecific preparation method, typically using a stereochemically pure starting material or intermediate compound.

[0318] pharmaceutically acceptable salts of the compounds described herein can be synthesized by conventional chemical methods from parent compounds containing an acidic or basic moiety. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable acid or base in water or an organic solvent, or in a mixture thereof. Examples of suitable organic solvents include, but are not limited to, ether, ethyl acetate (siRNA), ethanol, isopropanol, or acetonitrile.

[0319] As examples, and not as an limitation, the compounds of formulas (IA), (IB), (IC), (ID), or (II) described herein can be prepared according to the following general preparation procedures shown in Scheme 1 and the examples shown herein. Those skilled in the art will recognize that, in order to obtain the various compounds of formulas (IA), (IB), (IC), (ID), or (II) as described herein, the starting materials can be appropriately selected so that the ultimately desired substituents are carried as necessary through protected or unprotected reaction schemes (i.e., stable throughout the course of synthesis) to yield the desired product. Alternatively, it may be necessary or desirable to use suitable groups instead of the ultimately desired substituents, which are carried through the reaction scheme (i.e., stable throughout the course of synthesis) and can be substituted with the desired substituents as necessary.

[0320] If no temperature or temperature range is specified, the reaction should be understood to take place at room temperature.

[0321] If an isomerically pure sample is desired, the isomer mixture of the compound synthesized according to Scheme 1 can be separated by chiral supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). [ka]

[0322] composition In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (IA), (IB), (IC), (ID), or (II) as described herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0323] The composition may also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is non-toxic and should not interfere with the efficacy of the active ingredient. The pharmaceutically acceptable carrier may contain one or more excipients such as binders, disintegrants, swelling agents, suspending agents, emulsifiers, wetting agents, lubricants, flavorings, sweeteners, preservatives, colorants, solubilizers, and coatings. The exact properties of the carrier or other substance may depend on the route of administration, e.g., intramuscular, intradermal, subcutaneous, oral, intravenous, cutaneous, intramucosal (e.g., intestinal), intranasal, or intraperitoneal routes. For liquid injection formulations, e.g., suspensions and solutions, suitable carriers and excipients include water, glycols, oils, alcohols, preservatives, and colorants. For solid oral formulations, e.g., powders, capsules, caplets, gel caps, and tablets, suitable carriers and excipients include starch, sugars, diluents, granulators, lubricants, binders, and disintegrants. In the case of nasal spray / inhalant mixtures, the aqueous solution / suspension may contain water, glycol, oil, emollients, stabilizers, humectants, preservatives, fragrances, flavorings, etc., as appropriate carriers and additives.

[0324] The composition may be formulated with any substance suitable for administration to a target to facilitate administration and improve efficacy, including oral (enteral) administration and parenteral injection. Parenteral injections include intravenous injection or infusion, subcutaneous injection, intradermal injection, and intramuscular injection. The composition may also be formulated for other routes of administration, including transmucosal, ocular, rectal, long-acting implant, sublingual, sublingual administration from the oral mucosa bypassing the portal circulation, inhalation, or intranasal administration.

[0325] The form, route of administration, dosage, and regimen of a pharmaceutical composition depend on the severity of the disease, the patient's age, weight, and sex, and other conditions being treated. Pharmaceutical compositions can be formulated for different modes of administration, such as topical administration, oral administration, intranasal administration, parenteral administration, intraocular administration, intravenous administration, intramuscular administration, or subcutaneous administration.

[0326] In yet another embodiment, a method is provided for preparing a pharmaceutical composition comprising combining a compound of formula (IA), (IB), (IC), (ID), or (II) or its stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate with at least one pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared by any method known in the art in consideration of the present disclosure, and those skilled in the art will be familiar with such techniques used to prepare the pharmaceutical composition. For example, the pharmaceutical composition according to the present disclosure can be prepared by mixing a compound of formula (IA), (IB), (IC), (ID), or (II) with one or more pharmaceutically acceptable carriers by conventional pharmaceutical formulation techniques, including but not limited to conventional mixing, dissolution, granulation, emulsification, encapsulation, encapsulation, or lyophilization processes.

[0327] How to use In a general embodiment, a method is provided for treating or preventing pain in a subject in need thereof, the method comprising administering a therapeutically effective dose of a peripherally selective α2AR agonist to the subject, wherein treatment with a peripherally selective α2AR agonist results in fewer side effects than treatment with a non-peripherally selective α2AR agonist, such as by treating with a similar or equivalent dose.

[0328] In some embodiments, the peripherally selective α2AR agonist includes an α2AR activating moiety covalently bound to the peripherally distributed portion.

[0329] In another general embodiment, a method is provided for treating or preventing a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a peripherally selective α2AR agonist to the subject, wherein the peripherally selective α2AR agonist comprises an α2AR activating moiety covalently bound to its peripherally distributed portion.

[0330] The following embodiments apply to the two general aspects of the method of use described above.

[0331] In some embodiments, the α2AR activation portion is given by the following formula: [ka] It has, in the formula, Y, A, B, R 2 , R 3 m and n are defined as shown in equation (IA).

[0332] In some embodiments, the α2AR activation portion is given by the following formula: [ka] It has, in the formula, Y, A, B, R 2 , R 3 m and n are defined as shown in equation (IB).

[0333] In some embodiments, the α2AR activation portion is given by the following formula: [ka] It has, in the formula, Y, A, B, R 2 , R 3 m and n are defined as shown in equation (IC).

[0334] In some embodiments, the α2AR activation portion is given by the following formula: [ka] It has, in the formula, X 1 and Y1 It is defined as expression (ID).

[0335] In some embodiments, the α2AR activation portion is given by the following formula: [ka] The formula has the following characteristics, where A and B are defined as in formula (II).

[0336] In some embodiments, the peripheral distribution portion is given by the following formula: [ka] It has, in the formula, R T It is defined as shown in equation (IA).

[0337] In some embodiments, the peripheral distribution portion is given by the following formula: [ka] It has, in the formula, R T It is defined as shown in equation (II).

[0338] In another general embodiment, methods for activating α2AR and methods for treating or preventing a disease of interest using the compounds described herein or compositions containing the compounds together with one or more acceptable pharmaceutically acceptable carriers are provided.

[0339] In some embodiments, compounds of formula (IA), (IB), (IC), (ID), or (II) may be useful for activating α2AR.

[0340] In some embodiments, a method is provided for activating α2AR in a subject requiring α2AR activation, which includes administering a compound or composition described herein to the subject, for example, administering an effective amount of a compound or composition described herein to the subject.

[0341] In some embodiments, methods for treating or preventing diseases in humans or animals are provided.

[0342] In some embodiments, a method is provided for treating or preventing a disease of a target requiring such treatment, comprising administering a compound or composition described herein, for example, administering an effective amount of a compound or composition described herein.

[0343] In some embodiments, the diseases include glaucoma, pain, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, and cancer.

[0344] In some embodiments, the disease is pain.

[0345] In some embodiments, pain is nociceptive pain, neuropathic pain such as peripheral neuropathic pain, or mixed pain. Examples of peripheral neuropathic pain include, but are not limited to, diabetic neuropathy, postherpetic neuralgia, HIV-related pain, chemotherapy-induced peripheral neuropathy, and postoperative neuropathic pain.

[0346] In some embodiments, the compounds and pharmaceutical compositions described herein, when used to treat pain, cause few side effects in the treated subject, such as sedation, decreased heart rate, and decreased blood pressure.

[0347] In certain embodiments, the compounds and pharmaceutical compositions described herein do not induce a sedative reaction in the subject of treatment. [Examples]

[0348] The following embodiments are provided to further illustrate the nature of the Disclosure. It should be understood that these embodiments are not intended to limit the Disclosure, and the scope of the Disclosure should be determined by the appended claims.

[0349] Synthesis method Unless otherwise specified, abbreviations for chemical reagents and synthesis conditions have the following common meanings as known in the art: "ACN" refers to acetonitrile. "LDA" refers to lithium diisopropylamide. "EA" or "toluene" refers to ethyl acetate. "PE" refers to petroleum ether. "rt" and "rt" refer to room temperature. "THF" refers to tetrahydrofuran. "DIPEA" refers to diisopropylethylamine. "DCM" refers to dichloromethane. "HOBT" refers to hydroxybenzotriazole. "TLC" refers to thin-layer chromatography. "TLC" refers to thin-layer chromatography. "DMF" refers to dimethylformamide. "h" indicates time. "min" refers to minutes. "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. "DMAP" refers to 4-dimethylaminopyridine. "Prep-HPLC" refers to preparative high-performance liquid chromatography. "DPPF" refers to 1,1'-bis(diphenylphosphin)ferrocene. "NCS" refers to N-chlorosuccinimide. "TEA" refers to triethylamine. "TES" refers to triethylsilane. "Trt" refers to a trityl group or a triphenylmethyl group. "MeOH" refers to methanol. "EtOH" refers to ethanol. "t-BuXphos" refers to tert-butyl-Xantphos. "TMAl" refers to trimethylaluminum. "Xantphos" refers to 9,9-dimethyl-4,5-bis(diphenylphosphin)xanthene. "Pd(PPH3)4" refers to tetrakis(triphenylphosphine)palladium(0).

[0350] Example 1. Synthesis of Compound 1 [ka] Step 1: 400 mL of THF and 36 g (0.18 mol, 4.0 equivalents) of 3-bromobenzoic acid were added to a 500 mL reaction flask. After cooling to -65°C, 135 mL (4 mol / L, 0.428 mol, 7.5 equivalents) of n-butyllithium was added. The mixture was stirred at -65°C for 2 hours, after which 20 g (0.057 mol, 1.0 equivalent) of compound 1-1 and a further 400 mL of THF were introduced. After stirring at -65°C for 30 minutes, the mixture was warmed to room temperature over 16 hours. Completion was confirmed by LC-MS, and 270 mL of saturated ammonium chloride was added. The organic phase was then separated, concentrated under vacuum, and the residue was subjected to column chromatography (DCM-DCM:MeOH=92:8) to obtain 13 g of compound 1-2 in 40.4% yield.

[0351] Step 2: 150 ml of 55% HI, 7.5 g (13.3 mmol, 1.0 equivalent) of compound 1-2, and 4.1 g (133 mmol, 10.0 equivalent) of red phosphorus were added to a 200 ml sealed tube. The mixture was stirred at 160°C for 16 hours until LC-MS showed completion. After vacuum concentration, the residue was collected to produce 7.3 g of compound 1-3, achieving a yield of 100%.

[0352] Step 3: 240 ml of pyridine, 12.1 g (39.5 mmol, 1.0 equivalent) of compounds 1-3, and 55.1 g (197.5 mmol, 3.0 equivalents) of triphenylmethyl chloride were added to a 50 mL reaction flask. The mixture was stirred at 50°C for 2 hours until completion was confirmed by LC-MS. After concentration under reduced pressure, the residue was subjected to column chromatography (DCM-DCM:MeOH=92:8) to obtain 4.5 g of compounds 1-4 in 20.8% yield.

[0353] Step 4: 52 ml of DCM was added to a 100 ml reaction flask, followed by 1.3 g (2.37 mmol, 1.0 equivalent) of compound 1-4, 594 mg (7.11 mmol, 3.0 equivalents) of methoxyammonium chloride, 2.45 g (18.96 mmol, 8.0 equivalents) of DIPEA, 640 mg (4.74 mmol, 2.0 equivalents) of HOBT, and 999 mg (5.21 mmol, 2.2 equivalents) of EDCI. The mixture was stirred at room temperature for 5 hours until LC-MS confirmed the completion of the reaction. After vacuum concentration, the residue was purified by column chromatography (DCM-DCM:MeOH=91:9) to obtain 900 mg of compound 1-5 in 65.8% yield.

[0354] Step 5: 18 mL of DCM and 900 mg (1.56 mmol, 1.0 equivalent) of compounds 1-5 were added to a 50 mL reaction flask along with 9 mL of TFA. The reaction mixture was stirred at room temperature for 2 hours until LC-MS indicated completion. After vacuum concentration, the residue was subjected to column chromatography to obtain 670 mg of compound 1, achieving a yield of 98.5%. 1 H NMR:(400MHz DMSO)δ 14.33(s,2H),11.79(s,1H),9.00(d,J=0.9Hz,1H),7.67(d,J=7.8Hz,1H),7.60(s,1H),7.46(t,J=7.7Hz,1H),7.35(d,J =7.7Hz,1H),7.17-7.06(m,2H),6.94(s,1H),6.70(d,J=7.2Hz,1H),5.91(s,1H),3.69(s,3H),2.26(s,3H),2.13(s,3H). LC-MS:[M-TFA+1] + =336.2

[0355] Step 6: Compound 1 was separated by chiral HPLC to obtain Compound 1-A and Compound 1-B. A 30 × 250 mm column packed with CHIRALPAK® IG (particle size 10 μm) was used as the chiral stationary phase. A mixture of 60% volume mobile phase A and 40% volume mobile phase B was used as the mobile phase. *Mobile phase A: 0.2% NH3 in hexane + MeOH *Mobile phase B: 0.2% NH3 in EtOH+MeOH The operating conditions are as follows: Temperature: Ambient temperature Flow rate: 25mL / min Detection: UV 214nm

[0356] 500 mg of compound 1 was isolated by column chromatography. The first eluted enantiomer (compound 1-A) with a retention time of 4.18 minutes was isolated from the eluent in 80% yield with 100% enantiomer excess. The second eluted enantiomer (compound 1-B) with a retention time of 5.83 minutes was isolated from the eluent in 81% yield with 99.2% enantiomer excess.

[0357] In this application, the naming convention for separated enantiomers is systematic. "A" indicates the first eluted product from chromatography, and "B" indicates the second eluted product. For compounds whose chirality yields four different products, they are designated "A," "B," "C," and "D" based on the elution order. As a result, if a compound is named X, the separated products are systematically named "XA," "XB," "XC," and "XD."

[0358] Example 2. Synthesis of Compound 8 [ka] Step 1: 200 mL of THF and 9.10 g (34.1 mmol, 1.5 equivalents) of 2,6-dibromo-1-methoxybenzene were added to a 500 mL three-necked round-bottom flask under a nitrogen atmosphere. At 0°C, 27 mL (34.1 mmol, 1.5 equivalents) of isopropylmagnesium chloride lithium chloride complex was introduced. The mixture was stirred at 0°C for 6 hours, and then 10 g (22.7 mmol, 1 equivalent) of compound 8-1 was added while still below 0°C. Stirring was continued at room temperature (25°C) for 16 hours. This was then poured into water, washed with ethyl acetate, dried with Na2SO4, and purified by high-speed silica gel column to obtain 11.3 g of compound 8-2 (79%).

[0359] Step 2: In a 250 mL three-necked round-bottom flask, 113 mL of DCM, 11.3 g (18 mmol, 1.0 equivalent) of compound 8-2, HSiEt3 (21 g, 180 mmol, 10 equivalents), and TFA (21 g, 180 mmol, 10 equivalents) were placed under nitrogen at 0°C. This was stirred for 16 hours until it reached room temperature. Concentration under vacuum yielded compound 8-3 (17 g, crude).

[0360] Step 3: 17 g (18 mmol, 1.0 equivalent) of compound 8-3, TrtCl (12.6 g, 45 mmol, 2.5 equivalents), 170 ml of DCM, and Et3N (9.1 g, 90 mmol, 5 equivalents) were mixed in a 500 ml three-necked round-bottom flask under nitrogen. After stirring at 25°C for 16 hours, the process was confirmed by LC-MS. The product was processed in the same manner as in the previous step to obtain 7.1 g of compound 8-4 (64%).

[0361] Step 4: 100 ml of DMF, 6 g (9.8 mmol, 1.0 equivalent) of compound 8-4, Zn(CN)2 (1.26 g, 10.8 mmol, 1.1 equivalents), and Pd(PPh3)4 (1.26 g, 1.1 mmol, 0.11 equivalents) were added to a 250 ml three-necked round-bottom flask under nitrogen. After stirring at 120°C for 2 hours, completion was confirmed by LC-MS. Following standard workup, 5.1 g of compound 8-5 (93%) was obtained.

[0362] Step 5: 60 ml of EtOH, 2 g (3.6 mmol, 1.0 equivalent) of compound 8-5, and 12 ml of 30% KOH were added to a 100 ml single-necked flask under nitrogen. The mixture was refluxed for 72 hours. After concentration under vacuum and subsequent work-up, 1.9 g of compound 8-6 (91%) was purified.

[0363] Step 6: 20 ml of DCM, 1 g (1.73 mmol, 1.0 equivalent) of compound 8-6, EDCI (0.432 g, 2.25 mmol, 1.3 equivalents), DIPEA (0.893 g, 6.92 mmol, 4 equivalents), HOBt (0.234 g, 1.73 mmol, 1.0 equivalent), and methoxyammonium chloride (0.174 g, 2.08 mmol, 1.2 equivalents) were combined in a 100 mL single-necked flask under nitrogen. The mixture was stirred at 25°C for 16 hours, and then treated as described above to obtain 0.43 g (41%) of compound 8-7.

[0364] Step 7: 10 ml of DCM, 0.430 g (0.71 mmol, 1 equivalent) of compound 8-7, and BBr3 (0.435 g, 1.775 mmol, 2.5 equivalents) were mixed in a 25 ml single-necked flask under nitrogen at 0°C. Stirring was continued at 0°C for 3 hours until LC-MS showed completion, and then proceeded directly to the next step.

[0365] Step 8: The mixture from Step 7 and 10 ml of MeOH were added to a 50 ml single-necked flask under nitrogen. The mixture was heated under reflux for 16 hours, and completion was confirmed by LC-MS. After concentration under vacuum, and further purification steps including the addition of 10 ml of saturated NaHCO3 solution, washing with ethyl acetate, drying on Na2SO4, and purification by liquid phase method, 39 mg of compound 8 was obtained, achieving a yield of 16%. 1 H NMR:(400MHz DMSO)δ 12.25(s,3H),7.57(s,1H),7.52(d,J=7.8Hz,1H),6.98(dt,J=15.0,6.6Hz,3H),6.79(t,J=7.7H z,1H),6.73(d,J=7.2Hz,1H),6.37(s,1H),5.87(s,1H),3.35(s,1H),2.22(s,3H),2.08(s,3H). LC-MS:[M+1] + =352.2

[0366] Example 3. Synthesis of Compound 17 [ka] Step 1: In a 10 ml single-necked flask, 4 ml of DCM, 180 mg (0.33 mmol, 1 equivalent) of compound 17-1, 110 mg (1.00 mmol, 3 equivalents) of TEA, and 47 mg (0.5 mmol, 1.5 equivalents) of methylaminoformylchloride were first charged under N2 at 0°C. The reaction mixture was brought to 25°C and stirred for 16 hours. After confirmation of the completion of the reaction by LC-MS, the mixture was concentrated under vacuum and then purified using a high-performance silica gel column to obtain 150 mg of compound 17-2 in 75% yield.

[0367] Step 2: 3 ml of DCM, 150 mg (0.25 mmol, 1 equivalent) of compound 17-2, and 1.5 ml of TFA were added to a 10 ml single-necked flask under N2 at 25°C. After stirring for 2 hours and confirming completion by LC-MS, the reaction mixture was concentrated under vacuum and purified by high-speed silica gel column to obtain 33 mg of compound 17, which corresponds to a yield of 28%.

[0368] Step 3: 438 mg of compound 17 was separated using a chiral column, and compound 17-A (133 mg) was recovered. This was then subjected to preparative liquid chromatography using a neutral method to obtain 101 mg (yield = 23.06%) and compound 17-B (133 mg). These were also purified in the same manner to obtain 101 mg in yield 23.06%. 1H NMR:(400MHz CDCl3)δ 8.66(s,1H),7.19-7.02(m,2H),6.96(d,J=7.2Hz,1H),6.68(s,1H),5.93(s,1H),4.61(dd,J=9.3,4.1Hz,1H),3.99-3.87( m,2H),3.84-3.77(m,1H),3.65(ddd,J=17.3,13.3,7.2Hz,5H),3.46-3.31(m,2H),2.66(s,3H),2.31(s,3H),2.22(s,3H). LC-MS:[M-TFA+1] + =361.3

[0369] Example 4. Synthesis of Compound 22 [ka] Step 1: In a 50 mL three-necked flask, 10 mL of ACN, 300 mg (0.793 mmol, 1 equivalent) of compound 22-1, 335 mg (1.58 mmol, 2 equivalents) of tert-butyl N-(2-bromoethyl)carbamate, and 387 mg (1.189 mmol, 1.5 equivalents) of Cs2CO3 were added. The mixture was stirred at 60°C for 12 hours. Upon completion, it was poured into water and extracted with RINKAN, as shown by LC-MS. The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 300 mg of compound 22-2 as a white solid, which was then carried out without further purification to obtain 72.5%.

[0370] Step 2: 300 mg of compound 22-2, 10 ml of DCM, and 5 ml of TFA were added to a 50 ml three-necked flask. The mixture was stirred at room temperature (25°C) for 12 hours. After confirming completion by LC-MS, the mixture was diluted with water, adjusted to pH 10, and extracted with DCM. The organic phase was dried over Na2SO4, concentrated under vacuum, and the resulting residue was subjected to column chromatography on silica gel to obtain 85 mg of compound 22-3 as a yellow solid in 45.9% yield.

[0371] Step 3: 5 ml of DMF, 75 mg (0.233 mmol, 1 equivalent) of compound 22-3, 75 mg (0.583 mmol, 2.5 equivalents) of DIPEA, and 29 mg (0.257 mmol, 1.1 equivalents) of methanesulfonyl chloride were added to a 10 ml three-necked flask. The mixture was stirred at 25°C for 2 hours until the completion of the reaction was confirmed by LC-MS analysis. The mixture was then diluted with water, extracted with EA, the organic phase was dried over Na2SO4, and the mixture was concentrated under vacuum. Purification by silica gel column chromatography yielded 14 mg of compound 22 as a white solid, achieving a yield of 13.2%. Overall yield = 4.4%. LC-MS:[M+1] + =400.2 1 H NMR(400MHz,DMSO)δ 13.46(s,1H),8.27(s,1H),7.24(dd,J=13.6,5.7Hz,2H),7.04(d,J=11.2Hz,2H),6.93-6.49(m ,5H),5.68(s,1H),3.96(s,2H),3.29(d,J=4.5Hz,2H),2.91(s,3H),2.24(s,3H),2.12(s,3H).

[0372] Example 5. Synthesis of Compound 27 [ka] Step 1: In a 50 mL reaction flask, 10 mL of THF and 860 mg (3.39 mmol, 1.5 equivalents) of 1,3-dibromo-2-fluorobenzene were combined and cooled to -65°C. Next, 1.4 mL (3.39 mmol, 1.5 equivalents) of n-butyllithium was added. The mixture was stirred at this temperature for 2 hours, after which 1 g (2.26 mmol, 1 equivalent) of compound 27-1 and another 10 mL of THF were added. This was stirred at -65°C for a further 30 minutes, and then warmed to room temperature over 16 hours. Completion was confirmed by LC-MS, and 20 mL of saturated ammonium chloride was added. The organic phase was then separated, concentrated under vacuum, and purified by column chromatography to obtain 600 mg of compound 27-2 in 43% yield.

[0373] Step 2: 600 mg (0.971 mmol, 1 equivalent) of compound 27-2, 1.1 g (9.71 mmol, 10 equivalents) of triethylsilane, and 1.1 g (9.71 mmol, 10 equivalents) of TFA were added to a 50 mL three-necked flask. The mixture was stirred at 25°C for 1 hour. After completion, it was confirmed by LC-MS, poured into water, adjusted to pH=10, extracted with EA, dried over Na2SO4, and concentrated under vacuum. By purification via silica gel column chromatography, 170 mg of compound 27-3 was isolated as a yellow solid, yielding 48.7%.

[0374] Step 3: Add 10 ml of DMF, 170 mg (0.473 mmol, 1 equivalent) of compound 27-3, 158 g (0.568 mmol, 1.2 equivalents) of triphenylmethyl chloride, and 96 mg (0.946 mmol, 2 equivalents) of TEA to a 25 mL reaction flask. Stir the mixture at 25 °C for 12 hours until LC-MS indicated that the reaction was complete. Pour into water, extract with EA, dry over Na₂SO₄, concentrate, and purify the crude product by column chromatography to obtain 220 mg of compound 27-4 in 77.3% yield.

[0375] Step 4: A 25 mL reaction flask was prepared using 10 mL of DMF, 170 mg (0.283 mmol, 1 equivalent) of compound 27-4, 100 mg (0.848 mmol, 3 equivalents) of ZnCN, and 98 mg (0.0848 mmol, 0.3 equivalents) of tetrakis(triphenylphosphine)palladium. The mixture was stirred at 150°C for 30 minutes under microwave. After completion, the mixture was confirmed by LC-MS, worked up, and purified by column chromatography to obtain 130 mg of compound 27-5 in 84% yield.

[0376] Step 5: 10 mL of DMSO and 110 mg (0.201 mmol, 1 equivalent) of compound 27-5 were added to a 25 mL reaction flask and cooled to 0°C. Then, 3 mL of 30% H2O2 was added and the mixture was stirred at 0°C for 1 hour. After confirmation of completion by LC-MS, water was added to separate the organic phase, and the mixture was concentrated under vacuum. By column chromatography, 100 mg of compound 27-6 was obtained in 88.1% yield.

[0377] Step 6: In a 25 mL three-port flask, 10 mL of DCM and 110 mg of compound 27-6 were combined, and 5 mL of TFA was added at 0°C. The mixture was allowed to rise naturally to room temperature and stirred for 2 hours. Completion was indicated by LC-MS. The mixture was then concentrated under reduced pressure, and the residue was purified by TLC to obtain 25 mg of compound 27 as a white solid in 29.4% yield. Overall yield = 3.5%. LC-MS:[M-C2HF3O2+1]+=324.2 1 H NMR(400MHz,DMSO)δ 14.36(s,5H),8.97(s,3H),7.77(s,3H),7.64(s,3H),7.60(t,J=6.7Hz,3H),7.24(t,J=7.7Hz,3H),7 .15(d,J=7.3Hz,3H),7.13-6.98(m,9H),6.71(d,J=7.5Hz,3H),6.01(s,3H),2.27(s,9H),2.12(s,9H)

[0378] Example 6. Synthesis of Compound 28 [ka] Step 1: In a 500 ml reaction flask, 220 ml of DMF, 24.5 g (0.13 mol, 1 equivalent) of compound 28-1, 26.6 g (0.16 mol, 1.2 equivalents) of benzyl bromide, and 21.5 g (1.2 mol, 1.2 equivalents) of K2CO3 were combined. The mixture was heated at 95 °C for 16 hours. Completion of the reaction was confirmed by GC-MS. After filtration and concentration, 32 g of compound 28-2 was obtained in 88.5% yield by column chromatography.

[0379] Step 2: 5 ml of THF, 185 mg (7.6 mmol, 2.1 equivalents) of magnesium tips, and 2 g (7.2 mmol, 2.0 equivalents) of compound 28-2 were added to a 25 ml reaction flask. The mixture was stirred at 65°C for 1 hour, then cooled to room temperature for the next step. 20 ml of THF and 1.59 g (3.6 mmol, 1.0 equivalent) of (2,3-dimethylphenyl)-[1-(trityl)-1H-imidazole-4-yl]methanone were added to a 50 ml reaction flask. The pre-prepared Grignard reagent was added, and the reaction was heated at 80°C for 16 hours. Completion was confirmed by LC-MS. The mixture was quenched with 10 ml of water, extracted with EA, dried over Na2SO4, and then concentrated. 1.6 g of compound 28-3 was obtained in 69.2% yield by column chromatography.

[0380] Step 3: In a 100 mL reaction flask, 14 mL of DCM, 1.4 g (2.18 mmol, 1.0 equivalent) of compound 28-3, and 2.53 g (21.8 mmol, 10 equivalents) of TES were added. After cooling to 0°C, 2.48 g (21.8 mmol, 10 equivalents) of TFA was added. The mixture was heated at 25°C for 5 hours, and then concentrated under vacuum after completion was confirmed by LC-MS. The residue was subjected to column chromatography to obtain 500 mg of compound 28-4 in 68.4% yield.

[0381] Step 4: In a 5 mL reaction flask, 2 mL of THF, 100 mg (0.29 mmol, 1.0 equivalent) of compound 28-4, 7 mg (0.06 mmol, 0.2 equivalents) of DMAP, 94 mg (0.43 mmol, 1.5 equivalents) of Boc2O, and 44 mg (0.43 mmol, 1.5 equivalents) of TEA were mixed. The reaction mixture was kept at 25°C for 4 hours and confirmed by LC-MS. After vacuum concentration, the residue was purified by column chromatography to obtain 120 mg of compound 28-5 in yield 85.5%.

[0382] Step 5: A 10 mL reaction flask was loaded with 1.5 mL of acetic acid, 0.5 mL of water, and 120 mg (0.25 mmol, 1.0 equivalent) of compound 28-5. After cooling to 0°C, 165 mg (1.24 mmol, 5 equivalents) of NCS was added. The mixture was stirred at 0°C for 2 hours until LC-MS confirmed completion, and then proceeded to the next step without purification. The yield was recorded as 100%.

[0383] Step 6: 10 mL of 2 M NH2CH3 / THF was added to a 50 mL reaction flask and cooled to 0°C, after which crude compound 28-6 was introduced. Stirring was continued at 25°C for 16 hours, as demonstrated by LC-MS. After concentration under vacuum, the mixture was purified by column chromatography to obtain 40 mg of compound 28-7 in 40% yield.

[0384] Step 7: In a 5 mL reaction flask, 1 mL of DCM and 40 mg (0.088 mmol, 1.0 equivalent) of compound 28-7 were combined. After cooling the mixture to 0°C, 0.5 mL of TFA was added, and the mixture was then heated to 25°C for 2 hours, and completion was indicated by LC-MS. The concentrated mixture was purified by preparative HPLC to obtain 14 mg of compound 28 in 44.8% yield. Overall yield = 6.4%. LC-MS:[M+1-TFA] + =356.1 1 H NMR(400MHz,DMSO)δ 14.32(s,2H),9.01(s,1H),7.71(d,J=7.8Hz,1H),7.64-7.58(m,2H),7.46(dt,J=17.1,6.3Hz,2H),7.12(d t,J=15.1,7.4Hz,2H),6.95(s,1H),6.68(d,J=7.4Hz,1H),2.37(d,J=4.9Hz,3H),2.26(s,3H),2.12(s,3H).

[0385] Example 7. Synthesis of Compound 31 [ka] Step 1: 120 ml of THF, 5.08 g (27.15 mmol, 4.0 equivalents) of 4-bromo-2-methoxypyridine, and 10 ml of n-hexane containing 2.5N n-butyllithium (25.1 mmol, 3.7 equivalents) were added dropwise at -65°C to a 250 mL three-port reaction bottle. After maintaining the solution at -65°C for 1 hour, 3 g (6.79 mmol, 1 equivalent) of compound 31-1 was added. After a further 0.5 hours at -65°C, the reaction was allowed to proceed overnight at room temperature. Completion was confirmed by LC-MS. The reaction mixture was quenched with 100 ml of saturated ammonium chloride, the organic layer was separated and concentrated. The residue was mixed with 50 mL of DCM, stirred for 5 minutes, filtered, and dried under an infrared lamp to obtain 2.88 g (yield 77%) of compound 31-2.

[0386] Step 2: 20 ml of 57 wt.% HI, 2.35 g (4.599 mmol, 1.0 equivalent) of compound 31-2 and 1.43 g (45.99 mmol, 10 equivalents) of red phosphorus were placed in a 50 ml sealed tank. The mixture was stirred overnight at 160°C, completion was confirmed by LC-MS, the mixture was cooled to room temperature, and concentrated to obtain 5 g (100% yield) of crude compound 31-3.

[0387] Step 3: Compound 31-3 (1 g, crude) and 15 mL of POCl3 were added to a 5 mL reaction flask. The mixture was refluxed overnight, and completion was confirmed by LC-MS. The mixture was then cooled, concentrated under vacuum, and the residue was neutralized to pH=8 with saturated sodium bicarbonate. Extraction was performed with 40 mL of EA (3 times), dried over anhydrous sodium sulfate, concentrated, and 174 mg of compound 31-4 was obtained by column chromatography (30% yield).

[0388] Step 4: 174 mg (0.586 mmol, 1 equivalent) of compound 31-4, 10 mL of MeOH, 296 mg (2.93 mmol, 5 equivalents) of TEA, and 48 mg (0.0586 mmol, 0.1 equivalent) of PdCl2 (dppf) were introduced into a 200 mL high-pressure reactor. This reaction was carried out at 120 °C for 48 hours under 5 MPa of carbon monoxide, leaving 5% of the starting material as shown by LC-MS. After filtration and concentration, 270 mg of compound 31-5 was isolated by column chromatography (100% yield).

[0389] Step 5: 100 mg (0.312 mmol, 1 equivalent) of compound 31-5 and 5 mL of MeOH / NH3 (15 M / L) were placed in a 50 mL sealed tank. The mixture was stirred overnight at 68 °C, cooled to room temperature, concentrated under vacuum, and then purified to obtain 10 mg of compound 31 by pre-HPLC (yield 10%). LC-MS:[M+1] + =307.2 1 H NMR(400MHz,DMSO)δ 12.53(s,1H),8.52(d,J=4.7Hz,1H),8.10(s,1H),7.86(s,1H),7.79(s,1H),7.63(s,1H),7.35(d,J=3. 8Hz,1H),7.10-7.00(m,2H),6.81(d,J=7.2Hz,1H),6.66(s,1H),5.80(s,1H),2.24(s,3H),2.11(s,3H).

[0390] Example 8. Synthesis of Compound 32 [ka] Step 1: 300 mg (0.51 mmol, 1 equivalent) of compound 32-1, 108 mg (1.54 mmol, 3 equivalents) of 2-cyanoethylamine, 213 mg (1.54 mmol, 3 equivalents) of K2CO3, 47 mg (0.051 mmol, 0.1 equivalent) of Pd2(dba)3, and 55 mg (0.10 mmol, 0.2 equivalents) of Bulletfos were added to the bottom of a 50 mL single-neck flask. The mixture was stirred under nitrogen at 120 °C for 1 hour. Completion of the reaction was indicated by TLC. The mixture was then transferred to 100 mL of water and extracted three times with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of brine, dried over Na2SO4, and concentrated under vacuum to obtain 1 g of crude yellow oil. This was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 216 mg of compound 32-2 as a yellow powder, with a yield of 73.36%.

[0391] Step 2: 200 mg (0.35 mmol, 1 equivalent) of compound 32-2, 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid were placed in a 50 mL single-necked flask. The mixture was stirred at room temperature for 1 hour, and the completion of the reaction was confirmed by TLC. The solution was then concentrated under vacuum, and the crude product was subjected to column chromatography (dichloromethane:methanol = 1:0 to 90:10) to obtain 120 mg of compound 32. Further purification by preparative HPLC yielded 93 mg of compound 32 as a yellow powder, with an overall yield of 59.92%. Overall yield = 43.96%. LC-MS:[M+1] + =331.2. 1H NMR(400MHz,DMSO)δ 14.18(s,2H),8.91(s,1H),7.15-7.01(m,3H),6.90(s,1H),6.70(d,J=7.2Hz,1H),6.52(d,J=8.0Hz,1H),6.41(s,1H),6.36(d,J= 7.6Hz,1H),5.97(s,1H),5.65(s,1H),3.49-3.13(m,5H),2.67(t,J=6.5Hz,2H),2.25(s,3H),2.13(s,3H).Y=59.92%.Total yield=43.96%.

[0392] Example 9. Synthesis of Compound 58 [ka] Step 1: In a 100 mL reaction flask, 40 mL of THF and 4 g (15.5 mmol, 2.5 equivalents) of 2-chloro-3-fluoro-4-iodopyridine were added. After cooling the mixture to 0°C, 12 mL (15.5 mmol, 2.5 equivalents) of iPr-MgClLiCl was introduced. The reaction mixture was stirred at 0°C for 3 hours, then 1.16 g (2.63 mmol, 1.0 equivalent) of 2,3-dimethylphenyl)[1-(trityl)-1H-imidazole-4-yl]methanone was added, and the reaction mixture was stirred at 80°C for 16 hours. After completion, the reaction was confirmed by LC-MS, quenched with 40 mL of water, and extracted with EA. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to obtain 2.6 g of compound 58-1, achieving a yield of 29.3%.

[0393] Step 2: 1 g (1.74 mmol, 1.0 equivalent) of compound 58-1, 40 mL of MeOH, 40 mL of DMSO, 530 mg (5.24 mmol, 3.0 equivalents) of TEA, and 148 mg (0.17 mmol, 0.1 equivalents) of PdCl2 (dppf) were added to a 200 mL high-pressure reactor. The mixture was reacted with carbon monoxide at 5 MPa and 100 °C for 48 hours, and LC-MS showed a residual starting material of 5%. After concentration, the residue was purified by column chromatography to obtain 53 mg of compound 58-2 in yield of 51.2%.

[0394] Step 3: 25 mL of 16 M NH3 / MeOH and 530 mg (0.89 mol, 1.0 equivalent) of compound 58-2 were placed in a 50 mL sealed tube. The mixture was stirred at 30°C for 16 hours until LC-MS completion was confirmed, and then the residue was purified by column chromatography to obtain 360 mg of compound 58-3 in 67.8% yield.

[0395] Step 4: 3 mL of DCM, 100 mg (0.17 mmol, 1.0 equivalent) of compound 58-3, and 195 mg (1.7 mmol, 10 equivalents) of TES were added to a 10 mL reaction flask. After cooling to 0°C, 191 mg (1.7 mmol, 10 equivalents) of TFA was introduced. The reaction mixture was then heated to 100°C for 3.5 hours. LC-MS showed completion, and after concentration under vacuum, the residue was purified by preparative HPLC to obtain 16 mg of compound 58 in 28.8% yield. LC-MS:[M+1] + =325.2 1 H NMR(400MHz,CD3OD)δ 8.36(d,J=4.8Hz,1H),7.73(d,J=0.9Hz,1H),7.13(dt,J=22.7,10.1Hz,2H),7.03(t,J= 7.6Hz,1H),6.72(d,J=7.7Hz,1H),6.53(s,1H),6.05(s,1H),2.32(s,3H),2.21(s,3H).

[0396] Example 10. Synthesis of Compound 60 [ka] Step 1: 29 mL of THF and 2.9 g (43.9 mmol, 7.5 equivalents) of zinc were added to a 100 mL three-necked flask. The mixture was cooled to -10°C under a nitrogen atmosphere with stirring. Then, 4.1 g (21.6 mmol, 3.7 equivalents) of titanium tetrachloride was added dropwise at -10°C. The reaction mixture was stirred at 70°C for 16 hours, after which 950 mg (6.08 mol, 1.04 equivalents) of methyl 3-oxocyclohexanecarboxylate and 2.6 g (5.85 mol, 1 equivalent) of (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone were added. Stirring was continued at 80°C for 4 hours. Completion was confirmed by LC-MS. The reaction mixture was then diluted with 100 mL of water and 100 mL of EA, filtered, and the filtrate was extracted with EA. After washing with brine and drying over Na2SO4, the organic layer was concentrated under reduced pressure to obtain 950 mg of compound 60-1 as the crude product in 50% yield.

[0397] Step 2: In a 25 mL three-necked flask, 10 mL of DCM and 0.5 g (1.54 mmol, 1 equivalent) of compound 60-1 were added along with 10 mL of HCl / Et2O. The mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was complete. Concentration under reduced pressure yielded 400 mg of compound 60-2 as the crude product, with a yield of 100%.

[0398] Step 3: In a 250 mL three-necked flask, 1.2 mL of AcOH, 0.9 mL of hydroiodic acid (55%-58%), 50 mg (0.15 mmol, 1.0 equivalent) of compound 60-2, and 167 mg (5.4 mmol, 35 equivalents) of phosphorus were added. The reaction mixture was stirred at 100 °C for 16 hours. Completion was confirmed by LC-MS. The mixture was then added to water, adjusted to pH=7, and extracted with EA. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 70 mg of crude product. Purification by liquid chromatography yielded 6 mg of compound 60 in 10% yield. Overall yield: 5% LC-MS:[M-TFA-1]-=311.2 1H NMR(400MHz,DMSO)δ 14.20(s,2H),12.02(s,1H),9.02-8.89(m,1H),7.75-7.56(m,1H),7.13(ddt,J= 22.9,16.8,9.0Hz,3H),4.26-4.06(m,1H),2.28-2.08(m,8H),1.91-0.73(m,8H).

[0399] Example 11. Synthesis of Compound 61 [ka] Step 1: In a 50 mL reaction flask, 20 mL of toluene, 3.8 g (16.7 mmol, 1.0 equivalent) of methyl 3-(bromomethyl)benzoate, and 3.04 g (18.3 mmol, 1.1 equivalents) of triethyl phosphite were added. The mixture was stirred at 110 °C for 16 hours. After completion, the mixture was confirmed by LC-MS and the solution was concentrated. The residue was subjected to column chromatography to obtain 5.3 g of compound 61-1 in 99% yield.

[0400] Step 2: In a 100 mL reaction flask, 40 mL of THF, 2 g (7.0 mmol, 1.0 equivalent) of compound 61-1, and 3.4 g (7.7 mmol, 1.1 equivalents) of (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone were combined and cooled to 0°C. Then, 2.35 g (21 mmol, 3.0 equivalents) of potassium tert-butoxide was added. The mixture was stirred at 27°C for 16 hours, and completion was confirmed by LC-MS. The solution was then concentrated and purified by column chromatography to obtain 1.03 g of compound 61-2 in 26.3% yield.

[0401] Step 3: 10 mL of DCM and 500 mg of compound 61-2 were added to a 25 mL reaction flask, followed by the addition of 2.5 mL of TFA. The reaction mixture was stirred at 27°C for 1 hour. LC-MS showed completion, and after concentration, the residue was purified by column chromatography to obtain 240 mg of compound 61-3 in 84.5% yield.

[0402] Step 4: In a 10 mL reaction flask, 3 mL of THF, 240 mg of compound 61-3, and 120 mg (50%) of Pd / C were added. The mixture was stirred at 27 °C for 16 hours, confirmed by LC-MS, and the solution was filtered. The organic phase was concentrated, and the residue was purified by column chromatography to obtain 150 mg of compound 61-4 in 62.1% yield.

[0403] Step 5: In a 10 mL reaction flask, 3 mL of DMF, 80 mg (0.25 mmol, 1.0 equivalent) of compound 61-4, and 209 mg (2.5 mmol, 10 equivalents) of methoxyammonium chloride were added. The mixture was cooled to 0°C, and then 386 mg (3 mmol, 12 equivalents) of DIPEA and 142 mg (0.37 mmol, 1.5 equivalents) of HATU were added. After stirring at 27°C for 4.5 hours, LC-MS showed 40% residual raw material. The mixture was concentrated under vacuum to obtain 160 mg of compound 61-5, achieving a 100% yield.

[0404] Step 6: A 10 mL reaction flask was prepared using 1 mL of DCM and 160 mg of compound 61-5, and 0.5 mL of TFA was added. The mixture was stirred at 27°C for 1 hour, and completion was confirmed by LC-MS. After concentration under vacuum, the residue was purified by preparative HPLC to obtain 25 mg of compound 61 in yield of 15.3%. Overall yield: 2.1%. LC-MS:[M-C2HF3O2+1]+=350.2 1H NMR(400MHz,DMSO)δ 14.20(s,2H),11.69(s,1H),8.96(d,J=0.9Hz,1H),7.61(d,J=4.6Hz,2H),7.55-7.48(m,1H),7.31(t,J=6.4Hz,2H),7.07(dt,J=12 .8,4.6Hz,3H),4.74(t,J=7.9Hz,1H),3.70(s,3H),3.39(d,J=8.5Hz,1H),3.19(dd,J=13.8,7.3Hz,1H),2.21(s,3H),2.12(s,3H).

[0405] Example 12. Synthesis of Compound 139 [ka] Step 1: In a 100 ml single-necked flask, 50 ml of THF, 5 g (11.29 mmol, 1.0 equivalent) of (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone, 2.3 g (18.1 mmol, 1.6 equivalents) of ethyl chloroacetate, and 1.35 g (33.9 mmol, 3 equivalents, 60% by weight) of NaH were combined under a nitrogen atmosphere. The mixture was stirred at 25°C for 16 hours, confirmed to be complete by LC-MS, and concentrated under vacuum. After adding 50 ml of 10% KOH, the mixture was stirred for a further 16 hours at 100°C, followed by workup and purification via a high-performance silica gel column to obtain 3.4 g of 139-1 in 65.9% yield.

[0406] Step 2: In a 100 mL three-necked flask, 60 mL of ACN, 3.2 g (7.01 mmol, 1 equivalent) of 139-1, 3.14 g (14.02 mmol, 2 equivalents) of CAS:39684-80-5, and 3.42 g (10.51 mmol, 1.5 equivalents) of Cs2CO3 were added. The mixture was stirred at 60 °C for 12 hours, and completion was confirmed by LC-MS. The reaction product was work-processed and purified to obtain 930 mg of 139-2 in yield of 22.1%.

[0407] Step 3: 300 mg of 139-2, 3 ml of DCM, and 4 M HCl in 3 ml of dioxane were added to a 25 mL three-necked flask. The mixture was stirred at 25 °C for 3 hours, and completion was confirmed by LC-MS. The reaction mixture was then neutralized to pH=10, extracted, and purified to obtain 130 mg of 139-3 as a white solid in 52% yield.

[0408] Step 4: 5 ml of THF, 130 mg (0.260 mmol, 1 equivalent) of 139-3, 40 mg (0.390 mmol, 1.5 equivalents) of TEA, and 57 mg (0.286 mmol, 1.1 equivalents) of (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (CAS: 264608-29-9) were added to a 25 mL three-necked flask. The mixture was stirred at 25 °C for 18 hours, and its integrity was confirmed by LC-MS. The mixture was then post-processed and purified to obtain 80 mg of 139-4 as a white solid, resulting in a total concentration of 46.5%.

[0409] Step 5: Combine 139-4 (80 mg) with Pd(OH)2 / C (80 mg), 5 mL of methanol, and 5 mL of THF, and stir under a hydrogen atmosphere at 40°C for 18 hours. Filter off the catalyst, concentrate the filtrate, mix with 10 mL of DCM and 5 mL of TFA, stir for 10 minutes, and dry. The residue was purified by preparative HPLC to obtain 30 mg of 139 as a white solid in 46.3% yield. Overall yield = 1.63%. LC-MS:[M-C2HF3O2+1]+=422.2 1H NMR(400MHz,DMSO)δ 14.20(s,2H),9.00(s,1H),7.58(s,1H),7.21-6.95(m,3H),6.86(d,J=7.5Hz,1H),4.65 (dd,J=8.2,5.3Hz,1H),3.90(t,J=9.3Hz,1H),3.78(dd,J=16.0,8.9Hz,3H),3.50(d,J=5 .1Hz,2H),3.28(t,J=11.2Hz,2H),3.09(dd,J=11.1,5.4Hz,2H),2.92(d,J=6.3Hz,2H),2 .28(s,6H),2.00(d,J=4.4Hz,1H),1.72(d,J=12.9Hz,2H),1.28(qd,J=12.2,4.1Hz,2H).

[0410] Example 13. Synthesis of Compound 156 [ka] Step 1: 25 mL of toluene, 5 g (0.0188 mmol, 1.0 equivalent) of 3-fluoro-4-bromobenzyl bromide, and 3.44 g (0.0207 mmol, 1.1 equivalents) of triethyl phosphite were added to a 50 mL reaction flask. The mixture was stirred at 110 °C for 18 hours, and completion was confirmed by LC-MS. The reaction mixture was concentrated, and the residue was purified by column chromatography to obtain 5.69 g of compound 156-1 in 93.4% yield.

[0411] Step 2: In a 50 mL reaction flask, 20 mL of THF, 1 g (3.08 mmol, 1.0 equivalent) of compound 156-1, and 1.36 g (3.08 mmol, 1.0 equivalent) of (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone were added and cooled to 0°C. Then, 1.04 g (9.24 mmol, 3.0 equivalents) of potassium tert-butoxide was introduced. The mixture was stirred at 10°C for 18 hours, and completion was confirmed by LC-MS. The reaction product was then filtered, concentrated, and the residue was purified by column chromatography to obtain 1.31 g of 156-2 in 69.5% yield.

[0412] Step 3: 5 mL of DMF, 500 mg (0.817 mmol, 1.0 equivalent) of 156-2, 192 mg (1.634 mmol, 2.0 equivalents) of zinc cyanide, and 95 mg (0.0817 mmol, 0.1 equivalent) of Pd(PPh3)4 were placed in a 10 mL reaction flask. After stirring at 120 °C for 18 hours, TLC showed that 50% of the starting material remained. The mixture was diluted with 40 mL of ice water, extracted three times with 20 mL of EA, dried over anhydrous sodium sulfate, filtered, and concentrated under high pressure. Purification by column chromatography yielded 220 mg of 156-3 in yield of 83.5%.

[0413] Step 4: In a 5 mL reaction flask, combine 1.5 mL of THF, 1.5 mL of MeOH, 110 mg (0.197 mmol, 1.0 equivalent) of 156-3, 54 mg (0.394 mmol, 2.0 equivalents) of K2CO3, and 45 mg (0.394 mmol, 2.0 equivalents) of 30% H2O2 under nitrogen. Stir the mixture overnight at 20°C for 18 hours. After completion, confirm by LC-MS, pour the mixture into 10 mL of water, extract three times with 10 mL of EA, dry over Na2SO4, and concentrate under vacuum. Purification by column chromatography yielded 77 mg of 156-4 in 67.7% yield.

[0414] Step 5: In a 5 mL reaction flask, 3 mL of MeOH:THF (1:1), 90 mg (0.156 mmol, 1.0 equivalent) of 156-4, and 87 mg of Pd(OH)2 were added and stirred overnight at 48°C under a hydrogen atmosphere. The completion of the reaction was confirmed by LC-MS. The reaction product was filtered and concentrated, and the crude product was further treated with 2 mL of DCM and 0.5 mL of TFA, stirred for 0.5 hours, and then concentrated. Purification by preHPLC yielded 41 mg of compound 156 in 58.3% yield. Overall yield: 21.4% LC-MS:[M-C2HF3O2+1]+=338.2 1H NMR(400MHz,DMSO)δ 14.25(s,2H),8.97(s,1H),7.65-7.48(m,4H),7.09(dt,J=14.4,7.2Hz,5H),4.78(t,J=7.9H z,1H),3.42(dd,J=13.9,8.5Hz,1H),3.22(dd,J=13.9,7.3Hz,1H),2.23(s,3H),2.16(s,3H).

[0415] Example 14. Synthesis of Compound 182 [ka] Step 1: In a 50 mL flask, 20 mL of DMF, 2 g (9.66 mmol, 1.0 equivalent) of 4-bromo-2-thiophenecarboxylic acid, 2.93 g (28.98 mmol, 3.0 equivalents) of TEA, and 1.21 g (14.49 mmol, 1.5 equivalents) of methoxyammonium chloride were combined. 4.41 g (11.59 mmol, 1.2 equivalents) of HATU was added and the mixture was stirred at room temperature for 12 hours. After completion, the reaction was confirmed by LC-MS, the reaction product was quenched with water, and extracted with ethyl acetate. After drying over Na2SO4 and filtering, the concentrate was purified by column chromatography (PE:EA=67:33) to obtain 1.25 g of 182-1 as a white solid in 54.8% yield.

[0416] Step 2: In a 25 mL three-necked flask, 598 mg (2.53 mmol, 2.0 equivalents) of 182-1 was dissolved in 6 mL of THF and cooled to -80°C under nitrogen. n-BuLi (2.5 M, 2.5 mL, 6.33 mmol, 5.0 equivalents) was added and the mixture was stirred for 40 minutes. Then, a mixture of 560 mg (1.27 mmol, 1.0 equivalent) of (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone in 6 mL of THF was introduced. The mixture was stirred for 1 hour, quenched with water, and then heated and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated, then purified by column chromatography (DCM:MeOH = 90:10) and further recrystallized in PE:MTBE = 2:1. As a result, 67 mg of 182-2 was obtained as a pale yellow solid. The yield was 8.8%.

[0417] Step 3: In a 10 mL flask, 1 mL of DCM, 1 mL of TFA, 65 mg (0.11 mmol, 1.0 equivalent) of 182-2, and 38 mg (0.33 mmol, 3.0 equivalents) of TES were added. After stirring for 2 hours and confirming completeness by LC-MS, the mixture was concentrated and purified by preparative HPLC to obtain 20 mg of 182 as a white solid, resulting in a total concentration of 42.1%. Overall yield = 2.03%. LC-MS:[M-C2HF3O2+1]+=342.1 1H NMR(400MHz,DMSO)δ 14.36(s,2H),11.75(s,1H),9.06(s,1H),7.46(s,2H),7.12(p,J=7.4Hz,3H) ,6.75(d,J=7.3Hz,1H),5.88(s,1H),3.67(s,3H),2.28(s,3H),2.18(s,3H).

[0418] Example 15. Synthesis of Compound 188 [ka] Step 1: To a methanol solution of adamantane-1,3-dicarboxylic acid (18 g, 80.27 mmol, 1.0 equivalent), thionyl chloride (0.582 mL, 8.03 mol, 0.1 equivalent) was added at 0°C, and the mixture was stirred at 85°C for 12 hours. The completion of the reaction was confirmed by LC-MS. The concentrated mixture was diluted with water (50 mL), neutralized to pH=8 with saturated NaHCO3, extracted with ethyl acetate (30 mL x 3), dried, and concentrated to obtain 20 g of 188-1 as a white solid (100% yield).

[0419] Step 2: Dissolve 188-1 (20 g, 79.27 mmol, 1.0 equivalent) in methanol (350 mL), add NaBH4 (14.99 g, 0.39 mol, 5.0 equivalent) at 0°C, stir at 25°C for 12 hours, and after confirming completion, concentrate the reaction product, dilute with ethyl acetate, extract with water, dry, and purify to obtain 5 g of 188-2 as a white solid (yield 11.7%).

[0420] Step 3: DMSO (50 mL), 188-2 (4 g, 17.83 mmol, 1.0 equivalent), PySO3 (7.1 g, 44.58 mmol, 2.5 equivalents), and TEA (4.51 g, 44.58 mmol, 2.5 equivalents) were added to a 250 mL flask. The mixture was stirred at 25°C for 1 hour, confirmed by LC-MS, and the mixture was processed and purified to obtain 2 g of 188-3 as a white solid (yield 51.3%).

[0421] Step 4: In a 50 mL flask, THF (20 mL) was mixed with Zn (1.1 g, 16.87 mmol, 7.5 equivalents) and TiCl4 (1.58 g, 8.32 mmol, 3.7 equivalents) at -70°C, followed by mixing 188-3 (500 mg, 2.25 mmol, 1.0 equivalent) and the specific compound in THF. The mixture was stirred at 80°C for 2 hours to complete the reaction, followed by workup and purification to obtain 270 mg of 188-4 as a yellow solid (yield 19.1%).

[0422] Step 5: 188-4 (200 mg) was reacted with NaOH (5 mL, 8 M) in methanol at 20°C, heated to 115°C for 12 hours, cooled, adjusted to pH=4, extracted, and concentrated to obtain 80 mg of 188-5 as a yellow solid (yield 40.8%).

[0423] Step 6: 188-5 (60 mg, 0.096 mmol, 1.0 equivalent) was mixed with oxalyl dichloride (36.92 mg, 0.291 mmol, 3.0 equivalents) in DCM (1 mL) at 0°C, stirred at 15°C for 1 hour, and concentrated to obtain 60 mg of 188-6 as a white solid (100% yield), which was used directly in the next step.

[0424] Step 7: Dissolve 188-6 (60 mg) in THF (0.5 mL), treat with NH3·THF (8 mL) at 0°C, stir at 15°C for 1 hour, and concentrate to obtain 60 mg of 188-7 as a white solid (100% yield), which was used directly in the next step.

[0425] Step 8: 188-7 (60 mg) was mixed with Pd(OH)2 (60 mg) in MeOH:THF (16 mL, 1:1) and stirred at 45°C under a hydrogen atmosphere. The mixture was then concentrated, treated with DCM (1 mL) and TFA (0.5 mL), and further concentrated. After purification, 20 mg of 188 was obtained as a white solid (yield 43.4%). Total yield = 0.2%. LC-MS:[M-C2HF3O2+1]+=378.2 1H NMR(400MHz,DMSO)δ 14.20(s,2H),8.96(s,1H),7.66(s,1H),7.03(t,J=6.2Hz,3H),6.89(s,1H),6.67(s,1H),4.53(dd,J=8 .5,3.6Hz,1H),2.27(d,J=16.9Hz,6H),2.06(dd,J=14.4,9.0Hz,1H),1.95(s,2H),1.68-1.21(m,13H).

[0426] Example 16. Synthesis of Compound 196 [ka] Step 1: Zinc (5.6 g, 0.085 mol, 19 equivalents) was added to a solution of THF (20 mL), and TiCl4 (8.2 g, 0.043 mol, 9.6 equivalents) was added dropwise at 0°C. The reaction mixture was then heated under reflux at 70°C for 1 hour. After cooling to 30°C, a THF solution containing 2,3-dihydro-benzo[1,4]dioxin-6-carbaldehyde (1.8 g, 0.0108 mol, 2.4 equivalents) and (2,3-dimethylphenyl)(1-trityl-4-imidazolyl)methanone (2 g, 0.0045 mol, 1 equivalent) was introduced, and the mixture was refluxed under nitrogen at 65°C for 2 hours. Completion was confirmed by LC-MS. The reaction mixture was quenched with water, extracted with ethyl acetate, dried, and concentrated. Purification by column chromatography yielded 2.1 g of 196-1 as a white solid (100% yield).

[0427] Step 2: 196-1 (100 mg, 0.37 mmol, 1 equivalent) was mixed with Pd(OH)2 / C (100 mg) in a THF:MeOH (1:1) solution and stirred at 40°C for 16 hours under a hydrogen atmosphere. After confirming completion by LC-MS, the reaction product was filtered and concentrated to obtain the crude product. DCM (2 mL) and TFA (1 mL) were added to the crude product, which was then concentrated and purified by preparative HPLC to obtain 12 mg of 196 as a white solid (yield 9.7%). Total yield=9.7% LCMS:[M-C2HF3O2+1]+=335.2 1H NMR(400MHz,DMSO)δ 14.22(s,2H),8.94(s,1H),7.59(s,1H),7.13-6.99(m,3H),6.67(dd,J=7.5,4.9Hz,2H),6.59(dd,J=8.2,1.6Hz,1H),4. 64(t,J=7.7Hz,1H),4.16(s,4H),3.22(dd,J=13.9,8.8Hz,1H),3.01(dd,J=13.9,6.8Hz,1H),2.23(s,3H),2.15(s,3H).

[0428] Example 17. Synthesis of Compound 401 [ka] Step 1: In a 100 mL flask, 50 mL of dichloromethane and 4-iodo-1-trityl-1H-imidazole (11.8 g, 0.027 mol, 1.0 equivalent) were combined. After cooling the mixture to 0°C, iPrMgClLiCl (1.3 mol / L, 20.7 mL, 0.027 mol, 1.0 equivalent) was added. The mixture was stirred at 0°C for 2 hours, and then 3-bromobenzaldehyde (5 g, 0.027 mol, 1.0 equivalent) was introduced. Stirring was continued at 28°C for 16 hours until LC-MS confirmed the completion of the reaction. After cooling to 0°C and quenching with 44 mL of saturated ammonium chloride, the organic layer was separated, concentrated, and purified by column chromatography using ethyl acetate to obtain 7.1 g of 401-1, achieving a yield of 53%.

[0429] Step 2: 180 mL of dichloromethane, compound 401-1 (6.1 g, 12.35 mmol, 1.0 equivalent), and MnO2 (6.44 g, 74.1 mmol, 6.0 equivalents) were added to a 200 mL high-pressure tube. The mixture was stirred at 72 °C for 5 hours. Completion was confirmed by LC-MS, and the mixture was then filtered to obtain 5.6 g of compound 401-2, achieving a yield of 83.9%.

[0430] Step 3: 500 mL of diethyl ether and 20 g (82.67 mmol, 1 equivalent) of 3,4-dibromothiophene (Cas:3141-26-2) were added to a 1 L reaction vessel. After cooling to -78°C, 36.37 mL (90.94 mmol, 1.1 equivalents) of n-BuLi was added dropwise. The mixture was stirred at -78°C for 30 minutes, and then 14.02 g (90.94 mmol, 1.1 equivalents) of diethyl sulfate was added dropwise. Stirring was continued at 25°C for 5 hours until LC-MS confirmed completion of the reaction. After adding 25 mL of aqueous ammonia, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10 g of compound 401-3, achieving a yield of 63.3%.

[0431] Step 4: 5 mL of THF and 387.28 mg (2.03 mmol, 2 equivalents) of 401-3 were introduced into a 50 mL reaction flask. The mixture was cooled to -78 °C, and 0.81 mL (2.03 mmol, 2 equivalents) of n-BuLi was added dropwise. After stirring at -78 °C for 30 minutes, 500 mg (1.01 mmol, 1.0 equivalent) of a solution of 401-2 in 5 mL of THF was added. The reaction mixture was then stirred at 25 °C for 12 hours, as indicated by the completion of LC-MS. The mixture was diluted with 20 mL of water, the aqueous phase was extracted with EA (3 times, 5 mL each), the organic layers were combined, washed with brine (3 times, 5 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 400 mg of compound 401-4 in 65.2% yield.

[0432] Step 5: 7 mL of dioxane, 340 mg (0.561 mmol, 1.0 equivalent) of 401-4, 64.08 mg (0.67 mmol, 1.2 equivalents) of MsNH4, 10.28 mg (0.011 mmol, 0.02 equivalents) of Pd2(dba)3, 9.54 mg (0.022 mmol, 0.04 equivalents) of tBuxphos, and 365.85 mg (1.12 mmol, 2 equivalents) of Cs2CO3 were added to a 25 mL flask. The mixture was stirred at 100 °C for 5 hours. After confirming completion by LC-MS, it was concentrated under vacuum and purified by column chromatography to obtain 100 mg of compound 401-5, resulting in a 35.2% concentration.

[0433] Step 6: A 5 mL flask was prepared using 1 mL of DCM, 0.1 mL of TFA, 0.3 mL of TES, and 100 mg (1.0 equivalent) of 401-5. The mixture was stirred at 25°C for 2 hours, as indicated by the completion of LC-MS. After concentration under vacuum, 10 mg of compound 401 was obtained in 17.2% yield by pre-HPLC purification. Total yield=2.5% LCMS:[M-C2HF3O2+1]+=362.1 1H NMR(400MHz,DMSO)δ 14.37(s,2H),9.79(s,1H),9.06(d,J=0.7Hz,1H),7.34(dd,J=10.3,5.4Hz,1H),7.25(d,J=3.0Hz,1H),7.17-7.11(m,1H) ,7.06(s,2H),6.99-6.92(m,2H),5.58(s,1H),2.97(s,3H),2.46-2.37(m,1H),2.35-2.23(m,1H),1.08(t,J=7.4Hz,3H).

[0434] Example 18. Synthesis of Compound 502 [ka] Step 1: A 500 mL three-necked flask was loaded with 250 mL of ACN, 25 g (0.15 mol, 1 equivalent) of 502-1, 31.5 g (0.16 mol, 1.05 equivalent) of diethyl chloromalonate, and 43 g (0.31 mol, 2 equivalents) of K2CO3. The reaction mixture was refluxed overnight at 80°C. After confirming completion by LC-MS, the mixture was concentrated under vacuum and purified by silica gel column chromatography to obtain 40 g of 502-2. The yield was 83%.

[0435] Step 2: In a 1 L three-necked flask, 250 mL of DMF and 8 g (0.21 mol, 1.5 equivalents, 60%) of NaH were combined and cooled to 0°C. Then, 40 g (0.125 mol, 1 equivalent) of 502-2 dissolved in 100 mL of DMF was added at 0°C and the mixture was stirred for 1 hour. Next, 30 g (0.154 mol, 1.1 equivalents) of 3-(bromomethyl)benzonitrile was added to 100 mL of DMF at 0°C and the mixture was stirred overnight at 58°C. After completion (confirmed by LC-MS), the reaction mixture was quenched with water, extracted with EA, dried over Na2SO4, and concentrated. Purification by silica gel column chromatography yielded 36 g of 502-3 in 64% yield.

[0436] Step 3: In a 500 mL three-necked flask, 300 mL of DMSO, 36 g (0.08 mol, 1 equivalent) of 502-3, 9 g (0.15 mol, 2 equivalents) of NaCl, and 11 g (0.3 mol, 4 equivalents) of H2O were placed. This mixture was stirred overnight at 150°C. LC-MS showed that the reaction was incomplete. The mixture was work-treated and purified in the same manner as in the previous step to obtain 25 g of 502-4 in 86% yield.

[0437] Step 4: 200 mL of DMSO, 20 g (0.055 mol, 1 equivalent) of 502-4, 13 g (0.11 mol, 2 equivalents) of H2O2, and 15 g (0.11 mol, 2 equivalents) of K2CO3 were added to a 500 mL three-necked flask. The mixture was stirred overnight at room temperature, and after standard work-up, it was purified to obtain 8 g of 502-05. The yield was 38%.

[0438] Step 5: 40 mL of EtOH, 8 g (0.021 mol, 1 equivalent) of 502-5, and 12.6 g (0.21 mol, 10 equivalents) of ethylenediamine were placed in a 100 mL three-necked flask. The mixture was stirred overnight at room temperature and purified to obtain 7 g of 502-6 in 84% yield.

[0439] Step 6: 1 g (2.53 mmol, 1 equivalent) of 502-6, 7.5 mL of HMDS, and 0.5 mL of TMSI were added to a 25 mL one-necked flask. The mixture was stirred overnight at 130°C, concentrated under vacuum, and then added to 2 mL of DCM and 1 mL of TFA. The mixture was stirred at room temperature for 1 hour and concentrated. By purification, 10 mg of 502 was obtained in a final yield of 1%. Total yield=0.15% LCMS:[M-C2HF3O2+1]+=378.0 1H NMR(400MHz,DMSO)δ 10.45(s,2H),7.98(s,1H),7.85(s,1H),7.80(d,J=7.3Hz,1H),7.55(d,J=8.1Hz,2H),7.43(dt,J=14.9,7.6Hz,3H),7. 26(t,J=8.1Hz,1H),5.23(t,J=7.1Hz,1H),3.81(dd,J=14.5,6.8Hz,4H),3.60(d,J=7.7Hz,1H),3.50(d,J=5.7Hz,1H).

[0440] Example 19. Synthesis of Compound 503 [ka] Step 1: 250 mL of ACN, 25 g (0.15 mol, 1 equivalent) of (3-bromophenyl)acetic acid, 31.5 g (0.16 mol, 1.05 equivalent) of diethyl chloromalonate, and 43 g (0.31 mol, 2 equivalents) of K2CO3 were added to a 500 mL three-necked flask. The mixture was refluxed overnight at 80°C. After confirmation of completion by LC-MS, the mixture was concentrated and purified by silica gel chromatography eluting with Â1 / 20 to 1 / 10 of the original concentration with Â1 / PE to obtain 20 g of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (503-1) as a yellow oil in 73.60% yield.

[0441] Step 2: A solution of 1-bromo-2-methoxybenzene (28.99 g, 155 mmol) in anhydrous THF (150 mL) was cooled to -78°C, and n-BuLi (2.5 M in hexane, 62 mL, 155 mmol) was added dropwise. After stirring at -78°C for 30 minutes, a solution of 503-1 (20 g, 77.5 mmol) in dry THF (100 mL) was added dropwise. The solution was then warmed to room temperature and stirred for 16 hours. The reaction product was quenched with saturated NH4Cl solution, extracted with ethyl, and purified by silica gel chromatography eluted with 1 / 50 ethyl / PE to obtain 10 g of 2-(3-bromophenyl)-1-(2-methoxyphenyl)ethenone (503-2) as a yellow oil in 40.13% yield.

[0442] Step 3: 503-2 (1.5 g, 4.9 mmol), PdCl2 (dppf) (360 mg, 0.49 mmol), and sodium carbonate (1.04 g, 9.8 mmol) were dissolved in toluene:MeOH (10 mL, 1:1 ratio) and heated at 100°C for 3 days under a CO atmosphere. The reaction product was diluted with water, extracted with ethyl acetate, and then purified by silica gel chromatography. Ethyl acetate / betaethanol was gradually increased from 1% to 10% to eluate the mixture, yielding 700 mg of methyl 3-[2-(2-methoxyphenyl)-2-oxoethyl]benzoate (503-3), a yellow oily substance, in a yield of 46.94%.

[0443] Step 4: To a solution of methyl 3-[2-(2-methoxyphenyl)-2-oxoethyl]benzoate (600 mg, 2.1 mmol) and O-methylhydroxylamine hydrochloride (264.38 mg, 3.16 mmol) in toluene (8 mL), LiHMDS (1 M, 8.4 mL, 8.441 mmol) was added and the mixture was stirred at 25°C for 3 hours. After dilution with aqueous NH4Cl solution and extraction with siRNA, the product was purified by silica gel chromatography eluting with 1 / 20 DCM / MeOH to obtain 400 mg of N-methoxy-3-[2-(2-methoxyphenyl)-2-oxoethyl]benzamide (503-4) as a yellow oil in 60.45% yield.

[0444] Step 5: A solution of N-methoxy-3-[2-(2-methoxyphenyl)-2-oxoethyl]benzamide (400 mg, 1.3364 mmol) and NH4OAc (1.545 g, 20.046 mmol) in IPA (8.0 mL) was stirred at 25°C for 30 minutes, then NaBH3CN (335.92 mg, 5.34 mmol) was added and the mixture was heated at 80°C for 3 hours. After adjusting the pH to 8 with 2 M NaOH, the mixture was extracted with DCM and purified by silica gel chromatography eluted with 1 / 10 MeOH / DCM to obtain 320 mg of 3-[2-amino-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (503-5) as a white solid in 71.75% yield.

[0445] Step 6: 3-[2-amino-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (300 mg, 0.9988 mmol, 1 equivalent) was dissolved in DCM:DMF (5.0 mL, 10:1 ratio). To this mixture, 1-chloro-2-isocyanatoethane (421.59 mg, 3.9952 mmol) was added, and the mixture was stirred at 25°C for 6 hours. After dilution with water and extraction with DCM, the combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. Without further purification, the crude product (250 mg, yield 46.26%) was obtained as a yellow oil.

[0446] Step 7: A mixture of 3-(2-{[(2-chloroethyl)carbamoyl]amino}-2-(2-methoxyphenyl)ethyl)-N-methoxybenzamide (200 mg, 0.4927 mmol) dissolved in water (5.0 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was purified by biotage using a C18 column eluted with 5%-95% MeCN / H2O containing 0.1% NH4OH to obtain 48.25 mg of 3-[2-(4,5-dihydro-1,3-oxazole-2-ylamino)-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (503) as a white solid in 24.65% yield. Total yield=11.40% LCMS(ESI): m / z actual value 370.10[M+H]+. [M+1] + =370.10 1H NMR(400MHz,DMSO)δ 11.69(s,1H),7.66(s,1H),7.53(d,J=6.8Hz,1H),7.34(dt,J=18.4,7.6Hz,3H),7.21(t,J=8.0Hz,1H),6.93(dd,J=16.8,8.4Hz,3H),5.06(d,J= 6.4Hz,1H),4.02(t,J=8.4Hz,2H),3.80(s,3H),3.71(s,3H),3.38(t,J=8.4Hz,2H),2.89(dd,J=13.6,4.0Hz,1H),2.75(dd,J=13.6,10.0Hz,1H).

[0447] Example 20. Synthesis of Compound 504 [ka] Step 1: In a 250 mL flask, 100 mL of THF and 13.1 g (0.056 mol, 1.5 equivalents) of 1,3-dibromobenzene were combined. After cooling to -78°C, 22.4 mL (0.056 mol, 1.5 equivalents) of 2.5 M n-BuLi was added. The mixture was stirred at -78°C for 1 hour, and then a solution of 5 g (0.0373 mol, 1.0 equivalent) of 2,3-dimethylbenzaldehyde in 10 mL of THF was introduced. The reaction was continued at -78°C for another 1 hour, and then the mixture was warmed to room temperature overnight. After completion, the reaction was verified by LC-MS, the reaction product was quenched with 25 mL of saturated ammonium chloride, the organic layer was separated, dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (PE:EA=85:15) to obtain 8.6 g of 504-1 in 77.8% yield.

[0448] Step 2: 20 mL of DMF, 1 g (3.45 mmol, 1.0 equivalent) of 504-1, 492 mg (5.175 mmol, 1.5 equivalents) of MsNH2, 2.25 g (6.9 mmol, 2.0 equivalents) of Cs2CO3, 316 mg (0.345 mmol, 0.1 equivalent) of Pd2(dba)3, and 293 mg (0.69 mmol, 0.2 equivalents) of tBuxphos were placed in a 50 mL flask. The mixture was stirred at 110 °C for 16 hours, and completion was confirmed by LC-MS. The reaction product was quenched in ice water, extracted with EA, and dried over Na2SO4. Purification by column chromatography (PE:EA = 1:1) yielded 180 mg of 504-2 in 17% yield.

[0449] Step 3: 1.5 mL of DCM, 134 mg (0.439 mmol, 1.0 equivalent) of 504-2, 76 mg (0.659 mmol, 1.5 equivalents) of TMSN3, and 31 mg (0.0878 mmol, 0.2 equivalents) of InBr3 were added to a 5 mL flask. The mixture was stirred at 17 °C for 2 hours, and completion was confirmed by LC-MS. The mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 68:32) to obtain 105 mg of 504-3, with a yield of 72.4%.

[0450] Step 4: In a 5 mL flask, 1.5 mL of THF, 0.3 mL of water, 144 mg (0.436 mmol, 1.0 equivalent) of 504-3, and 229 mg (0.87 mmol, 2.0 equivalents) of PPh3 were added. The mixture was stirred at 50°C for 16 hours, completion was confirmed by LC-MS, and the mixture was concentrated under vacuum. Purification by TLC (DCM:MeOH = 20:1) yielded 62 mg of 504-4 in 46.7% yield.

[0451] Step 5: 1 mL of dioxane, 52 mg (0.171 mmol, 1.0 equivalent) of 504-4, and 60 mg (0.5 mmol, 2.9 equivalents) of 2-chloroethyl isothiocyanate were added to a 5 mL flask. The mixture was stirred at 80°C for 16 hours, completion was confirmed by LC-MS, and the mixture was concentrated under vacuum. Purification by preparative HPLC yielded 3.3 mg of compound 504 in 5% yield. Overall yield: 2.2% LCMS:[M-HCl+1]+=390.1 1H NMR(400MHz,MeOD)δ 7.40(t,J=7.9Hz,1H),7.27-7.20(m,2H),7.17(t,J=7.6Hz,2H),7.00(dd,J=23.2,7.5Hz,2H),6 .16(s,1H),4.02(t,J=7.5Hz,2H),3.65(t,J=7.6Hz,2H),2.95(s,3H),2.34(s,3H),2.19(s,3H).

[0452] Example 21. Synthesis of Compound 505 [ka] Step 1: A solution of 2-(3-bromophenyl)-1-(2-methoxyphenyl)ethenone (503-2, 2.0 g, 6.6 mmol), methanesulfonamide (0.75 g, 7.92 mmol), Pd(OAc)2 (150 mg, 0.663 mmol), Xantphos (0.76 g, 1.32 mmol), and Cs2CO3 (4.30 g, 13.20 mmol) in dioxane (20.0 ml) was heated under nitrogen at 100°C for 16 hours. After cooling, it was diluted with an aqueous NH4Cl solution and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (MeOH / DCM, 1%~10%) yielded N-{3-[2-(2-methoxyphenyl)-2-oxoethyl]phenyl}methanesulfonamide (505-1, 400 mg, yield 16.17%) as a yellow oily substance.

[0453] Step 2: A mixture of N-{3-[2-(2-methoxyphenyl)-2-oxoethyl]phenyl}methanesulfonamide (400 mg, 0.5323 mmol) and NH4OAc (1.448 g, 18.785 mmol) in isopropanol (8.0 ml) was stirred at 25°C for 0.5 hours, then NaBH3CN (314.80 mg, 5.0096 mmol) was added, and the mixture was heated at 80°C for 4.5 hours. After cooling, the mixture was filtered through Celite and concentrated. This was purified by preparative TLC (Âi / PE, 1 / 3) to obtain N-{3-[2-amino-2-(2-methoxyphenyl)ethyl]phenyl}methanesulfonamide (505-2, 240 mg, yield 53.82%) as a yellow oil.

[0454] Step 3: A solution of N-{3-[2-amino-2-(2-methoxyphenyl)ethyl]phenyl}methanesulfonamide (505-2, 160 mg, 0.4994 mmol) and 4,5-dihydro-1H-imidazole-2-sulfonic acid (224.96 mg, 1.4982 mmol) dissolved in butanol:water (5:1 ratio, 3.0 ml) was heated in a microwave reactor at 120°C for 2 hours. After cooling, the mixture was concentrated, diluted with water, and extracted with ELISA. The organic phase was combined, washed with brine, dried over sodium sulfate, concentrated, and purified by Biotage using a C18 column (eluted with 10%-95% MeCN / H2O, containing 0.1% TFA) to obtain N-{3-[2-(imidazolidine-2-ylideneamino)-2-(2-methoxyphenyl)ethyl]phenyl}methanesulfonamide (505, 8.38 mg, yield 4.31%) as a white solid. LCMS:[M+1] + =388.38 1H NMR(400MHz,DMSO)δ 9.69(s,1H),8.74(d,J=9.2Hz,1H),8.31(s,1H),7.67(s,1H),7.33-7.16(m,3H),7.11(s,1H),7.03(dd,J=17.2,8.4Hz,3 H),6.94(t,J=7.6Hz,1H),4.96-4.90(m,1H),3.88(s,3H),3.48(s,5H),3.09(dd,J=13.6,4.8Hz,1H),2.94-2.87(m,4H).

[0455] Example 22. Synthesis of Compound 510 [ka] Step 1: In a 100 mL flask, combine 20 mL of ACN, 2 g (0.01 mol, 1.0 equivalent) of 2,3-dimethylbenzyl bromide, 2 g (0.02 mmol, 2.0 equivalents) of TMSCN, and 20 mL (0.05 mmol, 2.0 equivalents) of THF containing TBAF, and reflux for 1.5 hours. After confirming completion by LC-MS, the mixture was concentrated and purified by column chromatography (PE:EA = 85:15) to obtain 1.42 g of 510-1 in 97.9% yield.

[0456] Step 2: In a 100 mL flask, 1.42 g (0.0098 mol, 1.0 equivalent) of 510-1 was added to 28 mL of ethanol and 5.7 mL of 30% KOH solution. The mixture was refluxed for 18 hours, concentrated, diluted with 20 mL of water, pH adjusted to 2 with 6 M HCl, filtered, and dried to obtain 1.35 g of 510-2 as a solid in 84.0% yield.

[0457] Step 3: Place 15 mL of methanol and 1.3 g (0.008 mol, 1.0 equivalent) of 510-2 into a 50 mL flask, cool to 0°C, and then add 1.89 g (0.0159 mol, 1.5 equivalents) of SOCl2. Stir the reaction mixture at 60°C for 18 hours, concentrate, and purify by column chromatography (PE:EA = 68:32) to obtain 1.37 g of 510-3 in 96.2% yield.

[0458] Step 4: In a 25 mL bottle, 10 mL of THF and 497 mg (2.81 mmol, 1.0 equivalent) of 510-3 were cooled to -80°C under nitrogen. After adding LDA (3.37 mL, 3.37 mmol, 1.2 equivalents), 731 mg (2.95 mmol, 1.05 equivalents) of 823-78-9 in 2 mL of THF were added. The mixture was warmed to room temperature overnight, quenched, and purified by column chromatography to obtain 670 mg of 510-4 in a yield of 68.9%.

[0459] Step 5: In a 50 mL bottle, 10 mL of DMF, 570 mg (1.65 mmol, 1.0 equivalent) of 510-4, 1.07 g (3.3 mmol, 2.0 equivalents) of Cs2CO3, 235 mg (2.47 mmol, 1.5 equivalents) of methanesulfonamide, 151 mg (0.165 mmol, 0.1 equivalent) of Pd2(dba)3, and 141 mg (0.33 mmol, 0.2 equivalents) of t-BuXphos were added. The mixture was stirred under nitrogen at 105°C for 2 hours, and the reaction product was work-treated and purified to obtain 600 mg of 510-5 in yield 85.7%.

[0460] Step 6: In a 10 mL bottle, 5 mL of toluene, 200 mg (0.554 mmol, 1.0 equivalent) of 510-5, 166.5 mg (2.77 mmol, 5.0 equivalents) of ethylenediamine, and TMAl (1.39 mL, 2.77 mmol, 5.0 equivalents) were stirred overnight at 110°C. After cooling and workup, the crude product was purified to obtain 29 mg of 510-6 in a yield of 13.5%.

[0461] Step 7: 1 mL of toluene and 29 mg (0.0745 mmol, 1.0 equivalent) of 510-6 were placed in a 5 mL bottle, followed by 57 mg (0.37 mmol, 5.0 equivalents) of POCl3. The mixture was stirred at 110°C for 3 hours, filtered, and purified to obtain 3.6 mg of 510 in yield of 11.9%. LC-MS=[M-HCl+1]+=372.2 1H NMR(400MHz,DMSO)δ 9.98(s,2H),7.35(d,J=7.1Hz,1H),7.24(t,J=7.7Hz,1H),7.15(dd,J=18.1,7.2Hz,2H),7.09-7.00(m,2H),6.95(d,J=7.4Hz,1 H),4.44(t,J=7.5Hz,1H),3.78(s,4H),3.46-3.40(m,1H),3.07(dd,J=13.4,7.1Hz,1H),2.90(s,3H),2.22(s,3H),2.11(s,3H).

[0462] Other compounds were synthesized in the same manner. The characteristic data of the compounds are shown in Table 2 below.

[0463] [Table 20]

[0464] [Table 21]

[0465] [Table 22]

[0466] [Table 23]

[0467] [Table 24]

[0468] [Table 25]

[0469] [Table 26]

[0470] Table 27

[0471] Table 28

[0472] Table 29

[0473] Table 30

[0474] Table 31

[0475] Table 32

[0476] Table 33

[0477] Table 34

[0478] Table 35

[0479] Table 36

[0480] [Table 37]

[0481] [Table 38]

[0482] Biological assays Example 1. FLIPR assay of α2AAR This experimental protocol included cell seeding and a FLIPR assay using an α2AAR (α2A-adrenergic receptor) cell line hosted on HEK293 cells. The growth medium used was DMEM (11965-092, Gibco) supplemented with 10% FBS (FSP500, Excell), 300 μg / mL G418 (10131-027, Gibco), and 2 μg / mL blastosidine S HCl (BS) (A11139-03, Gibco). On day 1, the culture medium was removed to initiate the cell seeding process, followed by rinsing the cells with DPBS (21-031-CVC, Corning). The cells were then treated with 0.05% EDTA-trypsin (25300-062, Gibco), incubated at 37°C for 1-2 minutes, and monitored under an inverted microscope. The cells were detached, resuspended in growth medium, and centrifuged at 1000 rpm for 5 minutes at room temperature. After discarding the supernatant, the cell pellet was divided into 10 × 10 5 The cells were resuspended in growth medium to a concentration of cells / mL. This suspension was added to a 384-well plate (Jul 38, 2019, Greiner) at a rate of 20 μL / well and incubated overnight at 37°C in 5% CO2.

[0483] On day 2, the FLIPR assay was initiated by preparing an assay buffer containing 20 mM HEPES (15630-106, Invitrogen), 1 × HBSS (14025-076, Invitrogen), and 0.5% BSA (B2064, Sigma). A 250 mM probenecid solution was prepared in this buffer. Fluo-4 Direct® Loading Buffer was prepared by dissolving Fluo-4 Direct® crystals (F10471, Invitrogen) in the FLIPR Assay Buffer and adding probenecid. The buffer was then vortexed and left to stand in the dark for 5 minutes. For the FLIPR procedure, the agonist active substance test compounds were serially diluted and transferred to a 384-well compound plate (25-Jan-39, Greiner). Next, the cell plates were treated with 2× Fluo-4 Direct® loading buffer and incubated in a 5% CO2 atmosphere at 37°C for 50 minutes, followed by 10 minutes at room temperature. Subsequently, FLIPR assay buffer was added to the compound plates, and then the plates were centrifuged.

[0484] Cell plates were analyzed for fluorescence signaling using the FLIPR Tetra+ System. For agonist testing, a reference compound was added to the cell plate and fluorescence was measured. Max-Min calculations were started from Read1 up to the maximum acceptable value. Data were analyzed using Prism software to calculate the activation rate for agonists and the inhibition rate for antagonists. The results were then fitted using a specific model to determine the EC of the agonists. 50 We made that decision.

[0485] The experimental protocol utilized various reagents and equipment, including penicillin / streptomycin (100×) (SV30010, Hyclone), poly-L-lysine hydrobromide (P1399, Sigma), and different types of 384-well plates such as 384-well PP 2.0 microplates (PP-0200, LABCYTE) and 384-well low dead-volume microplates (LP-0200, LABCYTE). The use of specific reference compounds, such as UK14304, was also essential to the assay.

[0486] Example 2. α2AAR binding assay The α2AR binding assay was performed using a stable HEK293 cell line specifically constructed by WuXi AppTec to target α2AAR. This assay primarily focused on the binding activity of the radioligand [3H]-RX 821002 (PerkinElmer, NET1153250UC) to α2AAR, with a membrane concentration of 0.5 μg / well and a radioligand concentration of 0.5 nM. The equipment essential for this assay includes, all sourced from Perkin Elmer: Unifilter-96 GF / C filter plates (Perkin Elmer, 6005174), 96-well conical polypropylene plates (Agilent, 5042-1385), TopSeal-A sealing film (Perkin Elmer, 6050185), MicroBeta2 reader (CNLL0153, Perkin Elmer, 1310887), and cell harvester (UNIFILTER-96, Perkin Elmer, 1951369). Both the assay buffer and wash buffer consist of 50 mM Tris-HCl at pH 7.4 (Tris base, Sigma, T1503-1KG).

[0487] The procedure began with the preparation of the test compound, reference compound, and yohimbine (Sigma, Y3125), and 1 μL of each was transferred to an assay plate by 8-step 4-fold serial dilutions. In this assay, 100 μL of membrane stock (0.5 μg / well) and 100 μL of 0.5 nM [3H]-RX 821002 were added to each well. After sealing, the plates were agitated at room temperature for 1 hour. Subsequently, Unifilter-96 GF / C filter plates were pre-immersed in 0.3% PEI (Sigma, P3143) for at least 30 minutes. The reaction mixture was then filtered and washed four times with cold wash buffer using a Perkin Elmer Cell harvester. After filtration, the plates were dried at 50°C for 1 hour. The next step involved sealing the bottom of the filter plate wells with Perkin Elmer Unifilter-96 backing seal tape and adding 50 μL of MicroScint-O cocktail (PerkinElmer, 6013611) to each well. The top of the plate was then sealed with TopSeal-A sealing film. Captured 3H was quantified using a Perkin Elmer MicroBeta2 Reader. The inhibition rate was calculated using the following formula: Inhibition Rate = (1 - (Assay Well Mean LC) / (Mean HC - Mean LC)) × 100%. Finally, the data were analyzed using Prism 5.0 software with a "log(inhibitor) vs. reaction--variable gradient" model. This comprehensive process accurately assessed the binding affinity of the compound to α2AAR.

[0488] The results of the α2AAR FLIPR assay and binding assay are shown in Table 3 below.

[0489] [Table 39]

[0490] [Table 40]

[0491] [Table 41]

[0492] [Table 42]

[0493] [Table 43]

[0494] Example 3. MDR1-MDCK permeability assay MDR1-MDCK II cells (obtained from Piet Borst at the Netherlands Cancer Institute) were fermented from day 4 to day 7 for confluent cell monolayer formation, with a total dose of 3.33 × 10⁴ cells. 5 Cells were seeded at a concentration of 1 / mL onto a polycarbonate membrane (PC) in a 96-well insert system.

[0495] α2AR agonists selected from Table 3s were diluted to a concentration of 2 μM in transport buffer (HBSS containing 10.0 mM Hepes, pH 7.4) from DMSO stock solution (DMSO < 1%) and applied to the apical or basal outer side of a cell monolayer. Digoxin was used as a positive control for P-glycoprotein (P-gp) substrates, and clonidine, dexmedetomidine, phaldomidine, and brimonidine were used as negative controls. The transmittance of the test compound in the A-to-B direction and / or B-to-A direction was measured in duplicate. Digoxin was tested in duplicate in the A-to-B and B-to-A directions at 10.0 μM. Plates were incubated in a CO2 incubator at 37.0 ± 1.0 °C for 2.5 hours using 5.0% CO2 at saturated humidity without shaking. In addition, the efflux ratio of each compound was measured. Test compounds and reference compounds were quantified by LC / MS / MS analysis based on the peak area ratio of the sample / IS.

[0496] Following the transport assay, the integrity of the cell monolayer was determined by applying a Lucifer Yellow rejection assay. After removing buffer from both the apical and basal chambers, 75 μL of 100 μM Lucifer Yellow was added to the transport buffer, and 250 μL of transport buffer was added to both the apical and basal chambers, respectively. The plates were incubated at 37.0°C for 30 minutes at 5.0% CO2 and 95.0% relative humidity without shaking. After 30 minutes of incubation, a 20 μL Lucifer Yellow sample was taken from the apical side, followed by the addition of 60 μL of transport buffer. Then, an 80 μL Lucifer Yellow sample was taken from the basal side. The relative fluorescence units (RFU) of Lucifer Yellow were measured at 425 / 528 nm (excitation / emission) using an Envision plate reader.

[0497] The apparent transmittance coefficient Papp (cm / s) was calculated using the following formula: Papp = (dCr / dt) × Vr / (A × C0) In the formula, dCr / dt is the cumulative concentration of the compound in the receiver chamber as a function of time (μM / s), and Vr is the volume of solution in the receiver chamber (0.075 mL at the tip and 0.25 mL at the base). A is the surface area for transport, i.e., 0.143 cm² for the area of ​​the single layer. C0 is the initial concentration (μM) in the donor chamber.

[0498] The emission ratio was calculated using the following formula: Emission ratio=Papp(BA) / Papp(AB)

[0499] The results of the MDR1-MDCK permeability assay are shown in Table 4 below.

[0500] [Table 44]

[0501] Example 4. In vivo drug distribution The binding affinity of various compounds, including clonidine HCl, dexmedetomidine HCl, 1-B HCl, and 44-B HCl, to plasma proteins was evaluated using warfarin as a control. The experiment utilized HT dialysis plates (HTD 96 b) and dialysis membranes with molecular weight cutoffs of 12–14 kDa. Plasma was derived from male C57BL / 6J mice treated with EDTA-K2 as an anticoagulant. The experimental procedure began with plasma thawing in cold tap water, followed by centrifugation at 3220 × g for 5 minutes to remove blood clots, and adjustment of pH to 7.4 ± 0.1.

[0502] The dialysis membranes were first hydrated in ultrapure water for approximately 1 hour, and then treated in a 20:80 ethanol-water mixture for 20 minutes. These prepared membranes can be used immediately or stored at 2-8°C for up to 1 month. The membranes were rinsed with ultrapure water before use.

[0503] The test compound and control compound were prepared at a concentration of 400 μM by diluting the stock solution with DMSO. The working solution was further diluted to prepare a 2 μM loading matrix solution, which was then thoroughly mixed. For the assay, 50 μL aliquots of these solutions were dispensed into a sample collection plate in double repeats and balanced with blank PBS to a final volume of 100 μL per well. A stop solution containing acetonitrile, tolbutamide, and labetalol was added, the sample was mixed, and cooled to 2–8°C.

[0504] During dialysis, 100 μL aliquots from the loading matrix were placed on the donor side of the dialysis well and mixed with an equal volume of PBS on the receiver side, and incubated at 37°C for 4 hours. After dialysis, samples were collected from both sides, equilibrated to 100 μL with the corresponding blank fluid, treated with stop solution, vortexed, and centrifuged to prepare for LC-MS / MS analysis.

[0505] Data analysis included calculating the proportions of unbound, bound, and recovered compounds after dialysis. The unbound rate was calculated as the ratio of the peak area of ​​the compound on the receiver side to the internal standard, reflecting the proportion that passed through the membrane. The bound rate was the complement of the unbound rate and represented the fraction retained on the donor side. The recovery rate was determined from the ratio of peak areas on both sides of the membrane, evaluating the dialysis efficiency in retaining the compound. These metrics provided insights into the amount of compound released, bound, and recoverable, elucidating its behavior in the dialysis system. The results for plasma protein binding ratios are shown in Table 5.

[0506] [Table 45]

[0507] The binding affinity of various compounds, including clonidine HCl, dexmedetomidine HCl, 1-B HCl, and 44-B HCl, to brain proteins was evaluated using propranolol as a control. For the initial preparation of the dialysis membrane, brain homogenate was thawed in a water bath at room temperature and then heated at 37°C for 10 minutes. The dialysis apparatus used was manufactured by HT Dialysis LLC, and consisted of an HT-Dialysis plate (model HTD 96 b) and dialysis membranes with molecular weights of 12-14 kDa.

[0508] The membranes underwent comprehensive pretreatment, including hydration in ultrapure water at room temperature for approximately 1 hour. They were then separated and immersed in a 20:80 ethanol:water solution for approximately 20 minutes. After this treatment, the membranes were either used immediately or stored at 2–8°C for up to 1 month, with a final rinse in ultrapure water before experimental use.

[0509] For compound preparation, the test substance and control substance were first dissolved, and a 400 μM working solution was prepared by mixing 4 μL of stock solution with 96 μL of DMSO. Next, 3 μL of the prepared solution was thoroughly mixed with 597 μL of matrix, and these working solutions were further diluted to 2 μM with a blank matrix.

[0510] During the assay, 50 μL aliquots of 2 μM compound-matrix mixture were dispensed in triples into a sample collection plate. Each aliquot was paired with an equal volume of blank PBS, and the total volume was standardized to 100 μL per well with a matrix-to-PBS ratio of 1:1. The samples were stabilized at T0 by adding a stop solution containing 500 μL of acetonitrile with 250 nM tolbutamide and labetalol to each well. The samples were then shaken at 800 rpm for 10 minutes and stored at 2–8°C.

[0511] The dialysis procedure included assembling the dialysis machine according to the manufacturer's specifications, filling the donor side of the dialysis well with matrix aliquots, and performing dialysis for 4 hours at 37°C in a humidified atmosphere of 5% CO2.

[0512] After dialysis, 50 μL of sample was collected from both the receiver and donor sides into a new 96-well plate. The volume was adjusted to 100 μL by adding an equal volume of the opposite blank matrix or PBS. The samples were prepared for LC-MS / MS analysis after thorough apex treatment and centrifugation. Blank control samples were prepared and processed in the same manner as the test conditions.

[0513] Data analysis included calculating the proportions of undiluted unbound and bound fractions, as well as recovering the compounds. The undiluted unbound fraction was determined using the following formula: Undiluted unbound fraction = 100 × 1 / D / ((1 / (F / T)-1)+1 / D) (where D is the dilution factor (10)). The undiluted binding fraction was calculated as 100 - undiluted unbound fraction. The recovery rate was calculated using the following formula: Recovery rate = 100 × (F+T) / T0 (where F and T represent the peak area ratio of the compound to the internal standard on the receiver and donor sides, respectively, after 4 hours of incubation). The brain protein binding results are shown in Table 6.

[0514] [Table 46]

[0515] Male C57BL / 6J mice were used in the in vivo distribution assay. Brain, spinal cord, and serum samples were collected for drug distribution calculations.

[0516] Before commencing the experiment, the mice were allowed to acclimate to the laboratory for at least three days. During this period, their general health was assessed by veterinary staff or other authorized personnel. The mice were divided into groups of up to four per cage, placed in polysulfone cages, and used certified aspen wood shavings or corn cob bedding. This bedding was regularly tested for environmental contaminants by the manufacturer. The laboratory environment was carefully controlled to maintain a temperature range of 20–26°C, relative humidity of 40–70%, and a 12-hour light / 12-hour dark cycle, although this cycle could be interrupted for research-related activities. Temperature and humidity were continuously monitored by a Vawasala ViewLinc monitoring system.

[0517] For administration, the appropriate amount of compound was accurately weighed and mixed with the appropriate volume of solvent to obtain a clear solution. This process may require vertex treatment or sonic treatment in a water bath. The formulation was administered to animals within 4 hours of preparation. Samples were then collected from each formulation for dose verification using either LC / UV or LC-MS / MS analysis.

[0518] For administration after the facility's SOP (Standard Operating Procedure), oral gastric tube feeding was used, and the dose volume was based on the animal's body weight measured on the morning of the administration day. Compounds such as clonidine HCl at 5 mg / kg, dexmedetomidine HCl at 5 mg / kg, compound 1-B at 5 mg / kg and 80 mg / kg, and compound 44-B at 5 mg / kg and 80 mg / kg were administered in a 20% HP-β-CD aqueous solution, and samples were planned to be collected at 0.5, 1, 2, and 8 hours post-administration.

[0519] Blood was collected from the saphenous vein or another suitable site, and approximately 0.1 mL per time point was collected in a pre-chilled, commercially available EDTA-K2 tube. The samples were kept on moist ice until centrifuged at 4°C and 3,200 g for 10 minutes. The plasma was then transferred to a pre-labeled 96-well plate or polypropylene tube, rapidly frozen on dry ice, and stored at -60°C or below until LC-MS / MS analysis.

[0520] Brain and spinal cord tissues were immediately collected, washed with cold saline, dried, and weighed. These samples were homogenized in a cold 15 mM PBS (pH 7.4):MeOH = 2:1 solution with a tissue-to-buffer ratio of 1:9. The homogenates were divided into two aliquots, one for immediate LC-MS / MS analysis and the other for backup, stored at -70±10°C. This comprehensive method ensures detailed and standardized collection and analysis of pharmacokinetic data in a controlled and scientifically rigorous manner.

[0521] The inventors have proposed the formula AUC ratio = tissue AUC 0-last / plasma AUC 0-last The AUC ratio was calculated using the following formula: LogBB = log 10 (Brain AUC) 0-last / plasma AUC 0-last ), LogSB=log 10 (Brain AUC) 0-last / spinal cord AUC 0-last ), Kp = brain AUC 0-last / plasma AUC 0-last And Kp,uu,brain = AUCb,u / AUCp,u = AUCbrain / AUCplasm × (fu,brain / fu,plasma). The results of drug distribution in vivo are shown in Table 7.

[0522] [Table 47]

[0523] Example 5. Efficacy test for partial nerve injury in mice Fifty male C57BL / 6 mice weighing 20–30 g were subjected to partial nerve injury (SNI) surgery, with six mice undergoing sham surgery and the remainder undergoing SNI surgery. Several days after SNI surgery, all animals were subjected to mechanical allodynia testing to obtain baseline paw withdrawal threshold (PWT). To evaluate the efficacy of the test compound, eligible mice with a baseline PWT < 0.6 g were randomly assigned to different groups (solvent group and test compound group) based on baseline PWT and six sham mice (eight mice per group) in the sham group.

[0524] After arriving at the animal facility, the animals were allowed to acclimate to the environment for 3 to 7 days. Three days before the first mechanical allo-pain test, the animals were allowed to acclimate to the test environment for 15 minutes per day.

[0525] Aseptic techniques were used by all surgeons, and all surgical instruments, including scissors, sharp forceps, scalpels, sterile cotton pads, needles, and metal clips, were sterilized before surgery. The animals were anesthetized with Zoletil 50 (50 mg / kg, 2.5 mL / kg, intraperitoneal administration) and xylazine hydrochloride (8 mg / kg, 2.5 mL / kg, intraperitoneal administration), pinched with toes to ensure complete anesthesia before incision, and eye ointment was applied to the rodents' eyes to prevent corneal drying. The hair on the posterior thigh was closely shaved, and the skin at the surgical site was swabded three times alternately with beta-zine and 70% ethanol, then dried. The biceps femoris muscle was incised to expose the sciatic nerve and its terminal branches, and the cutaneous nerve, general cervical nerves, and tibial nerve were severed by incising the biceps femoris muscle, leaving the cutaneous nerve intact. The wound was closed in layers, and the skin was sutured. Surgical instruments were cleaned and sterilized using a glass bead sterilizer after surgery. Animals recovering from anesthesia with a warming pad were subcutaneously injected with 1 mL of sterile saline to prevent dehydration, and were returned to their home cages once they were fully awake and able to move.

[0526] On day 11, the animals were individually placed in plastic enclosures with mesh bottoms to allow full foot access. For three consecutive days, the mice were adapted for 15 minutes daily. Baseline measurements of mechanical allodynia were performed on day 14. Animals that did not exhibit allodynia (PWT > 0.6g) were excluded, leaving 24 eligible animals (PWT < 0.6g). These were then randomly divided into three groups based on baseline PWT, in addition to 6 Siamese mice to form the Siamese group, resulting in a total of four groups of 6-8 mice each.

[0527] The therapeutic interventions for compounds 1-B, 10-B, 44-B, 45-B, 46-B, 47-B, 121, 136, 118, 156, and 175 at doses ranging from 1 mg / mL to 20 mg / mL were administered orally (po) at a dose of 1 mg / mL. Positive controls were administered subcutaneously at 1 mg / kg of morphine and po at 3 mg / kg of pregabalin, both prepared in 20% HP-β-CD solution. Compounds 1-B, 10-B, 44-B, 45-B, 46-B, and 47-B are active enantiomers of compounds 1, 10, 44, 45, 46, and 47, respectively, while compounds 121, 136, 118, and 156 are racemic mixtures. The solutions were vortexed to ensure complete and homogeneous mixing. The dose administered to mice was 10 ml / kg.

[0528] Mechanical allodynia testing was performed on the left hind limb of mice that had been individually placed in plastic enclosures with mesh bottoms for complete foot access and allowed to acclimate for 15 minutes prior to the test. After acclimatization, the midfoot hind limb was probed using eight Von Frey filaments of logarithmically increasing stiffness (0.02g (2.36), 0.04g (2.44), 0.07g (2.83), 0.16g (3.22), 0.4g (3.61), 0.6g (3.84), 1g (4.08), 1.4g (4.17)). The filaments were applied perpendicularly to the plantar surface of the paw pad with a force sufficient to cause slight buckling, and contact was maintained for 6–8 seconds. The test was performed at 5-second intervals to clearly distinguish the response to the previous stimulus, and a clear withdrawal or flinch when the filament was removed indicated a positive response, clearly indicating the response to the previous stimulus. The walking response was deemed ambiguous, prompting repeated stimulation. Following the Dixon up-down method, the test was initiated with a 0.16g (3.22g) filament, and the force of subsequent filaments was adjusted up or down according to the mouse's response. The maximum force used was a 1.4g (4.17g) filament, and the criterion for a positive response was a clear retraction or flinching of the foot immediately after filament removal.

[0529] The data were plotted in Prism 8.0 (Graph Pad Software, Inc.) using one-way or two-way ANOVA, followed by Dunnett or Tukey multiple comparisons, or by t-tests, followed by two-tailed comparison tests. The results are shown in Figures 1A to 1H.

[0530] Example 7. Efficacy of a mouse model of bone cancer pain. The animals were allowed to acclimate to the environment for 3-7 days after arrival at the facility. Male C3H / He mice were anesthetized by intraperitoneal injection of a combination of Zoletil 50 (50 mg / kg) and xylazine hydrochloride (8 mg / kg) and placed in a supine position. The right hind limb was shaved and sterilized. A minimal incision was made in the right hind leg, the patellar ligament was cut, and the cecum of the distal femur was exposed. The proximal part of the femur was perforated with a 0.3 mL injection needle. 2 × 10 4NCTC-2472 cells were suspended in a pellet consisting of 2 mL of cell stock by centrifugation at 1000 rpm for 4 minutes, washed twice with 2 mL of PBS, and then 2 × 10⁶ cells were prepared. 6 A 10 μL suspension containing (resuspended in PBS at a concentration of cells / mL) was slowly injected into the medullary lumen of the femur. Control animals received a 10 μL PBS injection (day 0). The animals were then allowed to acclimate to the test environment for a further 3 days before baseline PWT measurements were initiated.

[0531] On day 14, baseline measurements of mechanical allodynia were performed. Animals that did not exhibit allodynia (PWT > 0.6 g) were excluded. The remaining eligible animals were then randomly assigned to four groups based on their baseline PWT values, as outlined in Section 5.1. The animals received a single injection of test compounds at a dose of 10 mL / kg based on body weight, including oral pregabalin 3 mg / kg, subcutaneous morphine 1 mg / kg, oral 44-B 1 mg / kg, and oral 1-B 20 mg / kg and oral 44-B 20 mg / kg. Mechanical allodynia tests were performed at various post-administration time points as indicated by the different experimental requirements for the sham drug group and the solvent group. Each mouse was placed in a separate plastic enclosure with a mesh floor to allow free access to its feet and acclimate for 15 minutes prior to the test. Mechanical allodynia tests were performed and analyzed as described in the SNI model of Example 6. The results are shown in Figures 2A–2D.

[0532] Example 8. Evaluation of efficacy in a postoperative pain model in mice. Upon arrival at the facility, the animals were adaptively fed for 3–7 days. Furthermore, for 3 days prior to surgical procedures, all animals were placed in the test environment and allowed to acclimate for at least 15 minutes each day.

[0533] Aseptic techniques were strictly followed by all surgeons. All surgical instruments, including scissors, sharp forceps, scalpels, sterile cotton pads, needles, and metal clips, were sterilized before use. The animals were anesthetized with Zoletil 50 (50 mg / kg, 2.5 mL / kg, intraperitoneal) and xylazine hydrochloride (8 mg / kg, 2.5 mL / kg, intraperitoneal). Deep anesthesia was confirmed by pinching the toes before making the incision. To prevent corneal dryness, eye ointment was applied to the animals' eyes. The plantar surface of the left hind foot was washed three times alternately with betadine and 70% ethanol, and the surface was air-dried. A 0.5 mm longitudinal incision was then made through the skin and fascia from 2 mm proximal to the heel towards the toes. The plantar muscles were incised longitudinally, preserving the origin and insertion points. Hemostasis was achieved with gentle pressure, and the skin was closed with two mattress sutures. After surgery, all surgical instruments were cleaned and re-sterilized using a glass bead sterilizer. The animals were allowed to recover from anesthesia on a heated recovery pad and orally hydrated with 1 mL of sterile saline to prevent dehydration. Once fully awake and moving, the animals were returned to their home cages.

[0534] On postoperative day 1, all animals, including those in the naive group, were evaluated for mechanical allodynia using a touch sensory assessment device. Surgical animals that did not show allodynia (PWT > 0.6g) were excluded, leaving only 24 eligible surgical animals. These were randomly assigned to three groups based on their baseline PWT, forming a total of four groups, including the naive group.

[0535] The test compounds were administered to the animals: morphine at 3 mg / mL subcutaneously, 1-B HCl at 10 mg / mL orally, and 44-B HCl at 10 mg / mL orally, all at a dose of 10 mL / kg based on body weight. Naive animals were also evaluated, but no treatment was administered. Mechanical allodynia tests were performed and analyzed as described in the SNI model of Example 6. The results are shown in Figures 3A to 3C.

[0536] Example 9. In vivo efficacy study of treatment with the MC38 syngeneic model of subcutaneous colorectal cancer in female C57BL6 / J mice. The objective of this study is to evaluate the in vivo efficacy of a test skin sample for the treatment of MC38, a syngeneic model of subcutaneous colorectal cancer, in female C57BL6 / J mice. The mice are female Mus musculus C57BL6 / J, with an average age of 6–8 weeks, supplied by Beijing HFK Bioscience Co., LTD. The cages are polysulfone IVC cages maintained at a temperature of 20–26°C and humidity of 40–70%. The light cycle is 12 hours light, 12 hours dark. The mice are given free access to a standard rodent diet and are irradiated. They are also given free access to softened and filtered RO (reverse osmosis) water, which is autoclaved and filtered.

[0537] The study was designed according to the table below, using clonidine and compound 1-B HCl as the control and test samples, respectively. Due to poor mouse condition caused by high doses, the doses of clonidine in group G2 and 1-B HCl in group G4 were adjusted from 5 mg / mL to 2 mg / mL and from 10 mg / kg to 5 mg / kg, respectively, starting from day 4. The detailed design and formulation are shown in Table 8.

[0538] [Table 48]

[0539] MC38 cancer cells were maintained in vitro at 37°C in an atmosphere of 5% CO2 air using DMEM medium supplemented with 10% fetal bovine serum and 50 μg / mL hygromycin B. Cells in the exponential growth phase were collected and quantified by a cell counter before tumor inoculation. For tumor development, MC38 tumor cells (1 × 10⁶) were mixed with PBS in 0.1 mL of PBS. 6 (1) was injected subcutaneously into the right posterior flank region of each mouse. Randomization was performed on mice with an average tumor size of approximately 121.36 mm. 3 The study began when the target number of mice reached a certain level. Thirty mice were enrolled in the study. All animals were randomly assigned to five test groups, with six mice in each group. Randomization was performed using the "consistently matched distribution" method. The date of randomization was designated as day 0.

[0540] Treatment was initiated on the same day as randomization (Day 0) for each study design. After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice weekly after randomization), loss of eye / coat luster, and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. Tumor volume was measured twice weekly after randomization using calipers in two dimensions, and the volume was expressed in mm³ using the following formula: V = (L × W × W) / 2 (where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L)). Dosage and measurements of tumors and weight were performed in a clean bench. Weight and tumor volume were measured using StudyDirector® software (version 3.1.399.19).

[0541] All animals' body weight was monitored throughout the study, and animals that lost more than 20% of their body weight on the day of randomization were euthanized. Meanwhile, if the tumor volume was 3000 mm³, 3 If the threshold was exceeded, individual mice were euthanized. To prevent cannibalism, any animal showing ulceration or necrotic tumors was immediately isolated, housed alone, and monitored daily before euthanasia or until tumor regression was complete. Mice were rapidly euthanized if a) the tumor ulcerated and the ulcer diameter exceeded 5 mm, or if pus or necrosis was observed, or b) the tumor volume, including metastases, impaired the animal's normal physiological abilities, such as orientation, access to food or water, etc.

[0542] Body weight during randomization is shown in Figure 4A. Tumor growth in each treatment and control group is shown in Figure 4B. On day 17, mice were sacrificed, and tumors were removed and measured. The data are shown in Figure 4C. Tumor growth inhibition (TGI) and T / C were calculated based on tumor size data on day 17, the last day of treatment administration. Tumor volume is shown as mean ± SEM, and T / C% is expressed as TGI% = tumor volume of treatment group ÷ tumor volume of control group × 100%. TGI% = (1 - T / C) × 100%. The results of the pharmacodynamic analysis are shown in Table 9.

[0543] [Table 49]

[0544] Example 10. Spontaneous motor activity in mice This study evaluated the effects of clonidine, brimonidine tartrate, compound 1-B HCl, and compound 44-B HCl on the spontaneous motility activity of male C57BL / 6 mice. First, the mice were acclimatized to the test environment for 8 hours the day before the experiment, followed by at least 2 hours of acclimatization on the day of the experiment. The mice were then randomly divided into groups of 6 based on body weight to ensure a balanced distribution for administration of the drugs dissolved in 20% HP-β-CD water. On the day of the experiment, in one study, a fresh dose of clonidine at 1 mg / kg and compound 1-B HCl at concentrations of 1 mg / kg, 10 mg / kg, and 20 mg / kg were prepared and administered orally in a volume of 10 mL / kg. In the other study, a fresh dose of clonidine at 1 mg / kg, a dose of brimonidine tartrate at 1 mg / kg, and compound 44-B HCl at 1 mg / kg were prepared and administered orally in a volume of 10 mL / kg.

[0545] Spontaneous motility activity was monitored by placing mice in the center of a test chamber and measuring the distance moved every 5 minutes for 60 minutes using a video tracking system. The test started at T=0 minutes immediately after administration of the solvent or compound and ended at T=60 minutes. For data analysis, Prism 8.3.0 software was used to analyze distance variability over different time points using two-way ANOVA followed by Bonferroni's multiple comparison test, and to assess the total distance covered by the groups using one-way ANOVA followed by Dunnett's multiple comparison test. A significance level of p<0.05 was established to determine statistical significance. As shown in Figure 5, no significant sedation was observed after treatment with compound 1-B HCl at 1 mg / kg, 10 mg / kg, and 20 mg / kg in the first assay, and with compound 44-B HCl at 1 mg / kg in the second assay. However, clonidine at 1 mg / kg in the first assay and brimonidine tartrate at 1 mg / kg in the second assay resulted in significant sedation. The total distances between 0 and 60 minutes in the two tests are shown in Figures 5A and 5B.

[0546] Example 11. Effects on the motor function of mice After arriving at the facility, the animals were allowed to acclimate for one week. The day before starting rotarod training, the mice were randomly assigned to groups based on body weight to ensure homogeneity between groups in terms of body weight before any treatment was administered.

[0547] Training on the rotor rod was conducted two days before the trial phase. On the first training day, mice received three trials on the rotor rod at a speed of 6 rpm, each lasting 120 seconds, with a 30-minute interval between trials. If a mouse fell before the 120 seconds were completed, it was immediately returned to the rotor rod to complete the training period. The training on the following day consisted of one trial at the same speed of 6 rpm, but the duration was extended to 300 seconds. Mice that fell before the 300-second mark were similarly returned to the rotor rod and continued until the training time was full.

[0548] On the day of the experiment, mice were orally administered 10 mL / kg based on their body weight. The treatment included a solvent, clonidine (1 mg / kg), and 44-B HCl at three different doses (1 mg / kg, 10 mg / kg, and 20 mg / kg). The time of compound administration was defined as time 0.

[0549] Rotarod tests were performed at 30, 60, and 120 minutes after administration, with each session lasting 300 seconds at a speed of 6 rpm. The primary indicator was the latency time until the mouse fell off the rotarod, which was used as an indicator of the compound's effect on motor function.

[0550] The data was recorded in Microsoft Excel and then analyzed using GraphPad Prism. Statistical significance was assessed at a threshold p-value of less than 0.05, indicating a significant difference between treatment groups.

[0551] The detailed analysis method is described below. First, the data is evaluated for normal distribution and homogeneity of variance. If the data follows both a normal distribution and homogeneity of variance, a t-test is applied to comparisons involving two datasets, and a one-way ANOVA is used for analyses involving multiple datasets. If the data exhibits a normal distribution but heterogeneity of variance, Welch's t-test is used for two datasets, and a nonparametric test is used for multiple datasets. If the data does not fit a normal distribution, the Mann-Whitney test is applied to two datasets, and the Kruskal-Wallis test is applied to multiple datasets. The results are shown in Figures 6A-6D.

Claims

1. Compounds of formula (I-A), (I-B), or (I-C): 【Chemistry 1】 or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates (In the formula: In equation (I-A), Y is C(R １ ), N, -OC, -C-NH-, -CH ２ -C(O)- or -CH=N-, Y is C(R １ ) If R １ It is selected from H, D, and halogen. When Y is -O-C-, the oxygen atom is bonded to A, and the carbon atom is R Ｔ B is bound to both B and; When Y is -C-NH-, the carbon atom is R Ｔ The nitrogen atom is bonded to both A and B, A is a ring selected from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl, and 2,1,3-benzothiadiazole. B is, 【Chemistry 2】 and In the formula, X is NH, O, or S, and R ａ These are H and methyl, n is 0, 1, 2, or 3. Each R ２ is independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxyl, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, OR ４ , -CN, N ３ , NO ２ , N(R ４ ), ２ , OR ４ , SR ４ , C(O)R ４ , SO ２ , N(R ４ ), ２ , CH ２ , SR ４ and the alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxyl, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl are optionally substituted with one or more R ５ ; R ４ The alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocycloalkyl are selected from H, D, halogen, alkyl, alkenyl, alkynyl, alkoxyl, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocycloalkyl are optionally selected from one or more R ５ Replaced by, R ５ These are halogens, hydroxyl, -CN, and -NO ２ Selected from alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, Alternatively, two R's ２ If is substituted at an adjacent position to the phenyl ring, then the two R ２ The groups, together with the carbon atoms to which they are bonded, condense on ring A to form a ring that forms a bicyclic ring such as quinolinyl, indolyl, benzothienyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, sinnolinyl, quinoxalinyl, or 1,2,4-benzotriazinyl. m is 0, 1, 2, or 3. Each R ３ These are independently selected from H, D, halogens, -OH, -SH, optionally substituted alkyls, optionally substituted heterocycles, and optionally substituted aryls. Or, R ３ R is a group bonded to the -NH of the imidazole ring, ３ The formula is as follows: 【Transformation 3】 And in the formula: R ５ is hydrogen or alkyl, R ６ is hydrogen, alkyl, cycloalkyl, or alkenyl, R ７ is an amino acid residue, and R ８ is alkyl or cycloalkyl, R Ｔ is R Ｌ -R Ｐ And R Ｐ R is optional. Ｃ It has been replaced with, R Ｌ It is a linker, and one end is R Ｐ It is connected to one end, and the other end is connected to the Y, R Ｐ R Ｌ It is a part that connects to one end, and R Ｃ This is a cap, and this is R Ｐ It is a part that is joined together, In equation (I-B), Y is a bond, CH(R １ ), NH, -O-CH-, -C-NH-, -CH ２ -C(O)- or -CH=N-, Y is C(R １ ) If R １ It is selected from H, D, and halogen. When Y is -O-C-, the oxygen atom is bonded to A, and the carbon atom is bonded to B. When Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R ２ , n, R ３ , m and R Ｔ It is defined in formula (I-A) as described above, and In equation (I-C), Y is a bond, CH(R １ ), NH, -O-CH-, -C-NH-, -CH ２ -C(O)- or -CH=N-, Y is C(R １ ) If R １ It is selected from H, D, and halogen. When Y is -O-C-, the oxygen atom is bonded to A, and the carbon atom is bonded to B. When Y is -C-NH-, the carbon atom is bonded to A, the nitrogen atom is bonded to B, and A, B, R ２ , n, R ３ , m and R Ｔ (This is defined as above in equation (I-A)).

2. Compound of formula (II): 【Chemistry 4】 or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates (In the formula: A is, 【Transformation 5】 It was one of the selections, n1 is either 1 or 2. Each R １ These are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl, and -COOH. B is, 【Transformation 6】 It was one of the selections, In the formula, X is S, O, or NH. R Ｔ teeth, 【Transformation 7】 And, Ring M is C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, C ６－１２ Aryl, or C １－１２ It is a heteroaryl, and the C ３－１２ Cycloalkyl groups are optionally condensed with aryl groups. r is either 1 or 2. n2 is 0, 1, or 2. Each R ２ This is independently selected from hydrogen, halogen, hydroxyl, and alkoxy. R ３ is CN, hydroxy, alkoxy, -C(O)-C ０－１２ alkylene-CN, -C ０－１２ alkylene-C ２－１２ heterocyclyl, -SO ２ -alkyl, -C(O)-NR ４ R ４’ 、-SO ２ -NR ４ R ４’ 、-C ０－１２ alkylene-R ３’ 、-O-C ０－１２ alkylene-COOH, -C ０－１２ alkylene-N(R ４ )-C(O)-R ５ 、-C ０－１２ alkylene-N(R ４ )-SO ２ -R ５ 、-C ０－１２ alkylene-C １－１２ heteroaryl, -C ０－１２ alkylene-O-C ０－１２ alkylene-N(R ４ )-SO ２ -R ５ 、-C ０－１２ alkylene-P(=O)(R ４ )(R ４’ )、 【Transformation 8】 ,-NH-R ７ , or 【Chemistry 9】 Selected from, the above-C ０－１２ Alkilen-R ３’ One of the -CH ２ - The group is optionally an oxygen atom, or 【Chemistry 10】 It is replaced by the -C ０－１２ Alkilen-R ３’ is optionally substituted with one or more substituents selected from amino and alkylamino compounds, and the C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl has one or more R ４ａ It is replaced by an optional selection, R ３’ is -C(O)-NR ４ R ４’ , -SO ２ -NR ４ R ４’ , -C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-N(R) ４ )-C(O)-R ５ , -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , and C ０－１２ Alkylene-C １－１２ Selected from heteroaryls, Each R ４ａ These include hydroxy, alkyl, oxo, ketone, and -C ２－１２ Selected independently from heterocyclines, R ４ and R ４’ Each of these independently consists of hydrogen, alkyl, alkoxy, and -SO ２ -N(R) ６ａ ) ｔ , -C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ０－１２ Alkylene-OR ６ａ , or hydroxyalkyl, wherein the hydroxyalkyl is optionally substituted with an alkoxy, and the alkyl, C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, Or, R ４ and R ４’ Together with the nitrogen atom to which they are bonded, they form a heterocycle containing one or more heteroatoms selected from O, N, and S. Alternatively, one R ２ R ３ If adjacent to R ２ and R ３ Together with the atoms to which they are bonded, they form one or more R ４ａ This forms a ring that is substituted by any choice, R ５ is amino, alkylamino, C １－１２ Haloalkyl, -C ０－１２ Alkylene-OR ６ａ , -C ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkilen-SR ６ａ , -C ０－１２ Alkylene-CN,-C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ２－１２ Alkenyl, or alkyl optionally substituted with cyano, amide, trialkylammonium or thiolate, and the C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, Each R ６ａ is hydrogen, C １－１２ Alkyl, C １－１２ Alkoxy, -C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C ６－１２ Aryl and -C ０－１２ Alkylene-C １－１２ Selected independently from heteroaryls, the alkyl, C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, R ６ is an alkyl group optionally substituted with an alkoxy, amino, sulfonamide, carbamide, or cyano. R ７ is hydrogen, alkyl, -C ０－１２ Alkylene-COOH, optionally substituted with C ３－１２ Cycloalkyl, C ２－１２ Ariel, C １－１２ Heteroaryl, -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , -C ０－１２ Alkylene-P(=O)(R) ４ ) (Caution ４’ ), -C ０－１２ Alkylene-N(R) ４ ) - C (= S) - R ５ , -C(=S)-R ５ , or alkyl groups optionally substituted with cyano, R ８ These are alkoxy, amino, alkylamino, amide, sulfonamide, or carbamide. n3 is 0, 1, 2, 3 or 4. n4 is 1, 2, 3, 4, 5, or 6. t is 2 or 3, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4).

3. A, 【Chemistry 11】 That is, The compound according to claim 2.

4. A, 【Chemistry 12】 That is, The compound according to claim 2.

5. R １ The compound according to any one of claims 2 to 4, wherein is alkyl or halogen.

6. The compound according to any one of claims 2 to 5, wherein n1 is 2.

7. R Ｔ but, 【Chemistry 13】 That is, The compound according to any one of claims 2 to 6.

8. M is C ６－１２ Aryl or C １－１２ The compound according to any one of claims 2 to 7, wherein the compound is a heteroaryl, such as phenyl, thiophenyl, pyrimidinyl, or pyridinyl.

9. M is C ３－１２ Cycloalkyl or C ２－１２ Heterocyclyl, for example, cyclopentyl, cyclohexyl, or pyrrolidinyl, and the C ３－１２ Cycloalkyl or C ２－１２ The compound according to any one of claims 2 to 8, wherein a heterocyclyl is optionally condensed with an aryl group.

10. R ２ The compound according to any one of claims 2 to 9, wherein is hydrogen or halogen.

11. The compound according to any one of claims 2 to 10, wherein the pharmaceutically acceptable salt is a trifluoroacetate or hydrochloride salt.

12. Compound of formula (II-A): 【Chemistry 14】 And, In the formula, R １ , R ２ , R ３ and n1 is defined similarly to claim 2, The compound according to claim 2.

13. R １ The compound according to claim 12, wherein the compound is a halogen, a haloalkyl, a hydroxyl, an alkyl, or a -COOH.

14. The compound according to claim 12 or 13, wherein n1 is 2.

15. R ２ The compound according to any one of claims 12 to 14, wherein the compound is hydrogen, hydroxyl, or halogen.

16. R ３ ga-C(O)-NR ４ R ４’ or -SO ２ -NR ４ R ４’ And R ４ and R ４’ Each of these independently comprises hydrogen, alkyl, alkoxy, and -C. ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ０－１２ Alkylene-OR ６ａ or is a hydroxyalkyl group, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group, and the alkyl group, C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl has one or more R ４ａ A compound according to any one of claims 12 to 15, which is optionally substituted with [the specified compound].

17. R ３ C ０－１２ Alkylene-N(R) ４ )-C(O)-R ５ , -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ or -C ０－１２ Alkylene-OC ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ And R ４ is hydrogen or alkyl, R ５ is amino, alkylamino, C １－１２ Haloalkyl, -C ０－１２ Alkylene-OR ６ａ , -C ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkilen-SR ６ａ , -C ０－１２ Alkylene-CN,-C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ２－１２ The alkyl is optionally substituted with an alkenyl, cyano, or amide, and the C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl has one or more R ４ａ It is replaced by an optional choice. The compound according to any one of claims 12 to 15.

18. R ３ However, hydroxyl, -COOH, -CH(CH ３ )-COOH, 【Chemistry 15】 The compound according to any one of claims 12 to 15.

19. R ３ but, 【Chemistry 16】 And m is 0, 1, 2, 3, 4 or 5, R ６ This is an alkyl group optionally substituted with a sulfonamide, carbamide, or cyano. The compound according to any one of claims 12 to 15.

20. R ３ ga-NH-R ７ And R ７ C is a hydrogen atom, optionally substituted. ３－１２ Cycloalkyl, C １－１２ Heteroaryl, -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , -C ０－１２ Alkylene-P(=O)(R) ４ ) (Caution ４’ ), -C ０－１２ Alkylene-N(R) ４ ) - C (= S) - R ５ , -C(=S)-R ５ The compound according to any one of claims 12 to 15, which is an alkyl group optionally substituted with cyano.

21. R ３ but, 【Chemistry 17】 And n is 3 or 4, especially 4. The compound according to any one of claims 12 to 15.

22. Compound of formula (II-B): [Chemistry 18] and , where R １ , R ８ n1, n3 and n4 are defined similarly to claim 2. The compound according to claim 2.

23. R ８ However, -OCH ３ , -NH ２ , - NHCH ３ , -NHC(O)CH ３ The compound according to claim 22, which is a sulfonamide or a carbamide.

24. The aforementioned sulfonamide 【Chemistry 19】 The compound according to claim 23.

25. The carbamide mentioned above, 【Chemistry 20】 The compound according to claim 23.

26. Compounds selected from compounds 1-251, 401-403, 501-519, 601, and 602, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.

28. A method for treating or preventing a disease in a subject requiring a method for treating or preventing the disease, comprising administering to the subject a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27.

29. The method according to claim 28, wherein the disease is pain, glaucoma, spasticity, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory disease, or cancer.

30. A method for activating α2-adrenergic receptors (α2ARs) in a subject requiring activation of α2-adrenergic receptors (α2ARs), comprising administering a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27 to the subject.

31. A method for treating or preventing pain in a subject requiring treatment or prevention of pain, the method comprising administering a therapeutically effective amount of a peripherally selective α2-adrenergic receptor (α2AR) agonist to the subject.

32. The method according to claim 31, wherein the Kp, uu, and brain values ​​of the peripherally selective α2AR agonist are lower than 0.05, 0.02, or 0.

01.

33. The method according to claim 31 or 32, wherein the disease is neuropathic pain, nociceptive pain, or mixed pain.

34. The method according to any one of claims 31 to 33, wherein treatment with the aforementioned peripherally selective α2AR agonist has less sedative effect than treatment with a non-peripherally selective α2AR agonist.

35. The method according to any one of claims 31 to 34, wherein the peripherally selective α2AR agonist includes an α2AR activating moiety covalently bound to the peripherally distributed portion.

36. The method according to claim 31, wherein the α2AR activating portion is an α2AR agonist.

37. The α2AR activated portion is (R)-3-nitrobipheninine, A-193080, ADX-415, AGN192836, AGN-191103, AGN-197075, AGN-201781, AGN-241622, amitraz, apraclonidine, AR-08, betanidine, brimonidine, BRL-48962, bromocriptine, tyrazoline, clonidine, detomidine, detomidine carboxylic acid, dexmedetomidine, dipivefrin, DL-methylephedrine, droxidopa, epinephrine, ergotamine, etilephrine, etomidate, fadorumidine, guanabenz, guanethidine, guanfacine, guanxabenz, indanidine, lofexidine, medetomidine The method according to claim 36, wherein the α2AR agonist is selected from mephentermine, metamfetamine, metalaminol, methoxamine, methyldopa, methyldopert, methyldopert hydrochloride, methylnorepinephrine, mibazerol, moxonidine, naphazoline, norepinephrine, norphenephrine, octopamine, ODM-105, oxymetazoline, pergolide, phenylpropanolamine, povafonidine, propylhexedrine, pseudoephedrine, racepinephrine, rezatomidine, lylmenidine, romifidine, synephrine, talipexol, tashipimidine, thiamenidine, tizanidine, xylazine, xylometazoline, and functional derivatives thereof.

38. The method according to claim 36 or 37, wherein the α2AR activating portion is dexmedetomidine.

39. The method according to any one of claims 35 to 38, wherein the peripheral distribution portion includes a substrate element for an active efflux transporter.

40. The method according to claim 39, wherein the active efflux transporter is P-glycoprotein (P-gp).

41. The method according to claim 40, wherein the substrate element is a fragment of a P-gp substrate, and the P-gp substrate has an efflux ratio greater than 2, 5, 8, 10, 50, or 100.

42. The substrate elements of the aforementioned P-glycoprotein (P-gp) are as follows: 【Chemistry 21】 The method according to claim 39 or 40, selected from the above.

43. The method according to claim 39, wherein the active efflux transporter is a breast cancer resistance protein (BCRP) transporter.

44. The method according to claim 39, wherein the active efflux transporter is a multidrug resistance protein 2 (MRP2) transporter.

45. The peripheral distribution portion is as follows:-C ０－１２ Alkylene-COOH, -O-C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-P(O)(OH) ２ , -C(O)-NH-SO ２ -R ５ , -C(O)-NH-C ０－１２ Alkylene-COOH,-NH-C ０－１２ Alkylene-COOH, -SO ２ -OH, and 【Chemistry 22】 Includes structures selected from The method according to any one of claims 35 to 38.

46. The α2AR activation portion is given by 【Chemistry 23】 It has, During the ceremony, A is, 【Chemistry 24】 It was one of the selections, n1 is either 1 or 2. Each R １ These are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl, and -COOH. B is, 【Chemistry 25】 Selected from, In the formula, X is S, O, or NH. The method according to claim 35.

47. The aforementioned peripheral distribution part is given by 【Chemistry 26】 Having During the ceremony, R Ｔ teeth, 【Chemistry 27】 And ring M is C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, C ６－１２ Aryl, or C １－１２ It is a heteroaryl, and the C ３－１２ Cycloalkyl or C ２－１２ Heterocyclines are selectively condensed with aryl groups. r is either 1 or 2. n2 is 0, 1, or 2. Each R ２ This is independently selected from hydrogen, halogen, hydroxyl, and alkoxy. R ３ It is CN, hydroxy, alkoxy, -C(O)-C ０－１２ Alkylene-CN,-C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -SO ２ -alkyl, -C(O)-NR ４ R ４’ , -SO ２ -NR ４ R ４’ , -C ０－１２ Alkilen-R ３’ , -O-C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-N(R) ４ )-C(O)-R ５ , -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ０－１２ Alkylene-OC ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , -C ０－１２ Alkylene-P(=O)(R) ４ ) (Caution ４’ ), 【Chemistry 28】 ,-NH-R ７ , or 【Chemistry 29】 Selected from, the above-C ０－１２ Alkilen-R ３’ One of the -CH ２ - The group is optionally an oxygen atom, or 【Transformation 30】 It is replaced by the -C ０－１２ The alkylene-COOH is optionally substituted with one or more substituents selected from amino and alkylamino groups, and the C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl has one or more R ４ａ It is replaced by an optional selection, R ３’ is -C(O)-NR ４ R ４’ , -SO ２ -NR ４ R ４’ , -C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-N(R) ４ )-C(O)-R ５ , -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , C ０－１２ Alkylene-C １－１２ Selected from heteroaryls, Each R ４ａ These include hydroxy, alkyl, oxo, ketone, and -C ２－１２ Selected independently from heterocyclines, R ４ and R ４’ Each of these independently consists of hydrogen, alkyl, alkoxy, and -SO ２ -N(R) ６ａ ) ｔ , -C ０－１２ Alkylene-COOH, -C ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ０－１２ Alkylene-OR ６ａ , or hydroxyalkyl, wherein the hydroxyalkyl is optionally substituted with an alkoxy, and the alkyl, C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, Or, R ４ and R ４’ Together with the nitrogen atom to which they are bonded, they form a heterocycle containing one or more heteroatoms selected from O, N, and S. Alternatively, one R ２ R ３ If adjacent to R ２ and R ３ Together with the atoms to which they are bonded, they form one or more R ４ａ This forms a ring that is substituted by any choice, R ５ is amino, alkylamino, C １－１２ Haloalkyl, -C ０－１２ Alkylene-OR ６ａ , -C ０－１２ Alkylene-N(R) ６ａ ) ｔ , -C ０－１２ Alkilen-SR ６ａ , -C ０－１２ Alkylene-CN,-C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C １－１２ Heteroaryl, -C ２－１２ Alkenyl, or alkyl optionally substituted with cyano, amide, trialkylammonium or thiolate, and the C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, Each R ６ａ is hydrogen, C １－１２ Alkyl, C １－１２ Alkoxy, -C ０－１２ Alkylene-C ３－１２ Cycloalkyl, -C ０－１２ Alkylene-C ２－１２ Heterocyclyl, -C ０－１２ Alkylene-C ６－１２ Aryl and -C ０－１２ Alkylene-C １－１２ Selected independently from heteroaryls, the alkyl, C ３－１２ Cycloalkyl, C ２－１２ Heterocyclyl, and C １－１２ Each heteroaryl is one or more R ４ａ It is replaced by an optional selection, R ６ is an alkyl group optionally substituted with an alkoxy, amino, sulfonamide, carbamide, or cyano. R ７ is hydrogen, alkyl, -C ０－１２ Alkylene-COOH, optionally substituted with C ３－１２ Cycloalkyl, C ２－１２ Ariel, C １－１２ Heteroaryl, -C ０－１２ Alkylene-N(R) ４ ) - SO ２ -R ５ , -C ０－１２ Alkylene-P(=O)(R) ４ ) (Caution ４’ ), -C ０－１２ Alkylene-N(R) ４ ) - C (= S) - R ５ , -C(=S)-R ５ , or alkyl groups optionally substituted with cyano, R ８ These are alkoxy, amino, alkylamino, amide, sulfonamide, or carbamide. n3 is 0, 1, 2, 3 or 4. n4 is 1, 2, 3, 4, 5, or 6. t is 2 or 3, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4. The method according to claim 35.

48. A manufacturing process for a peripherally acting α2AR agonist, wherein the process includes covalently binding a non-peripherally selective α2AR agonist to a peripherally distributed portion.

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