Imidazole-containing compound, derivative and application thereof

Abstract

The present disclosure relates to novel alpha2 adrenergic receptor (alpha2AR) agonists and uses thereof. Specifically, the present disclosure relates to imidazole-containing compounds, in particular to compounds represented by formula (I-A), formula (I-B), formula (I-C), formula (I-D) or formula (II). The compounds are useful as peripheral selective alpha2AR agonists for the treatment or prevention of related diseases.

Description

Interactive reference for related applications

[0001] This application claims priority to U.S. Patent Application No. 63 / 515,229, filed July 24, 2023; U.S. Patent Application No. 63 / 550,274, filed February 6, 2024; U.S. Patent Application No. 63 / 550,228, filed February 6, 2024; and U.S. Patent Application No. 63 / 557,039, filed February 23, 2024, all of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure relates to novel α2-adrenergic receptor (α2AR) agonists and their uses. In particular, this disclosure relates to novel imidazole-containing compounds and their derivatives. These compounds can be used as α2AR agonists for the treatment or prevention of related diseases. Background Technology

[0003] The α2-adrenergic receptor (α2AR) family, as part of G protein-coupled receptors, plays a crucial role in a variety of biological functions in the central nervous system (CNS). α2ARs are essential in regulating neurotransmitter release, thereby influencing a range of central physiological processes. Agonists targeting these receptors, such as clonidine and dexmedetomidine, have been successfully used to treat a variety of conditions primarily confined to the central nervous system, including hypertension, sedation in intensive care, and agitation associated with attention deficit hyperactivity disorder (ADHD) and schizophrenia or bipolar disorder.

[0004] Clonidine was originally developed for the treatment of hypertension. After oral administration, clonidine diffuses into the central nervous system and activates the α2AR in the nucleus tractus solitarius (NTS), subsequently triggering pathways that inhibit excitatory cardiovascular neurons. This cascade effectively reduces sympathetic output from the central nervous system, resulting in a clinical decrease in arterial blood pressure.

[0005] It was subsequently discovered that clonidine induces sedation by activating central presynaptic and postsynaptic α2ARs in the locus coeruleus (LC) (a nucleus in the dorsal part of the pons). Dexmedetomidine, which was later developed and approved for sedation, is particularly used in adult patients undergoing initial intubation and mechanical ventilation in intensive care settings, due to its superior α2AR selectivity and more suitable pharmacokinetic properties for sedation.

[0006] In addition to its antihypertensive and sedative effects, clonidine, under the brand name Duraclon, has been approved for epidural administration, marking a significant advancement in cancer pain management. However, the therapeutic application of α2AR agonists for analgesia faces challenges, primarily due to their potential to induce a range of other adverse biological reactions in the central nervous system. Documented studies indicate that Duraclon can induce centrally mediated sedation, hypotension, and bradycardia, limiting its use; these adverse effects persist throughout analgesia. This sedative effect significantly restricts the safe dosage that can be administered. Therefore, despite the recognition of the importance of α2AR agonists like clonidine and dexmedetomidine for pain management in academic research and clinical settings, their sedative effects pose a significant obstacle to their widespread use in medical applications.

[0007] Therefore, there is an urgent need to develop novel α2AR agonists in order to provide significant benefits in treatments such as pain management, for example, by reducing sedation effects, thereby broadening the range of treatment options to address current unmet medical needs. Summary of the Invention

[0008] In one general aspect, this disclosure relates to a method of treating or preventing disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peripherally selective α2-adrenergic receptor (α2AR) agonist.

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

[0010] In some embodiments, the Kp,uu,brain of the peripherally selective α2AR agonist is less than 0.05, 0.02, or 0.01.

[0011] In some implementations, the disease is selected from the group consisting of: pain, rosacea, spasms, and aging.

[0012] In some implementations, the central nervous system-mediated biological effects (such as sedation, hypotension, and bradycardia) induced by treatment with the peripherally selective α2AR agonist are reduced compared to treatment with a non-peripherally selective α2AR agonist.

[0013] In another general aspect, this disclosure provides a peripherally selective α2AR agonist comprising an α2AR activation portion and a peripheral distribution portion linked by covalent bonds, and its use in the treatment of diseases.

[0014] In another general aspect, this disclosure relates to a method of treating or preventing disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peripherally selective α2AR agonist, wherein the peripherally selective α2AR agonist comprises an α2AR activation portion and a peripheral distribution portion covalently linked.

[0015] In some implementations, the sedative effect induced by treatment with the peripherally selective α2AR agonist is weaker compared to treatment with a non-peripherally selective α2AR agonist.

[0016] In another general aspect, this disclosure relates to a compound of formula (IA): , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in, Y is C(R) 1 ), N, -OC-, -C-NH-, -CH2-C(O)- or -CH=N-; when Y is C(R 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A, and the carbon atom is attached to both RT and B; When Y is -C-NH-, the carbon atom is simultaneously attached to RT and A, and the nitrogen atom is attached to B; A is selected from the following rings: phenyl, pyridinyl, thiopheneyl, furanyl, pyrroleyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl and 2,1,3-benzothiadiazole; B is , ,or Where X is NH, O or S, and R a It consists of H and methyl groups; n is 0, 1, 2, or 3; R 2 Each is independently selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, OR 4 -CN, N3, NO2, N(R) 4 2. SR 4 C(O)R 4 SO2N(R) 4 )2、CH2SR 4; wherein the alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryl, heterocyclic, or heterocyclic alkyl groups are optionally surrounded by one or more R groups. 5 replace; R 4 Selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, and said alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, optionally separated by one or more R 5 replace; R 5 Selected from halogens, hydroxyl groups, -CN, -NO2, alkyl groups, alkoxy groups, alkenyl groups, alkenyloxy groups, alkynyl groups, cycloalkyl groups, cycloalkoxy groups, aryl groups, aryloxy groups, aralkyl groups, heteroaryl groups, heteroaryl groups, heterocyclic groups, and heterocyclic alkyl groups; or, When two R 2 When the two Rs are substituted at adjacent positions on the benzene ring, 2 The group, together with the carbon atom it is attached to, forms a bicycle fused with ring A, such as quinolinyl, indolyl, benzothiophenyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, zolinyl, quinoxalinyl, or 1,2,4-benzotriazineyl; m is 0, 1, 2, or 3; R 3 Each is independently selected from H, deuterium, halogen, -OH, -SH, optionally substituted alkyl, optionally substituted heterocyclic and optionally substituted aryl; or, R 3 It is a group linked through the imidazole ring -NH- group, and R 3 It has the following formula: , , , ,or , in, R 5 It is hydrogen or alkyl; R 6 It is hydrogen, alkyl, cycloalkyl, or alkenyl; R 7 It is an amino acid residue; and R 8 It is an alkyl or cycloalkyl group; R T It is R L -R P And R P Optionally R C replace; in: R L It is a connector, one end of which is connected to R. P The other end is connected to Y; R P It is connected to R L One end portion; and R C It is an end cap base, which is connected to R P The part.

[0017] In another general aspect, this disclosure relates to a compound of formula (IB), , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in: Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R) 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and A, B, R 2 n, R 3 m and R T As defined in the above formula (IA).

[0018] In another general aspect, this disclosure relates to a compound of formula (IC), , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in: Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R) 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and B, R 2 n, R 3 m and R T As defined in the above formula (IA).

[0019] In another general aspect, this disclosure relates to a compound of formula (ID), , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in: Y 1 It is CH or N; X 1 Selected from H, D and halogens; R T It is as defined in the above formula (IA).

[0020] In another general aspect, this disclosure relates to a compound of formula (II), , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in, A is selected from one of the following: , , ; n1 is 1 or 2; R 1 Each is independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl and -COOH; B is selected from one of the following: , , ,and , Where X is S, O, or NH; R T yes or Ring M is C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 heteroaryl, wherein the C 3-12 The cycloalkyl group is optionally fused with the aryl group; r is 1 or 2; n2 is 0, 1, or 2; R 2 Each is independently selected from hydrogen, halogens, hydroxyl groups, and alkoxy groups; R 3 Selected from CN, hydroxyl, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclic groups, -SO2-alkyl groups, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene-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’ ), -NH-R 7 or ; in, The -C 0-12 Alkylene-R 3’ One of the -CH2- groups is optionally replaced by an oxygen atom or Instead, the -C 0-12 Alkylene-R 3’ Optionally substituted with one or more substituents selected from amino and alkylamino groups, and the C 2-12 Heterocyclic groups and the C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 3’ Selected from -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene -COOH, -C0-12 Alkylene-N(R) 4 )-C(O)-R 5 -C 0-12 Alkylene-N(R) 4 )-SO2-R 5 and C 0-12 Alkylene-C 1-12 Mixed aromatics; R 4a Each is independently selected from hydroxyl, alkyl, oxo, ketone and -C 2-12 Heterocyclic groups; R 4 and R 4’ Each of these components is independent of hydrogen, alkyl, alkoxy, -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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Or, R 4 and R 4’ Together with the nitrogen atom to which it is attached, it forms a heterocycle comprising one or more heteroatoms selected from O, N, and S; Or, when an R 2 Adjacent to R 3 At that time, R 2 and R 3 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 4a Replacement ring; R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl, or optionally alkyl groups substituted with cyano, amide, trialkylamine, or thiolate; wherein, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6a Each is independently selected from hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Heteroaryl; wherein the alkyl, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6 It is an alkoxy, amino, sulfonamide, urea, or optionally substituted alkyl group; R 7 It is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted C 3-12 cycloalkyl, C 2-12 Aryl, 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 groups; R 8It is an alkoxy group, amino group, alkylamino group, amide group, sulfonamide group, or urea group; 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.

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

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

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

[0024] In some embodiments, the compound of formula (II) is a compound of formula (II-D): , in, n2 is 0 or 1; R 3 Selected from -C(O)-NHR 4 -SO2-NHR 4 -NH-C(O)-R 5 -NH-SO2-R 5 and -NH-R 7 ; R 4 It is -C 0-12 Alkylene-NHR 6a -C 0-12Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a Or alkyl groups substituted with trialkylamines; and wherein C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 5 It is -C 0-12 Alkylene-NHR 6a -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a Or alkyl groups substituted with trialkylamines; wherein C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6a Each independently selected from -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic groups and -C 0-12 Alkylene-C 1-12 heteroaryl; of which C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 7 It 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 n1 and n1 are defined as in equation (II) above.

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

[0026] In some embodiments, the compound of formula (II) is a compound of formula (II-F): , in, R 2 Adjacent to R 3 And R 2 and R 3 Together with the carbon atom to which it is attached, it forms an optional structure with one or more R atoms. 4a Substituted heterocycles; and R 1 R 4a n1 and n1 are defined as in equation (II) above.

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

[0028] In some embodiments, the compound of formula (II) is a compound of formula (II-H): , in, M is C 6-12 Aryl or C 1-12 Mixed aromatics; R 3 Selected from -C 0-12 Alkylene -COOH, -OC 0-12 Alkylene -COOH, -C0-12 Alkylene -P(O)(OH)2, -C(O)-NH-SO2-R 5 -C(O)-NH-C 0-12 Alkylene -COOH, -NH-C 0-12 Alkylenes -COOH, -SO2-OH and ;where -C 0-12 The alkylene-COOH may optionally be substituted with one or more substituents selected from amino and alkylamino groups; and, R 1 R 2 And n1 is defined as in equation (II) above.

[0029] In another aspect, this disclosure relates to a pharmaceutical composition comprising a compound as described herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0030] On the other hand, this disclosure relates to the use of compounds as described herein, or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, in the preparation of medicaments for the treatment or prevention of diseases (including pain, glaucoma, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, cancer, etc.) in subjects in need.

[0031] Other features and advantages of this disclosure will become apparent from the accompanying descriptions provided herein, including various embodiments. The provided embodiments illustrate different components and methods that can be used to implement this disclosure. These embodiments do not constitute a limitation on the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used to implement this disclosure. Attached Figure Description

[0032] The above and other objects, features and advantages of the exemplary embodiments will become more apparent and readily understood from the following description in conjunction with the accompanying drawings.

[0033] Figures 1A to 1H PWT values ​​of the sham-operated group, SNI mouse model, solvent control group, and drug treatment group 1 hour after drug administration.

[0034] Figure 1A Pregabalin PO: 3 mg / mL; Figure 1B 1 mg / mL morphine sc; Figure 1C : 1 mg / mL compound 1-B po and 10 mg / mL compound 1-B po; Figure 1D : 1 mg / mL of compound 10-B po; Figure 1E : 1 mg / mL of compound 44-B po and 1 mg / mL of compound 45-B po; Figure 1F : 1 mg / mL of compound 46-B po and 1 mg / mL of compound 47-B po; Figure 1G : 2 mg / mL compound 121 po and 2 mg / mL compound 136 po; and Figure 1H : 2 mg / mL compound 118 po and 2 mg / mL compound 156 po.

[0035] Figures 2A to 2D PWT values ​​of the sham surgery group, bone cancer pain mouse model, solvent control group, and drug treatment group 1 hour after drug administration.

[0036] Figure 2A Pregabalin PO: 3 mg / mL; Figure 2B 1 mg / mL morphine sc; Figure 2C : 1 mg / mL compound 44-B po; and Figure 2D : 20 mg / mL compound 1-B po and 20 mg / mL compound 44-B po.

[0037] Figures 3A to 3C PWT values ​​of sham-operated group and postoperative pain mouse model, solvent control group and drug treatment group 1 hour after drug administration.

[0038] Figure 3A : 10 mg / mL of compound 1-B po; Figure 3B : 10 mg / mL compound 44-B po; and Figure 3C 3 mg / mL morphine sc.

[0039] Figures 4A to 4C Body weight curves of mice in different groups in the MC38 subcutaneous colorectal cancer syngeneic model ( Figure 4A ), tumor volume growth curve ( Figure 4B ) and tumor volume on day 17 ( Figure 4C ), including group 1 (control group, 0 mg / kg, po, QD) Group 2 (Clonidine, 5 mg / kg, po, QD) - Days 0-17 Days 0 to 3; 2 mg / kg, po, QD Days 4 to 17), Group 3 (compound 1-B HCl, 5 mg / kg, po, BID) Days 0 to 17) and Group 4 (compound 1-B HCl, 10 mg / kg, po, BID) Days 0 to 3; 5 mg / kg, po, QD (Days 4 to 17). Data are expressed as "mean ± standard error".

[0040] Figures 5A to 5B Tests for clonidine and compound 1-B HCl Figure 5A And tests for clonidine, brimonidine tartrate, and compound 44-B HCl. Figure 5B Total distance traveled within 0 to 60 minutes. Data are expressed as mean ± SEM (n=6). Compared with the solvent control group, p<0.001. A one-way ANOVA was performed, followed by Dunnett's multiple comparisons.

[0041] Figures 6A to 6D Effects of clonidine and compound 44-B HCl on the rotarod test in C57BL / 6 mice 30 min after drug administration ( Figure 6A Its incubation period is 30 minutes. Figure 6B ), 60 min ( Figure 6C ) and 120 min ( Figure 6D ). Detailed Implementation

[0042] Background Art and various publications, articles, and patents cited or described in this specification are incorporated herein by reference in their entirety. Discussions of documents, actions, materials, devices, articles, etc., in this specification are intended to provide context for this disclosure and are not intended to acknowledge that any or all of the foregoing constitute prior art.

[0043] Unless otherwise defined, the technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art. In case of any ambiguity, the definitions of the terms set forth in this specification shall prevail.

[0044] In this document and the accompanying claims, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" include plural references (one or more).

[0045] Unless otherwise stated, "at least" preceding a series element should be understood as referring to each element in the series. For example, "at least A, B, and C" means that A, B, and C each exist individually. "At least one" preceding a series element should be understood as referring to a single element or any combination of two or more elements in the series. For example, "at least one A, B, and C" means that only A exists, only B exists, only C exists, A and B exist simultaneously, A and C exist simultaneously, B and C exist simultaneously, or A, B, and C exist simultaneously. Depending on the context, "at least one" may also cover the case where any element has multiple instances; for example, "at least one A, B, and C" may also include the case where A exists alone in multiple copies, or where A exists in multiple copies and is combined with any or more of B and C.

[0046] When the conjunction "and / or" is used to connect multiple elements, it should be understood to encompass both individual and combined options. For example, when two elements are connected by "and / or": the first option refers to the case where only the first element applies without involving the second element; the second option refers to the case where only the second element applies without involving the first element; and the third option refers to the combined case where both the first and second elements apply. Any of the above options falls within the scope of the meaning of "and / or" and thus satisfies the requirements of this term. The simultaneous application of multiple options also falls within its scope and satisfies the requirements of this term.

[0047] Unless otherwise stated, any numerical values ​​(such as concentrations or concentration ranges) mentioned herein should be understood to be modified with "about" in all cases. Therefore, numerical values ​​typically include ±10% of the stated value. For example, the expression "10 times" includes both 9 times and 11 times. Numerical ranges as used herein explicitly include all possible combinations and permutations of subranges, and all individual values ​​within that range (including integers and fractions within the range), unless the context clearly indicates otherwise.

[0048] In this article, "subject" refers to any animal, such as a mammal, particularly a human, that is to be treated or has been treated using the methods described herein. The term "mammal" as used herein encompasses all mammals, including but not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (such as monkeys or apes), and humans.

[0049] The term "pharmaceutically acceptable salt" refers to a salt form of the compound that is safe, effective, and possesses the desired biological activity suitable for topical administration to mammals. Pharmaceutically acceptable salts include salts formed from acidic or basic groups in the specified compound. Pharmaceutically acceptable acid addition salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronide, glucosyl ether, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pyrantel (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthylcarbamate)). Certain compounds disclosed herein can form pharmaceutically acceptable salts with a variety of amino acids. Suitable alkaline salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts. A review of pharmaceutically acceptable salts can be found in the paper by Berge et al., published in the Journal of Pharmaceutical Sciences, Vol. 66, pp. 1-19 (1977), which is incorporated herein by reference.

[0050] As used herein, the term "alkyl" refers to a saturated, monovalent, straight-chain, 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 specific number of carbon atoms, which is explicitly defined by a subscript number following the symbol "C" when the subscript explicitly defines the number of carbon atoms that particular alkyl group may contain. For example, "C1 to C..." 10 Alkyl or C 1-10 Alkyl groups include alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C1 to C8 alkyl groups" or "C 1-8 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0051] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond. Alkenyl groups may be unsubstituted or substituted with one or more suitable substituents. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). When a subscript number follows the symbol "C," the subscript explicitly defines the number of carbon atoms that particular alkenyl group may contain. For example, "C2 to C..." 10 "Alkenyl" or "C" 2-10"Alkenyl" includes alkenyl groups having 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C2 to C8 alkenyl" or "C 2-8 "Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0052] As used herein, the term "alkynyl" refers to a straight-chain 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 containing both a triple bond and a double bond. When a subscript number follows the symbol "C", the subscript explicitly defines the number of carbon atoms that particular alkynyl group may contain. For example, "C2 to C2..." 10 "Alkyne" or "C" 2-10 "Alynyl" includes alkynyl groups having 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C2 to C8 alkynyl" or "C 2-8 "Alynyl" indicates an alkynyl group having 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0053] 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 specific number of carbon atoms, such as "C3 to C6 cycloalkyl" or "C6 cycloalkyl". 3-6 Cycloalkyl groups include those with 3, 4, 5, or 6 carbon atoms, namely cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Polycyclic cycloalkyl groups include bridged rings, fused rings, and spirocyclic structures, where all ring atoms are carbon atoms. A spirocyclic group is a polycyclic system in which two rings share a single carbon atom (called a "spiro atom," usually a quaternary carbon atom). A fused ring is a polycyclic system in which two rings share two adjacent atoms (called "bridgehead atoms"), meaning the two rings share a single covalent bond that directly connects the bridgehead atoms. A bridged ring is a polycyclic system in which two rings share three or more atoms, and the bridgehead atoms are connected by a bridge chain containing at least one atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0054] As used herein, the term "aryl" refers to a group containing any carbonyl aromatic group, including but not limited to phenyl, naphthyl, anthraceneyl, and phenanthryl. The aryl moiety is a group known in the art; a detailed description can be found in the *Hawley Dictionary of Chemical Abbreviations* (Lewis, RJ, ed., 13th edition, John Wiley & Sons, New York, 1997). The aryl group may be unsubstituted or optionally substituted with one or more suitable substituents. The aryl group may comprise a monocyclic (i.e., monocyclic) or polycyclic (i.e., bicyclic or tricyclic) structure. For example, the aryl group may be a monocyclic aryl group, such as phenyl.

[0055] As used herein, the term "heterocyclic group" includes stable monocyclic and polycyclic hydrocarbon structures containing at least one heteroatom ring member (such as sulfur, oxygen, or nitrogen), and the ring system is saturated or partially unsaturated, excluding fully aromatic ring systems. Heterocyclic groups may be unsubstituted or optionally substituted with one or more suitable substituents on any one or more carbon atoms and / or nitrogen heteroatoms. Heterocyclic groups may comprise monocyclic structures (i.e., monocyclic) or polycyclic structures (i.e., polycyclic, such as bicyclic). Polycyclic heterocyclic groups include bridged rings, fused rings, and spirocyclic structures, wherein at least one ring atom of at least one ring system is a heteroatom (e.g., oxygen, nitrogen, or sulfur), and the definitions of bridged rings, fused rings, and spirocyclics are as described above. The heterocyclic ring can be linked to the parent molecule via any suitable heteroatom (typically nitrogen) or carbon atom in the ring. The term "4 to 9-membered monocyclic or bicyclic heterocyclic group" includes any monocyclic or bicyclic structure comprising four, five, six, seven, eight, or nine members, containing at least one heteroatom ring member selected from oxygen, nitrogen, and sulfur (or independently selected from oxygen and nitrogen), optionally containing one to three additional heteroatoms (independently selected from oxygen, nitrogen, and sulfur, or independently selected from oxygen and nitrogen), and the ring system is a saturated or partially unsaturated structure, but excludes fully aromatic ring systems.

[0056] In some embodiments, the term "heterocyclic group" refers to a 4-, 5-, 6-, or 7-membered monocyclic group, and a 6-, 7-, 8-, or 9-membered bicyclic group, wherein at least one ring of the group has at least one heteroatom (O, S, or N), wherein the ring containing the heteroatom typically has one, two, or three heteroatoms, for example, one or two heteroatoms, which are independently selected from O, S, and / or N, or independently selected from O and N. When a subscript number appears after the symbol "C", the subscript explicitly defines the number of carbon atoms that the particular heterocyclic group may contain in addition to the heteroatoms it may contain. For example, "C1 to C..." 10 Heterocyclic group or C 1-10 Heterocyclic groups include heterocyclic groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C1 to C8 heterocyclic groups" or "C 1-8 "Heterocyclic group" refers to a heterocyclic group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0057] Examples of monocyclic heterocyclic groups include, but are not limited to: aziridine, oxaziridine, tetrahydrofuranyl, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, isoxazolidine, thiazoalkyl, isothiazolidine, dioxopentyl, dithiopentanyl, piperidinyl, piperazinyl, dioxalyl, morpholinyl, aziridine-heptyl, oxaziridine-heptyl, oxaziridine-heptyl (e.g., 1,4-oxaziridine-heptyl, 1,2-oxaziridine-heptyl), etc. Examples of bicyclic heterocyclic groups include, but are not limited to: 2-aza-bicyclo[2.2.1]heptyl, 8-aza-bicyclo[3.2.1]octyl, 2-aza-spiro[3.3]heptyl, 3-aza-bicyclo[2.2.2]octyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, 7-oxa-2-aza-spiro[3.5]nonyl, and 5-aza-spiro[2.3]hexyl, etc.

[0058] As used herein, the term "heteroaryl" refers to a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom ring member (such as sulfur, oxygen, or nitrogen). Heteroaryl groups may be unsubstituted or optionally substituted with one or more suitable substituents. Heteroaryl groups may comprise monocyclic structures (i.e., monocyclic) or polycyclic structures (i.e., polycyclic, such as bicyclic or tricyclic). Each ring of a heteroatom-containing heteroaryl group 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 does not exceed four and each ring contains at least one carbon atom. Polycyclic heteroaryl groups (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, for bicyclic heteroaryl groups, the fused rings constituting the bicyclic system may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Heteroaryl groups can be linked to the parent molecule via nitrogen or carbon atoms available in any of their ring systems. In some embodiments, the term "heteroaryl" refers to a 5- or 6-membered monocyclic group and a 9- or 10-membered bicyclic group, wherein at least one ring of the group has at least one heteroatom (O, S, or N), wherein the heteroatom-containing ring typically has one, two, or three heteroatoms (e.g., one or two heteroatoms), the heteroatom being selected from O, S, and / or N. The heteroaryl group may be unsubstituted or optionally substituted with one or more suitable substituents on any one or more carbon atoms and / or nitrogen heteroatoms. The nitrogen and sulfur heteroatoms in the heteroaryl group may optionally be oxidized (i.e., forming N→O and S(O)r, where r is 0, 1, or 2).

[0059] When a subscript number follows the symbol "C", that subscript explicitly defines the number of carbon atoms that the specific heteroaryl group may contain, in addition to the heteroatoms it may contain. For example, "C1 to C..." 10"Heteroaryl" or "C1-10 heteroaryl" includes heteroaryl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C1 to C8 heteroaryl" or "C 1-8 "Heteroaryl" refers to a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0060] Exemplary monocyclic heteroaryl groups include, but are not limited to: pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Exemplary bicyclic heteroaryl groups include, but are not limited to: indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, and indolazinyl. lizinyl), benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0061] As used herein, the term "alkoxy" refers to an –O-alkyl group, where alkyl is defined as above. Alkoxy groups are bonded to the parent molecule via an oxygen atom. Alkoxy groups can have a specific number of carbon atoms, for example, "C1 to C2". 10 "alkoxy" or "C"1-10 "Alkoxy" includes alkoxy groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C1 to C4 alkoxy" or "C 1-4 "Alkoxy" refers to an alkoxy group having 1, 2, 3, or 4 carbon atoms. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy), butoxy (e.g., n-butoxy, isobutoxy, tert-butoxy), pentoxy (e.g., n-pentoxy, isopentoxy, neopentoxy), etc. Alkoxy groups may be unsubstituted or substituted with one or more suitable substituents. Similarly, "alkathio" or "thioalkoxy" refers to the aforementioned alkyl groups bonded to the parent molecule via a sulfur atom, such as -S-methyl, -S-ethyl, etc. Representative examples of alkathio groups include, but are not limited to: -SCH3, -SCH2CH3, etc.

[0062] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Correspondingly, the term "halogenated" refers to fluorinated, chlorinated, bromine, and iodinated substances.

[0063] "Haloalkyl" includes groups in which branched and straight-chain saturated aliphatic hydrocarbon groups are substituted with one or more halogen atoms. "Fluoroalkyl" or "fluoroalkyl" specifically refers to the aforementioned alkyl groups substituted with at least one fluorine atom (e.g., one to three fluorine atoms), and specific examples include, but are not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Suitable examples of fluoroalkyl groups particularly include, but are not limited to: -CF3, -CHF2, -CH2CF3, -CF2CF3, etc.

[0064] The term "hydroxyl" is used interchangeably and refers to –OH.

[0065] The term "carboxyl group" is used interchangeably and refers to –COOH.

[0066] The term "ester group" refers to -COOR, where R is an alkyl group as defined above.

[0067] The term "cyano" refers to –CN.

[0068] The term "oxo" refers to the double bond oxygen group, that is, the substituent represented by the formula =O.

[0069] The term "ketone" refers to -C(O)R, where R is an alkyl group as defined above.

[0070] As used in this article, "amino" refers to –NH2. One or more hydrogen atoms in an amino group can be replaced by a substituent (such as an alkyl group), and the resulting group is called an "alkylamino". An alkylamino group is a group in which one or two hydrogen atoms in an amino group are replaced by an alkyl group, and the nitrogen atom of the alkylamino group is bonded to the parent molecule. Examples of alkylamino groups include: methylamino (-NHCH3), dimethylamino (-N(CH3)2), -NHCH2CH3, etc.

[0071] As used herein, the term "aminoalkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group substituted with one or more amino groups. For example, "C 1-4 "Aminoalkyl" includes alkyl groups having 1, 2, 3, or 4 carbon atoms and being substituted with one or more amino groups. Aminoalkyl groups are bonded to the parent molecule through the carbon atom of the alkyl moiety of the group. Representative examples of aminoalkyl groups include, but are not limited to: -CH2NH2 (aminomethyl), -CH2CH2NH2 (2-aminoethyl), and -CH2CH(NH2)CH3 (2-aminopropyl).

[0072] As used herein, the term "amide group" refers to –C(O)N(R)2, where each R is independently an alkyl group (including branched and straight-chain alkyl groups) or a hydrogen atom. The amide group is bonded to the parent molecule via a carbonyl carbon atom. Examples of amide groups include, but are not limited to: -C(O)NH2, -C(O)NHCH3, and –C(O)N(CH3)2.

[0073] The terms "hydroxylated alkyl" and "hydroxyalkyl" are used interchangeably and refer to a branched or straight-chain aliphatic hydrocarbon group substituted with one or more hydroxyl groups. The hydroxyalkyl group is bonded to the parent molecule through the carbon atom of the alkyl moiety. Hydroxyalkyl groups may have a specific number of carbon atoms, for example, "C1 to C2". 10 "Hydroxyalkyl" or "C" 1-10 "Hydroxyalkyl" includes hydroxyalkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms; similarly, "C1 to 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), hydroxyethyl (-CH2CH2OH), etc.

[0074] As used herein, the term "amide" refers to –N(R')C(O)R, where R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl groups. Examples of amide groups include, but are not limited to: -NHC(O)CH3 (acetamido), -NHC(O)CH2CH3 (propamido), and –N(CH3)C(O)CH3 (N-methylacetamido).

[0075] As used herein, the term "ureido" refers to –N(R')C(O)N(R)2, where R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Examples of ureido groups include, but are not limited to: -NHC(O)NH2 (ureido), -NHC(O)NHCH3 (methylureido), and –NHC(O)NH(Ph) (phenylureido).

[0076] According to common practice in this field: In the structural formulas described herein, the bonding sites used to represent groups, parts or substituents, and the core skeleton or parent molecule structure are used to represent the connection sites.

[0077] When the bond line of a substituent intersects the bond between two atoms in the ring, it indicates that the substituent can be attached to any atom in the ring.

[0078] As used herein, the term "substituted" refers to any organic group (e.g., alkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, etc.) where at least one hydrogen atom is substituted by a non-hydrogen group, and the substituted group must meet the normal valence requirement and form a stable compound. When a particular group is "substituted," the group may have one or more substituents (e.g., 1-5, 1-3, or 1-2 substituents), which are independently selected from the list of substituents. The term "independently" when referring to a substituent means that when multiple substituents are present, the substituents may be the same or different from each other. Examples of suitable substituents include, but are not limited to: alkyl, halogen, haloalkyl, alkoxy, amide, hydroxy, hydroxyalkyl, amino, carboxyl, ester, oxo, cyano, etc.

[0079] When any variable appears multiple times in any composition or structural formula of a compound, its definition for each occurrence is independent of its definition for any other occurrence. For example, if a group shows that it is substituted by 0-3 R groups, it means that the group can be optionally substituted by a maximum of three R groups, and each occurrence of R is independently selected from the defined range of R.

[0080] The terms "optional" or "optionally" indicate that the described event or situation may but does not have to occur, and such descriptions include both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted heterocyclic group" means that the substituent may be present but is not required to be present, and this description includes both the case where the heterocyclic group is substituted by a suitable substituent and the case where it is not substituted by any substituent.

[0081] Those skilled in the art will understand that, in some embodiments of this disclosure, the compound structure may contain one or more asymmetric carbon atoms. In this document, any chemical structural formula in which bonding is indicated only by solid lines (without solid or dashed wedge lines), or where no specific atom is specifically indicated by a particular configuration (e.g., R or S), should be understood to cover every possible stereoisomer or any mixture thereof. Stereoisomers include enantiomers and diastereomers: an enantiomeric system refers to mirror-image stereoisomers that cannot be superimposed; a mixture of equal amounts of enantiomers constitutes a racemic mixture or a racemic mixture; diastereomers (or diastereomers) refer to stereoisomers that are not mirror images of each other. A diastereomer is formed when two or more stereoisomers of a compound have different configurations at their equivalent stereocenters and are not mirror images of each other. Substituents (such as alkyl groups, heterocyclic groups, etc.) may contain R-type or S-type stereocenters.

[0082] Some embodiments contain chemical structures labeled with (R) or (S) configuration terms. When (R) or (S) is used in the name of a compound or its chemical structure representation, it indicates that the compound is a single isomer at the corresponding stereocenter, and its absolute configuration has been clearly determined to be (R) or (S).

[0083] Based on this disclosure, those skilled in the art can obtain stereochemically pure isomers using known techniques. For example, diastereoisomers can be separated by physical separation methods (such as stepwise crystallization and chromatography); enantiomers can be separated by selective crystallization to form diastereoisomer salts with optically active acids or bases, or by chiral chromatography. Pure stereoisomers can also be synthesized using stereochemically pure starting materials, or prepared using stereoselective reactions.

[0084] The compounds described herein can also form tautomers. The term "tautomer" refers to a form in a particular compound structure that can interconvert through the movement of hydrogen atoms and electrons. Such tautomers are structural isomers that readily interconvert, usually accompanied by the migration of protons (hydrogen atoms). Thus, two structures can reach equilibrium through the movement of π electrons and atoms (usually hydrogen). All tautomer forms of the compounds described herein, as well as mixtures thereof, are within the scope of this disclosure.

[0085] The compounds described herein may exist in solvated or non-solventized forms. The term "solvent" refers to a physical association formed by the compounds of this document with one or more solvent molecules through interactions such as hydrogen bonding. Solvent molecules in a solvate may exist in a regular and / or random arrangement and may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. The compounds of this document may form solvates with water (i.e., hydrates) or common organic solvents, exemplary solvates including but not limited to hydrates, ethanol compounds, methanol compounds, and isopropanol compounds. Solvation methods are well known in the art.

[0086] The scope of this disclosure also includes the isotopic forms of all atoms in the compounds described herein (including intermediates and final products). An isotope is an atom having the same atomic number but different mass numbers. General examples (non-limiting) include: isotopes of hydrogen including deuterium and tritium; isotopes of carbon including... 13 C and 14 C.

[0087] This disclosure also includes isotopically labeled compounds. "Isotopically labeled" or "radioactively labeled" compounds refer to derivatives in which one or more atoms are replaced by atoms having a different atomic mass or mass number than those commonly found in nature (i.e., naturally occurring). Isotopically labeled compounds are typically prepared using conventional techniques known to those skilled in the art, or using processes similar to those described herein (using appropriate isotopically labeled reagents instead of the originally used unlabeled reagents).

[0088] The compound names used in this article are intended to cover all possible isomer forms, including stereoisomers of the compound (e.g., enantiomers, diastereomers, racemates, or any mixture thereof).

[0089] In one general aspect, this disclosure relates to a method for treating or preventing disease in a subject in need, the method comprising administering a therapeutically effective amount of a peripherally selective α2AR agonist to the subject.

[0090] In some embodiments, the peripherally selective α2AR agonist activates at least one α2AR subtype, particularly α2A AR, α2B AR, or α2C AR.

[0091] In some implementations, the diseases include glaucoma, pain, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, cancer, etc.

[0092] In some implementations, the disease is selected from the group consisting of: pain, rosacea, spasms, and aging.

[0093] In some implementations, the sedation induced by treatment with the peripherally selective α2AR agonist is weaker than that induced by treatment with a non-peripherally selective α2AR agonist, for example at the same or equivalent doses.

[0094] In some embodiments, the peripherally selective α2AR agonist comprises an α2AR activation portion and a peripheral distribution portion linked by covalent bonds.

[0095] In another general aspect, this disclosure provides a peripherally selective α2AR agonist comprising an α2AR activating portion and a peripheral distribution portion linked by covalent bonds, and its use in the treatment or prevention of disease.

[0096] In some implementations, the diseases include glaucoma, pain, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, cancer, etc.

[0097] In some implementations, the disease is pain.

[0098] Pain, as a complex and multidimensional sensory and emotional experience, poses a significant challenge to human health. It is not only an important symptom of physical illness but also a key factor affecting quality of life, causing immense psychological and physical distress to patients. Neuropathic pain and nociceptive pain are important components of pain. Neuropathic pain is caused by lesions or diseases of the somatic sensory nervous system and can be divided into central neuropathic pain and peripheral neuropathic pain. Central neuropathic pain includes post-spinal cord injury pain, post-stroke pain, and multiple sclerosis-related pain; peripheral neuropathic pain includes diabetic neuropathy, postherpetic neuralgia, HIV-related pain, chemotherapy-induced peripheral neuropathy, and postoperative neuropathic pain.

[0099] Current first-line treatments include gabapentin, tricyclic antidepressants, and norepinephrine / serotonin reuptake inhibitors. While these medications can alleviate pain to some extent, long-term use leads to side effects that reduce patients' quality of life. Second-line treatments, such as opioid receptor agonists, not only have side effects but also high addiction rates, causing significant social repercussions, and still cannot fully meet the pharmacological needs for treating neuropathic pain.

[0100] Alpha-2AR agonists (such as clonidine and dexmedetomidine) are considered important pain management tools in academic research and clinical practice. Scientific studies have shown that administration of alpha-2AR agonists via the epidural route can effectively relieve pain. However, the therapeutic benefits of this class of drugs have significant limitations: existing alpha-2AR agonists are often accompanied by a series of biological reactions, including sedation, hypotension, bradycardia, drowsiness, dizziness, depression, orthostatic hypotension, constipation, nausea, stomach upset, dry mouth, nasal dryness, erectile dysfunction, fluid retention, edema, and changes in pupil size. These adverse reactions (especially sedation) limit the safe dosage, thus restricting the widespread use of this class of drugs in long-term pain management. This not only affects patients' quality of life but also limits the applicability of this class of drugs to different types and degrees of pain symptoms. These biological effects (especially sedation) severely restrict the application of alpha-2AR agonists in medical practice.

[0101] Therefore, it is necessary to develop novel α2AR agonist compounds with lower sedative effects for pain management. This work aims to make a significant contribution to the field of pain management by providing not only a more effective but also a safer long-term non-opioid alternative. The compounds and methods described herein can be used to address this unmet medical need.

[0102] As used herein, the term "effective amount" refers to the amount of a composition or compound that, in an tissue system or subject, can elicit a biological or medical response sought by researchers, veterinarians, physicians, or other professionals, including the relief of symptoms of a disease, condition, or condition being treated. Effective amounts can vary depending on a variety of factors, such as the subject's physical condition, age, weight, health status, etc., and the specific disease, condition, or condition to be treated. Those skilled in the art can readily determine an effective amount based on this disclosure.

[0103] According to a particular embodiment, an effective amount refers to an amount sufficient to activate α2AR of the composition or compound described herein. In another particular embodiment, an effective amount refers to an amount sufficient to treat or prevent the disease or alleviate symptoms associated with the disease.

[0104] In some implementations, the pain is nociceptive pain, neuropathic pain (e.g., peripheral neuropathic pain), or mixed pain.

[0105] In some implementations, the neuropathic pain includes cancer-related pain, diabetic neuropathy, postherpetic 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, as well as metabolic, endocrine, and toxic neuropathy, chronic postoperative pain, traumatic peripheral nerve injury, entrapment syndrome, and hereditary neuropathy.

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

[0107] In some embodiments, the peripherally selective α2AR agonist comprises an α2AR activation portion and a peripheral distribution portion linked by covalent bonds.

[0108] In another general aspect, this disclosure relates to a method of treating or preventing disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peripherally selective α2AR agonist, wherein the peripherally selective α2AR agonist comprises an α2AR activation portion and a peripheral distribution portion covalently linked.

[0109] In some implementations, the diseases include glaucoma, pain, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, cancer, etc.

[0110] In some implementations, the disease is glaucoma or cancer.

[0111] In some implementations, the disease is pain.

[0112] In some implementations, the pain is nociceptive pain, neuropathic pain (e.g., peripheral neuropathic pain), or mixed pain.

[0113] In some implementations, the neuropathic pain includes cancer-related pain, diabetic neuropathy, postherpetic 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, as well as metabolic, endocrine, and toxic neuropathy, chronic postoperative pain, traumatic peripheral nerve injury, entrapment syndrome, and hereditary neuropathy.

[0114] In some implementations, the pain is postoperative pain.

[0115] In some implementations, treatment with the peripherally selective α2AR agonist causes fewer side effects, for example at the same or equivalent doses, compared to treatment with a non-peripherally selective α2AR agonist.

[0116] In some implementations, treatment with the peripherally selective α2AR agonist does not cause side effects.

[0117] The following implementation plan applies to all the general aspects described above.

[0118] In some implementations, the side effects are sedation, decreased heart rate, and decreased blood pressure, especially sedation.

[0119] As used herein, the term "non-peripherally selective α2AR agonist" refers to a compound that, after administration, readily distributes to the central nervous system 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.

[0120] Without being bound by theoretical constraints, if α2AR agonists bind to and activate α2AR in the central nervous system, they may produce the aforementioned side effects in patients, such as sedation, decreased heart rate, decreased blood pressure, depression, bradycardia, orthostatic hypotension, constipation, nausea, stomach upset, dry mouth, dry nasal mucosa, erectile dysfunction, fluid retention, edema, and changes in pupil size.

[0121] As used herein, the term "peripherally selective α2AR agonist" refers to compounds that act primarily outside the central nervous system (CNS), and whose properties are typically derived from being blocked by the blood-CNS barrier. The blood-CNS barrier, a physical barrier between the blood and the CNS, protects the CNS from toxins and pathogens in the blood. This barrier includes the blood-brain barrier, the blood-spinal cord barrier, and the blood-cerebrospinal fluid barrier. Because these compounds are essentially blocked outside the CNS, they can act in other parts of the body while mitigating or eliminating side effects associated with brain or spinal cord action. Examples of peripherally selective α2AR agonists include, but are not limited to, the compounds described herein, such as compounds of formulas (IA), (IB), (IC), (ID), or (II).

[0122] Compared to non-peripherally selective α2AR agonists, peripherally selective α2AR agonists primarily bind to or activate α2AR outside the CNS, thus producing fewer or no of the aforementioned side effects. This invention successfully addresses this unmet clinical need by developing a series of peripherally selective α2AR agonists.

[0123] In some embodiments, the peripherally selective α2AR agonist binds to α2AR with a Ki value ranging from 250 nM to 1000 nM, 50 nM to 250 nM, 10 nM to 50 nM, or less than 10 nM. In other embodiments, the peripherally selective α2AR agonist activates α2AR with an EC50 value ranging from 250 nM to 1000 nM, 50 nM to 250 nM, 10 nM to 50 nM, or less than 10 nM.

[0124] Non-peripherally selective α2AR agonists and peripherally selective α2AR agonists can be distinguished by blood-brain barrier (BBB) ​​permeability: drugs targeting the central nervous system (CNS) must first cross the BBB; conversely, peripherally selective drugs exert their effects primarily outside the CNS, mainly due to their obstruction by the blood-brain barrier (BBB). The BBB significantly restricts these drugs from entering the CNS, resulting in significantly higher drug concentrations outside the CNS than inside. Any method known in the art can be used to determine the BBB permeability of a compound, for example, the Kp value (the ratio of intracerebral drug concentration to blood drug concentration) can be used as an experimental measure of BBB permeability.

[0125] As used in this article, "Kp" or "B / P ratio" refers to the concentration ratio of a compound in brain tissue to that in blood. Kp is often calculated in the form of "logBB," which is the logarithm of the ratio of the concentration in the brain to that in the blood. Kp is a commonly used numerical parameter characterizing the permeability of the blood-brain barrier. In some embodiments, when the Kp value after administration of a compound is below 0.4, 0.2, 0.1, 0.05, 0.02, or 0.01, the compound is considered to have "peripheral selectivity."

[0126] Kp,uu,brain is another commonly used parameter characterizing blood-brain barrier permeability. In this article, "Kp,uu,brain" or "Kp,uu" refers to the unbound brain-plasma partition coefficient, reflecting the ability of a drug to cross the blood-brain barrier after systemic administration. Kp,uu can more accurately measure the distribution balance of unbound drugs between brain tissue and plasma.

[0127] Any method known in the art can be used to determine Kp, uu, brain. Exemplary methods include: the area under the curve (AUC) method, which calculates the ratio of the area under the curve of unbound drug in brain tissue to that in plasma after a single dose; and the steady-state concentration method, which uses the ratio of the concentration of unbound drug in interstitial fluid to that in plasma at steady state.

[0128] In some embodiments, a compound is considered to have "peripheral selectivity" when its Kp,uu,brain value is below 0.4, 0.2, 0.1, 0.05, 0.02, or 0.01 after administration. In further embodiments, peripheral selectivity is considered to be present when the Kp,uu,brain value is below 0.05, 0.02, or 0.01.

[0129] In some embodiments, the peripherally selective α2AR agonist comprises an α2AR activation portion and a peripheral distribution portion linked by covalent bonds.

[0130] In some embodiments, the α2AR activation portion is a non-peripherally selective α2AR agonist or another peripherally selective α2AR agonist.

[0131] In some embodiments, the α2AR activating moiety is an α2AR agonist selected from the following: (R)-3-nitrobiphenyline, A-193080, ADX-415, AGN-192836, AGN-191103, AGN-197075, AGN-201781, AGN-241622, amitraz, apraclonidine, AR-08, bethanidine, brimonidine, BRL-48962, bromocriptine, cirazoline, clonidine, detomidine, and detomidine carboxylic acid. acid), dexmedetomidine, dipivfrin, DL-methylephedrine, droxidopa, epinephrine, ergotamine, etilefrine, etomidate, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, indanidine, lofexidine, medetomidine, mephentermine, methamphetamine, metaraminol, methoxamine, methyldopa, methyldopa ethyl ester, methyldopa ethyl hydrochloride.hydrochloride, methylnorepinephrine, mivazerol, moxonidine, naphazoline, norepinephrine, norfenefrine, octopamine, ODM-105, oxymetazoline, pergolide, phenylpropanolamine, povafonidine, propanediol, and acetylcholine. Propylhexedrine, pseudoephedrine, racepinephrine, rezatomidine, rilmenidine, romifidine, synephrine, talipexole, tasipimidine, tiamenidine, tizanidine, xylazine, xylometazoline and their functional derivatives.

[0132] The term "functional derivative" of an α2AR agonist as used herein refers to any compound derived from the α2AR agonist through a chemical reaction. Exemplary derivatives include, but are not limited to, acidic or basic salts, prodrugs, and compounds containing protected functional groups such as hydroxyl, amino, carboxyl, and carbonyl groups.

[0133] In some embodiments, the α2AR activation portion is a non-peripherally selective α2AR agonist, such as dexmedetomidine, brimonidine, and clonidine.

[0134] In some implementations, the α2AR activation portion is dexmedetomidine.

[0135] As used herein, the term "peripheral distribution portion" refers to a structural unit capable of enhancing or improving the peripheral selectivity of an α2AR agonist. In some embodiments, this structural unit functions to make the α2AR agonist a peripherally selective α2AR agonist.

[0136] According to embodiments of this disclosure, the peripheral distribution portion may be the following chemical fragments: • Type A fragments: Fragments that can increase the overall molecular polarity of a compound or decrease its overall lipophilicity; • Type B fragments: Fragments that can increase the overall molecular weight or molecular size of a compound; and • C-type fragment: A fragment containing efflux transporter substrate elements.

[0137] In some implementations, the peripheral distribution portion is a type A segment.

[0138] In some embodiments, the type A fragment can increase the total number of hydrogen bonds within the compound molecule, such as the number of hydrogen bond donors and acceptors. In a preferred embodiment, the type A fragment is a hydrogen bond donor.

[0139] In some embodiments, the type A fragment may increase the overall molecular polarity of the compound. For example, such type A fragments may contain polar functional groups or charged groups. Examples of polar functional groups include, but are not limited to: hydroxyl, amino, amide, sulfonamide, carboxyl, ether, imine, hydroxylamine, ester, aldehyde, ketone, nitro, phosphate, thioether, and sulfone groups. Examples of charged groups include, but are not limited to: quaternary ammonium salts and organic acids (such as carboxylic acids and sulfonic acids).

[0140] In some embodiments, the type A fragment may reduce the overall lipophilicity of the compound. Examples of such type A fragments include, but are not limited to, alkyl or acyl groups attached to functional groups such as hydroxyl and amino groups.

[0141] In some embodiments, the type A fragment is not a tertiary amine or a group that contributes to the formation of intramolecular hydrogen bonds.

[0142] In some implementations, the peripheral distribution portion is a type B segment.

[0143] In some 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), sterically hindered aryl groups, and additional cyclic or heterocyclic groups.

[0144] In some implementations, the peripheral distribution portion is a C-shaped segment.

[0145] In some embodiments, the C-type fragment comprises a substrate element of an efflux transporter, wherein 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 enables the compound to become a substrate of such an efflux transporter. In other words, the term refers to a fragment of an efflux transporter substrate.

[0146] In some implementations, the C-type fragment comprises a P-gp substrate element.

[0147] Without being bound by theory, P-gp efflux is a significant limiting factor for blood-brain barrier penetration. Any method known in the art can be used to determine whether a compound is a P-gp substrate. For example, efflux ratios obtained through in vitro P-gp experiments (MDCK-MDR1 cell model) can be used to identify P-gp substrates. When a compound's efflux ratio is greater than 2, 5, 8, 10, 50, or 100, the compound is considered a P-gp substrate.

[0148] Other rules for identifying potential P-gp efflux substrates include: • The total number of nitrogen and oxygen atoms (N+O) ≥ 8; • Molecular weight (MW) > 400; and / or • Acidic compounds have a pKa > 4.

[0149] Conversely, if a compound satisfies N+O<4, MW<400 and / or is a basic compound with pKa<8, then the compound is a non-P-gp substrate.

[0150] The P-gp efflux effect can be improved through specific structural modifications, such as: eliminating the steric hindrance of hydrogen bond donor atoms by connecting sterically hindered groups or demethylating nitrogen atoms; and enhancing hydrogen bond formation ability by removing adjacent electron-withdrawing groups or introducing hydrogen bond groups such as amides.

[0151] In some implementations, the P-gp substrate element includes one or more of the structural modifications described above.

[0152] In some embodiments, the P-gp substrate element is selected from: .

[0153] In some embodiments, the C-type fragment contains a substrate element of the BCPR transporter.

[0154] In some embodiments, the C-type fragment contains a substrate element of the MPR2 transporter protein.

[0155] In some embodiments, the C-type fragment does not contain substrate elements of uptake transport proteins (e.g., LAT1, GLUT1, MCT1, CAT1, CNT2, OATP, PEPT1, PEPT2, and OCT).

[0156] In some embodiments, the peripheral distribution portion may reduce and / or minimize brain exposure to peripherally selective α2AR agonists.

[0157] In some embodiments, the peripheral distribution portion reduces passive transcellular BBB permeability by increasing the topological polar surface area (TPSA), increasing the molecular weight, enhancing polarity, or adding hydrogen bonds (especially hydrogen bond donors).

[0158] In some embodiments, the peripheral distribution portion introduces acidic groups into the peripherally selective α2AR agonist.

[0159] In some embodiments, the peripheral distribution portion includes a P-gp substrate element, wherein the P-gp substrate element enhances P-gp efflux by increasing lipophilicity, increasing the number of hydrogen bond acceptors, eliminating steric hindrance around the hydrogen bond acceptors, or removing electron-withdrawing groups adjacent to the hydrogen bond acceptors.

[0160] In some embodiments, the peripheral distribution portion makes the compound a dual substrate for both P-gp and BCRP.

[0161] compound In one general aspect, this disclosure relates to a compound of formula (IA): Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, Y is C(R) 1 ), N, -OC-, -C-NH-, -CH2-C(O)- or -CH=N-; when Y is C(R 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is bonded to A, and the carbon atom is simultaneously bonded to R. T and B; When Y is -C-NH-, the carbon atom is simultaneously bonded to R. T And A, and the nitrogen atom is attached to B; A is selected from the following rings: phenyl, pyridinyl, thiopheneyl, furanyl, pyrroleyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl and 2,1,3-benzothiadiazole; B is , ,or Where X is NH, O or S, and R a It consists of H and methyl groups; n is 0, 1, 2, or 3; R 2Each is independently selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, OR 4 -CN, N3, NO2, N(R) 4 2. SR 4 C(O)R 4 SO2N(R) 4 )2、CH2SR 4 ; wherein the alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryl, heterocyclic, or heterocyclic alkyl groups are optionally surrounded by one or more R groups. 5 replace; R 4 Selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, and said alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, optionally separated by one or more R 5 replace; R 5 Selected from halogens, hydroxyl groups, -CN, -NO2, alkyl groups, alkoxy groups, alkenyl groups, alkenyloxy groups, alkynyl groups, cycloalkyl groups, cycloalkoxy groups, aryl groups, aryloxy groups, aralkyl groups, heteroaryl groups, heteroaryl groups, heterocyclic groups, and heterocyclic alkyl groups; or, When two R 2 When the two Rs are substituted at adjacent positions on the benzene ring, 2 The group, together with the carbon atom it is attached to, forms a bicycle fused with ring A, such as quinolinyl, indolyl, benzothiophenyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, zolinyl, quinoxalinyl, or 1,2,4-benzotriazineyl; m is 0, 1, 2, or 3; R 3 Each is independently selected from H, deuterium, halogen, -OH, -SH, optionally substituted alkyl, optionally substituted heterocyclic and optionally substituted aryl; or, R 3 It is a group linked through the imidazole ring -NH- group, and R 3 It has the following formula: , , , ,or , in, R 5 It is hydrogen or alkyl; R 6 It is hydrogen, alkyl, cycloalkyl, or alkenyl; R 7 It consists of amino acid residues; and, R 8 It is an alkyl or cycloalkyl group; R T It is R L -R P And R P Optionally R C replace; in: R L It is a connector, one end of which is connected to R. P The other end is connected to Y; R P It is connected to R L One end portion; and, R C It is an end cap base, which is connected to R P The part.

[0162] The term "R" used in this article L "Refers to the connecting unit that covalently links two functional groups or structural parts within the same molecule. R" L One end is connected to R P The other end is connected to Y. R L It can be any part capable of enabling linking, such as the linker used in proteolytic targeting chimeras (PROTACs) and the non-cleavable linker in antibody-drug conjugates (ADCs). L Examples include, but are not limited to: polyethylene glycol (PEG) and alkyl chains of different lengths, glycols, alkynyl groups, triazoles, saturated heterocycles (such as piperazine and piperidine), thioethers, maleimide hexanoyl linkers, etc.

[0163] In some implementation schemes, R L The group is selected from alkyl, polyethylene glycol, other glycols, cycloalkyl, heterocyclic, aryl and heteroaryl groups; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by at least one substituent selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy and hydroxyalkyl groups.

[0164] In some implementations, the R L Selected from: Or a combination of two or more of the above segments; when R L When combining two or more of the aforementioned segments, the segments can be connected in any order.

[0165] According to the implementation scheme of this disclosure, R p It can be the following chemical components: • Parts that can increase the overall molecular weight of a compound, such as sterically hindered functional groups and additional molecular structures (including long alkyl chains, sterically hindered aryl groups, and additional cyclic structures such as cyclohexane or cyclopentane rings). • Groups that can increase the overall molecular polarity of a compound, such as hydroxyl, amino, amide, sulfonamide, ether, imino, hydroxylamine, ester, aldehyde, ketone, nitro, phosphate, and thioether groups; and • The part of a compound that can impart a charge, such as functional groups that can ionize at physiological pH (including carboxylic acids, quaternary ammonium salts, and quaternary phosphonium salts).

[0166] In some implementations, when R P Not R C When replacing, R P for: .

[0167] In some implementations, when R P R C When replacing, R P for: .

[0168] The term "R" used in this article C "refers to covalently connected to R" P The chemical portion at the end.

[0169] In some implementation schemes, R C Selected from: -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -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 Heterocyclic group, -NH-C 0-12 Alkylene-C 1-12 heteroaryl, -OC 0-12 Alkylene-C 3-12 cycloalkyl, -OC 0-12Alkylene-C 2-12 Heterocyclic groups, -OC 0-12 Alkylene-C 1-12 Heteroaryl and alkyl groups substituted with trialkylammonium, wherein C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each heteroaryl group may optionally be substituted by one or more substituents selected from hydroxyl, alkyl, oxo, and ketone groups.

[0170] In some implementations, R C yes: .

[0171] In some implementations, R C yes:

[0172] In another general aspect, this disclosure relates to a compound of formula (IB): Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R) 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and A, B, R 2 n, R 3 m and R T As defined in the above formula (IA).

[0173] In another general aspect, this disclosure relates to a compound of formula (IC): , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R)1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and A, B, R 2 n, R 3 m and R T As defined in the above formula (IA).

[0174] In another general aspect, this disclosure relates to a compound of formula (ID): Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. Where: Y 1 For CH or N; X 1 Selected from H, deuterium, and halogens; and R T As defined in the above formula (IA).

[0175] In some embodiments, the compound of formula (IA) has formula (IA-1): , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, R 1 Selected from H, D and halogens; A is a ring selected from phenyl, pyridyl, thiophenyl, furanyl, pyrroleyl, 4H-pyran, or 4H-thiopyran; R 2 n, R 3 m and R T It is as defined in the above formula (IA).

[0176] In some embodiments, the compound of formula (IA) has formula (IA-2): , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, 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-; When Y is -O-CH-, the oxygen atom is bonded to A, and the carbon atom is simultaneously bonded to R. Tand ; When Y is -C-NH-, the carbon atom is simultaneously bonded to R. T and A, and the nitrogen atom is connected to ; X is NH, O, or S; and R 2 , n and R T It is as defined in the above formula (IA).

[0177] In some embodiments, when the compound of formula (IA) has formula (IA-1) or (IA-2), R T yes or ; in, Ring M is C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 heteroaryl, wherein the C 3-12 The cycloalkyl group is optionally fused with the aryl group; r is 1 or 2; n2 is 0, 1, or 2; R 2 Each is independently selected from hydrogen, halogens, hydroxyl groups, and alkoxy groups; R 3 Selected from CN, hydroxyl, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclic groups, -SO2-alkyl groups, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene-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 0-12Alkylene-P(=O)(R) 4 (R) 4’ ), -NH-R 7 or ; in, The -C 0-12 Alkylene-R 3’ One of the -CH2- groups is optionally replaced by an oxygen atom or Instead, the -C 0-12 Alkylene-R 3’ Optionally substituted with one or more substituents selected from amino and alkylamino groups, and the C 2-12 Heterocyclic groups and the C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 3’ Selected from -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 and C 0-12 Alkylene-C 1-12 Mixed aromatics; R 4a Each is independently selected from hydroxyl, alkyl, oxo, ketone and -C 2-12 Heterocyclic groups; R 4 and R 4’ Each of these components is independent of hydrogen, alkyl, alkoxy, -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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Or, R 4 and R 4’ Together with the nitrogen atom to which it is attached, it forms a heterocycle comprising one or more heteroatoms selected from O, N, and S; Or, when an R 2 Adjacent to R 3 At that time, R 2 and R 3 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 4a Replacement ring; R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl, or optionally alkyl groups substituted with cyano, amide, trialkylamine, or thiolate; wherein, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6a Each is independently selected from hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Heteroaryl; wherein the alkyl, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6 It is an alkoxy, amino, sulfonamide, urea, or optionally substituted alkyl group; R 7 It is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted C 3-12 cycloalkyl, C 2-12 Aryl, 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 groups; R 8 It is an alkoxy group, amino group, alkylamino group, amide group, sulfonamide group, or urea group; 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.

[0178] In another general aspect, this disclosure relates to a compound of formula (II): , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. in, A is selected from one of the following: , , ; n1 is 1 or 2; R 1 Each is independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl and -COOH; B is selected from one of the following: , , ,and , Where X is S, O, or NH; R T yes or Ring M is C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 heteroaryl, wherein the C 3-12 The cycloalkyl group is optionally fused with the aryl group; r is 1 or 2; n2 is 0, 1, or 2; R 2 Each is independently selected from hydrogen, halogens, hydroxyl groups, and alkoxy groups; R 3 Selected from CN, hydroxyl, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclic groups, -SO2-alkyl groups, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene-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’ ), -NH-R 7 or ; in, The -C 0-12 Alkylene-R 3’ One of the -CH2- groups is optionally replaced by an oxygen atom or Instead, the -C 0-12 Alkylene-R 3’ Optionally substituted with one or more substituents selected from amino and alkylamino groups, and the C2-12 Heterocyclic groups and the C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 3’ Selected from -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 and C 0-12 Alkylene-C 1-12 Mixed aromatics; R 4a Each is independently selected from hydroxyl, alkyl, oxo, ketone and -C 2-12 Heterocyclic groups; R 4 and R 4’ Each of these components is independent of hydrogen, alkyl, alkoxy, -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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Or, R 4 and R 4’ Together with the nitrogen atom to which it is attached, it forms a heterocycle comprising one or more heteroatoms selected from O, N, and S; Or, when an R 2 Adjacent to R 3 At that time, R 2 and R 3Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 4a Replacement ring; R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl, or optionally alkyl groups substituted with cyano, amide, trialkylamine, or thiolate; wherein, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6a Each is independently selected from hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Heteroaryl; wherein the alkyl, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6 It is an alkoxy, amino, sulfonamide, urea, or optionally substituted alkyl group; R 7 It is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted C 3-12 cycloalkyl, C 2-12 Aryl, C 1-12 heteroaryl, -C 0-12 Alkylene-N(R) 4 )-SO2-R5 -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 groups; R 8 It is an alkoxy group, amino group, alkylamino group, amide group, sulfonamide group, or urea group; 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.

[0179] In some implementation schemes, A is Or (structural formula) .

[0180] In some implementation schemes, A is or .

[0181] In some implementation schemes, R 1 It is an alkyl group, such as methyl.

[0182] In some implementation schemes, R 1 It is a halogen, such as fluorine or chlorine.

[0183] In some implementation schemes, R 1 It is an alkoxy group, such as -OMe (methoxy group).

[0184] In some implementation schemes, R 1 It can be a hydroxyl group, -COOH, or -CH2OH.

[0185] In some implementation schemes, R 1 It is a haloalkyl group, such as trifluoromethyl or -CH2CH2F.

[0186] In some implementation schemes, B is or .

[0187] In some implementation schemes, B is or , where X is S, O or NH.

[0188] In some implementation schemes, R T for .

[0189] In some implementation schemes, R T for .

[0190] In some implementations, ring M is C 6-12 Aryl or C 1-12 Mixed aromatic compounds.

[0191] In some implementations, ring M is C 3-12 cycloalkyl or C 2-12 Heterocyclic groups, where C 3-12 cycloalkyl or C 2-12 The heterocyclic group may optionally fuse with the aryl group.

[0192] In some embodiments, ring M is phenyl, pyridyl, pyrimidinyl, phenylthio, cyclopentyl, or cyclohexyl.

[0193] In some implementations, ring M is or .

[0194] In some implementation schemes, R 2 It is hydrogen.

[0195] In some implementation schemes, R 2 It is a hydroxyl group.

[0196] In some implementation schemes, R 2 It is a halogen, such as fluorine or chlorine.

[0197] In some implementations, the pharmaceutically acceptable salt of the compound of formula (I) is a trifluoroacetate or hydrochloride.

[0198] In some embodiments, the compound of formula (II) is the compound of formula (II-A): , in, R 1 R 2 R 3 n1 is defined in equation (II) above.

[0199] In some implementation schemes, R 1 It is a halogen, a haloalkyl, a hydroxyl, an alkyl, or -COOH.

[0200] In some implementation schemes, R 1 It can be methyl, ethyl, hydroxyl, fluorine, chlorine, trifluoromethyl, -CH2CH2F or -COOH.

[0201] In some implementations, n1 is 2.

[0202] In some implementation schemes, R2 It is hydrogen, hydroxyl, or halogen.

[0203] In some implementation schemes, R 2 It is either fluorine or chlorine.

[0204] In some implementation schemes, R 3 It is -C(O)-NR 4 R 4’ or -SO2-NR 4 R 4’ , where R 4 and R 4’ Each is independently hydrogen, alkyl, alkoxy, -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a Or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a Replace, where R 4a R 6a And t is as defined above.

[0205] In some implementation schemes, R 4 and R 4’ Each is independently hydrogen, alkyl, alkoxy, or hydroxyalkyl.

[0206] In some implementation schemes, R 4 and R 4’ Each independently is , , , , or .

[0207] In some implementation schemes, R 4 and R 4’ Each is independently of being alkoxylated (e.g. ) substituted hydroxyalkyl, wherein p is 0, 1, 2 or 3, especially p is 2.

[0208] In some implementation schemes, R 3 It is -C(O)-NR4 R 4 or -SO2-NR 4 R 4’ , where R 4 and R 4’ Together with the nitrogen atoms they are attached to, they form heterocycles containing one or more heteroatoms selected from O, N, and S, especially R. 4 and R 4’ Together with the nitrogen atoms they are attached to, they form six-membered heterocycles.

[0209] In some implementation schemes, R 3 It is hydroxyl group, -COOH, -CH(CH3)-COOH, -CN, , , , , , or .

[0210] In some implementation schemes, 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 , where R 4 It is hydrogen or alkyl, and R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 alkylene-cyano, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl, or optionally alkyl group substituted with cyano or amide group; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12Each of the heteroaryl groups is optionally bounded by one or more R 4a Replace, where R 4a R 6a The definition of t is the same as above.

[0211] In a particular implementation, R 5 It is amino, alkylamino, alkoxy, alkyl or -C 2-12 Alkenyl group.

[0212] In a particular implementation, R 5 It is an alkyl group substituted with a cyano group, such as -CH2CN.

[0213] In a particular implementation, R 5 It is an alkyl group substituted with an amide group, such as -CH2CH2C(O)NH2.

[0214] In a particular implementation, R 5 Alkyl groups substituted with alkoxy groups, trialkylammonium groups, or thiols are used.

[0215] In a particular implementation, when R 5 -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic groups or -C 0-12 Alkylene-C 1-12 When heteroaryl, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Mixed aromatic compounds are selected from: , , , , , , , , , , , and .

[0216] In a particular implementation, when the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is subjected to one or more R 4a When replacing, R 4a It can be hydroxyl, methyl, oxo, or -C(O)-CH3.

[0217] In some implementation schemes, R 3 for Where m is 0, 1, 2, 3, 4 or 5, and R 6 It is a sulfonamide, a urea group, or an alkyl group optionally substituted with a cyano group.

[0218] In a particular implementation, R 6 The sulfonamide is represented by the formula –N(R')SO2-R, wherein R and R' are each independently selected from hydrogen and alkyl groups, particularly R 6 It is -NHSO2CH3.

[0219] In a particular implementation, R 6 The urea group is represented by the formula –N(R')C(O)N(R)2, wherein R and R' are each independently selected from hydrogen, alkyl and heteroaryl groups, and in particular R 6 for .

[0220] In a particular implementation, R 6 Alkyl groups optionally substituted with cyano groups, such as C14 groups optionally substituted with cyano groups. 1-4 Alkyl groups, specifically those C groups substituted with cyano groups. 1-4 alkyl.

[0221] In a particular implementation, m is 1, 2, or 3, especially 2.

[0222] In some implementation schemes, R 3 -NH-R 7 , where R 7 Hydrogen, or optionally substituted 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 optionally alkyl groups substituted with cyano; wherein R 4 R 4 'and R 5 The definition is the same as above.

[0223] In a particular implementation, R 7 It is hydrogen.

[0224] In a particular implementation, R 7 for , , or .

[0225] In a particular implementation, R 7 Alkyl groups optionally substituted with cyano groups, such as C14 groups optionally substituted with cyano groups. 1-4 Alkyl groups, specifically those C groups substituted with cyano groups. 1-4 alkyl.

[0226] In a particular implementation, R 3 for n is 3 or 4, especially 4.

[0227] In some embodiments, the compound of formula (II) is a compound of formula (II-B): Among them, R 1 R 8 n1, n3 and n4 are as defined in equation (II) above.

[0228] In some implementation schemes, R 1 It is hydrogen or alkyl, such as alkyl, especially methyl.

[0229] In some implementations, n1 is 2.

[0230] In some implementations, n3 is 0, 1, or 3.

[0231] In some implementations, n4 is 2, 3, or 5.

[0232] In some implementation schemes, R 8 It is an alkoxy group, such as C 1-4 Alkyl groups, especially methoxy or ethoxy groups.

[0233] In some implementation schemes, R 8 It is an amino group.

[0234] In some implementation schemes, R 8 It is an alkylamino group, such as C 1-4 Alkylamino, particularly methylamino.

[0235] In some implementation schemes, R 8 It is an amide group represented by the formula –N(R')C(O)R, wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl and heteroaryl.

[0236] In some implementation schemes, R 8 The amide group is represented by the formula –N(R')C(O)R, especially R 8 It is -NHC(O)CH3.

[0237] In some implementation schemes, R8 It is a sulfonamide group represented by the formula –N(R')SO2R, wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl and heteroaryl.

[0238] In a particular implementation, R 8 The sulfonamide group is represented by the formula –N(R')SO2R, where R and R' are each independently selected from hydrogen, -C 0-12 Alkylene-C 2-12 Heterocyclic and alkyl groups, especially R 8 It is -NHSO2CH3.

[0239] In some implementation schemes, R 8 It is a urea group represented by the formula –N(R')C(O)N(R)2, wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl and heteroaryl.

[0240] In a particular implementation, R 8 The urea group is represented by the formula –N(R')C(O)N(R)2, wherein R and R' are each independently selected from hydrogen, alkyl and heteroaryl groups, and in particular R 8 -NHC(O)NHCH3 or .

[0241] In some embodiments, when the compound is a compound of formula (II), R 8 For -OCH3, -NH2, -NHCH3, -NHC(O)CH3, , , or .

[0242] In some embodiments, the compound of formula (II) is a compound of formula (II-C): , in, n2 is 1 or 2; and R 1 R 2 R 3 and n1 are as defined in equation (II) above.

[0243] In some implementation schemes, R 1 It is an alkyl group, such as methyl (CH3).

[0244] In some implementations, n1 is 2.

[0245] In some implementations, n2 is 1.

[0246] In some implementation schemes, R 2 It is hydrogen or halogen.

[0247] In a particular implementation, R 2 It is fluorine.

[0248] In some implementation schemes, R 3 -C(O)-NR 4 R 4 ', where R 4 and R 4 Each can be independently hydrogen, hydroxyl, alkyl, alkoxy, -SO2-NHCH3, -SO2-NH-Ph, -CH2-COOH, -CH2-CH2-COOH or .

[0249] In some implementation schemes, R 3 -SO2-NR 4 R 4 ', where R 4 and R 4 Each is independently hydrogen, hydroxyl, or -C 0-12 Alkylene-C 2-12 Heterocyclic group.

[0250] In some implementation schemes, R 3 -NH-C(O)-R 5 -N(CH3)-C(O)-R 5 or -NH-SO2-R 5 , where R 5 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 Heterocyclic groups or -C 0-12 Alkylene-C 2-12 Heterocyclic group.

[0251] In a particular implementation, R 5 It is an alkyl group, such as methyl.

[0252] In a particular implementation, R 5 -C 0-12 Alkylene-alkoxy groups, such as -CH2-OCH3.

[0253] In a particular implementation, R 5 -C 0-12 Alkylene-C 3-12 cycloalkyl, for example .

[0254] In a particular implementation, R 5 -C 0-12 Alkylene-NH-C 1-12 Alkyl groups, such as -NH-CH3.

[0255] In a particular implementation, R 5 -C 0-12 Alkylene-NH-C 2-12 Heterocyclic groups, for example , , .

[0256] In a particular implementation, R 5 -C 0-12 Alkylene-C 2-12 Heterocyclic groups, for example , or .

[0257] In some implementation schemes, R 3 It is -SO2-alkyl, for example -SO2-CH3.

[0258] In some implementation schemes, R 3 -C 0-12 Alkylene-COOH, such as -COOH, -CH2-COOH, -C(CH3)2-COOH, -CH2-CH2-COOH.

[0259] In some implementation schemes, R 3 -C 0-12 Alkylene-P(=O)(R) 4 (R) 4 '),For example .

[0260] In some implementation schemes, R 3 -C 0-12 Alkylene-C 1-12 heteroaryl, for example , , , , , , .

[0261] In some implementation schemes, R 3 -NH-R 7 For example, -NH-CH3, -NH-C(=S)-R 5 ,For example .

[0262] In some embodiments, the compound of formula (II) is a compound of formula (II-D): , in, n2 is either 0 or 1; R 3 Selected from -C(O)-NHR 4 -SO2-NHR 4 -NH-C(O)-R 5 -NH-SO2-R 5 and -NH-R 7 ; R 4 -C 0-12 Alkylene-NHR 6a -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a , or alkyl groups substituted with trialkylammonium; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 5 -C 0-12 Alkylene-NHR 6a -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a , or alkyl groups substituted with trialkylammonium; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Each R 6a Independently selected from -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic groups and -C 0-12 Alkylene-C 1-12Heteroaryl; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; 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 are as defined in equation (II) above.

[0263] In some implementation schemes, R 1 It is an alkyl group, such as methyl (CH3).

[0264] In some implementation schemes, R 1 It is an alkoxy group, such as -OMe.

[0265] In some implementations, n1 is 1.

[0266] In some implementations, n1 is 2.

[0267] In some implementations, n2 is 0.

[0268] In some implementations, n2 is 1.

[0269] In some implementation schemes, R 2 It is hydrogen or halogen.

[0270] In some implementation schemes, R 3 -C(O)-NHR 4 or -SO2-NHR 4 , where R 4 -C 0-12 Alkylene-NHR 6a -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a, or alkyl groups substituted with trialkylammonium; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a Replace, where R 4a and R 6a The definition is as above.

[0271] In a particular implementation, R 4 yes , , , , or .

[0272] In some implementation schemes, R 3 -NH-C(O)-R 5 or -NH-SO2-R 5 , where R 5 -C 0-12 Alkylene-NHR 6a -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a , or alkyl groups substituted with trialkylammonium; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a Replace, where R 4a and R 6a The definition is as above.

[0273] In a particular implementation, R 5 The alkyl group is replaced by a trialkylammonium group.

[0274] In a particular implementation, when R 5 -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic groups or -C 0-12 Alkylene-C 1-12 When heteroaryl, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Mixed aromatic compounds are selected from: , , , , , , , , , , and .

[0275] In a particular implementation, when the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is subjected to one or more R 4a When replacing, R 4a It can be hydroxyl, methyl, oxo, or -C(O)-CH3.

[0276] In some implementation schemes, R 3 -NH-R 7 , where 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 ;where R 4 and R 5 The definition is as above.

[0277] In a particular implementation, R 7 yes or .

[0278] In some embodiments, the compound of formula (II) is a compound of formula (II-E): , Where x is 0 or 1; y is 0 or 1; X is S, O, or NH; and R 1 R 2 R 3 n1 and n2 are as defined in formula (II) above.

[0279] In some implementations, x is 0, y is 1, and X is S, O, or NH.

[0280] In some implementations, x is 0 or 1, y is 0, and X is NH.

[0281] In some implementation schemes, each R 1 It is independently selected from hydrogen, halogen, alkoxy, and alkyl.

[0282] In a particular implementation, R 1 It can be methyl, chloro, or methoxy.

[0283] In some implementations, n2 is 1.

[0284] In some implementations, n2 is 2.

[0285] In some implementation schemes, R 2 It is hydrogen.

[0286] In some implementation schemes, R 3 -C(O)-NR 4 R 4 ', where R 4 and R 4 Each is independently hydrogen or alkoxy.

[0287] In some implementation schemes, R 3 -SO2-NR 4 R 4 ', where R 4 and R 4 Each is independently hydrogen or alkyl.

[0288] In some implementation schemes, R 3 -NH-C(O)-R 5 or -NH-SO2-R 5 , where R 5 It is an alkyl group or -C 0-12 Alkylene-C 2-12 Heterocyclic group.

[0289] In a particular implementation, R 5 It is an alkyl group, such as methyl.

[0290] In a particular implementation, R 5 -C 0-12 Alkylene-C 2-12 Heterocyclic groups, for example or .

[0291] In some embodiments, the compound of formula (II) is a compound of formula (II-F): , in, R 2 Adjacent to R3 And R 2 and R 3 Together with the carbon atoms to which they are attached, they form optionally one or more R 4a Substituted heterocycles; and R 1 R 4a n1 is defined as in equation (II) above.

[0292] In some implementation schemes, R 2 and R 3 Together with the carbon atoms to which they are attached, they form optionally one or more R 4a Replacement of 5- or 6-membered heterocycles.

[0293] In some embodiments, the compound of formula (II-F) is the compound of formula (II-F-1): Where M1 is arbitrarily determined by one or more R 4a Substituted heterocycles.

[0294] In some embodiments, the compound of formula (II) is a compound of formula (II-G): , in, Each R 2 Independently selected from hydroxyl and alkoxy groups; R 3 Selected from hydroxyl and alkoxy groups; and R 1 n1 and r are as defined in equation (II) above.

[0295] In some implementations, an R 2 Adjacent to R 3 .

[0296] In some implementation schemes, each R 2 It is independently selected from hydroxyl and methoxy groups.

[0297] In some implementation schemes, R 3 Selected from hydroxyl and methoxy groups.

[0298] In some embodiments, the compound of formula (II-G) is a compound of formula (II-G-1) or (II-G-2): , .

[0299] In some embodiments, the compound of formula (II) is a compound of formula (II-H): , in, M is C 6-12 Aryl or C 1-12 Mixed aromatics; R 3 Selected from -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 Alkylenes -COOH, -SO2-OH and ; wherein -C 0-12 The alkylene-COOH group is optionally substituted with one or more substituents selected from amino and alkylamino groups; and R 1 R 2 and n1 are as defined in equation (II) above.

[0300] In some implementations, M is phenyl.

[0301] In some implementations, M is pyridyl.

[0302] 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.

[0303] In a specific implementation, a compound selected from compounds 1-251, 401-403, 501-509, 601 and 602, or their tautomers, stereoisomers, pharmaceutically acceptable salts or solvates, are provided.

[0304] All possible combinations of embodiments of the compounds of formulas (IA), (IB), (IC), (ID), or (II) described above, as well as their tautomers, stereoisomers, pharmaceutically acceptable salts, and solvates, are considered to be covered within the scope of this disclosure.

[0305] Exemplary compounds of formula (IA), (IB), (IC), (ID), or (II) include, but are not limited to, the following compounds, and any tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof: Table 1

[0306] Exemplary R of formula (IA), (IB), (IC), (ID) or (II) T Including but not limited to the following structures: Table 1a Example R T

[0307] Preparation method The compounds described herein can be prepared by various methods outlined below and specific examples in the subsequent Examples section. The compounds prepared by these methods may exist as mixtures of stereoisomers, including racemic mixtures of enantiomers, which can be separated by resolution procedures known in the art, such as liquid chromatography using a chiral stationary phase. Alternatively or additionally, stereochemically pure isomers of the compounds described herein can be derived from correspondingly stereochemically pure starting materials, intermediates, or reagents. If a specific stereoisomer is desired, it can be synthesized using stereospecific preparation methods, typically using stereochemically pure starting materials or intermediate compounds.

[0308] Pharmaceutically acceptable salts of the compounds described herein can be prepared by conventional chemical methods from parent compounds containing acidic or basic groups. Typically, these salts are prepared by reacting the free acidic or basic form of the compound with a stoichiometric amount of a suitable acid or base in water, an organic solvent, or a mixture of both. Examples of suitable organic solvents include, but are not limited to, diethyl ether, ethyl acetate (EtOAc), ethanol, isopropanol, or acetonitrile.

[0309] By way of example, and not limitation, the compounds of formulas (IA), (IB), (IC), (ID), or (II) described herein can be prepared according to the general preparation procedure shown in Scheme 1 below and the embodiments of this disclosure. Those skilled in the art will understand that, in order to obtain different variants of the compounds herein, starting materials may be appropriately selected to ensure the stability of the desired substituents during the reaction, and protection strategies may be employed as needed to obtain the target product; alternatively, suitable groups that are stable during the reaction and can be readily replaced with the desired substituents may be used as substitutes.

[0310] Unless otherwise specified, the reaction is to be carried out at room temperature.

[0311] When pure samples of isomers are required, the mixture of compound isomers synthesized according to Scheme 1 can be separated by chiral supercritical fluid chromatography (SFC) or high performance liquid chromatography (HPLC).

[0312] Option 1: Composition In one aspect, 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.

[0313] The composition may also include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier should be non-toxic and should not interfere with the efficacy of the active ingredient. A pharmaceutically acceptable carrier may include one or more excipients, such as binders, disintegrants, swelling agents, suspending agents, emulsifiers, wetting agents, lubricants, flavoring agents, sweeteners, preservatives, dyes, solubilizers, and coating agents. The specific properties of the carrier may depend on the route of administration, such as intramuscular, intradermal, subcutaneous, oral, intravenous, cutaneous, intramucosal (e.g., intestinal), intranasal, or intraperitoneal routes. For example, for liquid injectable formulations (such as suspensions and solutions), suitable carriers and additives include water, glycols, oils, alcohols, preservatives, colorants, etc. For solid oral formulations (e.g., powders, capsules, capsule tablets, gel capsules, and tablets), suitable carriers and additives include starch, sugars, diluents, granulators, lubricants, binders, disintegrants, etc. For nasal sprays / inhalation mixtures, the aqueous solution / suspension may contain water, glycols, oils, emollients, stabilizers, humectants, preservatives, fragrances, flavoring agents, etc., as suitable carriers and additives.

[0314] The composition can be formulated in any form suitable for administration to subjects to facilitate administration and improve efficacy, including but not limited to oral (enteral) administration and parenteral injection. Parenteral injection includes intravenous injection or infusion, subcutaneous injection, intradermal injection, and intramuscular injection. The composition can also be formulated for other routes of administration, including transmucosal, ocular, rectal, long-acting implantation, sublingual administration, oral mucosal administration (bypassing portal vein circulation), inhalation, or intranasal administration.

[0315] The dosage form, route of administration, dosage, and regimen of the pharmaceutical composition depend on the condition to be treated, such as the severity of the disease and the patient's age, weight, and sex. The pharmaceutical composition may be formulated for different routes of administration, such as topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular, or subcutaneous.

[0316] In another aspect, a method for preparing a pharmaceutical composition is provided, comprising mixing a compound of formula (IA), (IB), (IC), (ID), or (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, with at least one pharmaceutically acceptable carrier. Based on this disclosure, the pharmaceutical composition can be prepared by any method known in the art, and such techniques for preparing pharmaceutical compositions will be familiar to those skilled in the art. For example, the pharmaceutical composition according to this disclosure can be prepared by mixing a compound of formula (IA), (IB), (IC), (ID), or (II) with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical formulation techniques, including but not limited to conventional mixing, dissolving, granulation, emulsification, encapsulation, embedding, or lyophilization processes.

[0317] How to use In one general aspect, a method for treating or preventing pain in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of a peripherally selective α2AR agonist, wherein treatment with the peripherally selective α2AR agonist causes fewer side effects, for example at similar or equivalent doses, compared to treatment with a non-peripherally selective α2AR agonist.

[0318] In some embodiments, the peripherally selective α2AR agonist comprises an α2AR activation portion covalently linked to the peripherally distributed portion.

[0319] In another general aspect, a method for treating or preventing disease in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of a peripherally selective α2AR agonist, wherein the peripherally selective α2AR agonist comprises an α2AR activation portion covalently linked to a peripherally distributed portion.

[0320] The following implementation plan applies to the overall concept of the two usage methods mentioned above.

[0321] In some implementations, the α2AR activation portion has the following structural formula: Where Y, A, B, R 2 R 3 m and n are as defined in equation (IA).

[0322] In some implementations, the α2AR activation portion has the following structural formula: Where Y, A, B, R 2 R 3 m and n are as defined in equation (IB).

[0323] In some implementations, the α2AR activation portion has the following structural formula: Where Y, A, B, R 2 R 3 m and n are as defined in equation (IC).

[0324] In some implementations, the α2AR activation portion has the following structural formula: , where X and Y are as defined in equation (ID).

[0325] In some implementations, the α2AR activation portion has the following structural formula: , where A and B are as defined in equation (II).

[0326] In some embodiments, the peripheral distribution portion has the following structural formula: , where Rᵀ is defined in equation (IA).

[0327] In some embodiments, the peripheral distribution portion has the following structural formula: Rᵀ is defined in equation (II). In another general aspect, methods for activating α2AR and for treating or preventing disease in subjects are provided, said methods using compounds described herein or compositions comprising said compounds and one or more pharmaceutically acceptable carriers.

[0328] In some implementations, compounds of formula (IA), (IB), (IC), (ID), or (II) can be used to activate α2AR.

[0329] In some embodiments, a method for activating α2AR in a subject in need is provided, comprising administering to the subject a compound or composition described herein, for example, administering an effective amount of a compound or composition described herein.

[0330] In some implementations, a method for treating or preventing disease in humans or animals is provided.

[0331] In some embodiments, a method for treating or preventing a disease in a subject in need is provided, comprising administering to the subject a compound or composition described herein, for example, administering an effective amount of a compound or composition described herein.

[0332] In some implementations, the disease is selected from glaucoma, pain, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, cancer, etc.

[0333] In some implementations, the disease is pain.

[0334] In some implementations, the pain is nociceptive pain, neuropathic pain (e.g., peripheral neuropathic pain), or a mixture of both. 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.

[0335] In some embodiments, the compounds and pharmaceutical compositions described herein cause fewer side effects (such as sedation, decreased heart rate, and decreased blood pressure) in the treated subjects when treating pain.

[0336] In some embodiments, the compounds and pharmaceutical compositions described herein do not induce a sedative response in the treated subjects.

[0337] Example The following examples are intended to further illustrate the substance of this disclosure. It should be understood that the following examples do not limit this disclosure, and the scope of this disclosure is defined by the appended claims.

[0338] Synthesis method Unless otherwise stated, abbreviations for chemical reagents and synthesis conditions have their common meanings known in the art, as follows: "ACN" refers to acetonitrile; "LDA" refers to lithium diisopropylaminodimethylamine. "EA" or "EtOAc" refers to ethyl acetate; "PE" refers to petroleum ether; "rt" and "rt" refer to room temperature; "THF" refers to tetrahydrofuran; "DIPEA" refers to N,N-diisopropylethylamine; "DCM" refers to dichloromethane; "HOBT" refers to 1-hydroxybenzotriazole; "TLC" refers to thin-layer chromatography; "DMF" refers to N,N-dimethylformamide; "h" refers to hours; "min" refers to minutes; "EDCI" refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; "DMAP" refers to 4-dimethylaminopyridine; "Prep-HPLC" refers to preparative high-performance liquid chromatography. "DPPF" refers to 1,1'-bis(diphenylphosphine)ferrocene; "NCS" refers to N-chlorosuccinimide; "TEA" refers to triethylamine; "TES" refers to triethylsilane; "Trt" refers to triphenylmethyl; "MeOH" refers to methanol; "EtOH" refers to ethanol; "t-BuXphos" refers to 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; "TMAI" refers to trimethylaluminum; "Xantphos" refers to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; "Pd(PPh3)4" refers to tetra(triphenylphosphine)palladium(0).

[0339] Example 1. Synthesis of Compound 1 Step 1: Add 400 mL of THF and 36 g (0.18 mol, 4.0 eq) of 3-bromobenzoic acid to a 500 mL reaction flask. After cooling to -65 °C, add 135 mL (4 mol / L, 0.428 mol, 7.5 eq) of n-butyllithium. Stir the mixture at -65 °C for 2 hours, then add 20 g (0.057 mol, 1.0 eq) of compound 1-1 and an additional 400 mL of THF. After stirring at -65 °C for 30 minutes, allow the mixture to warm to room temperature over 16 hours. Confirm the reaction is complete by LC-MS, and add 270 mL of saturated ammonium chloride solution. Separate the organic phase, concentrate under vacuum, and purify the residue by column chromatography (DCM-DCM:MeOH = 92:8) to give 13 g of compound 1-2, yield 40.4%.

[0340] Step 2: Add 150 mL of 55% HI, 7.5 g (13.3 mmol, 1.0 eq) of compounds 1-2, and 4.1 g (133 mmol, 10.0 eq) of red phosphorus to a 200 mL sealed tube. Stir the mixture at 160 °C for 16 hours until LC-MS indicates the reaction is complete. After vacuum concentration, collect the residue to give 7.3 g of compounds 1-3, 100% yield.

[0341] Step 3: Add 240 mL of pyridine, 12.1 g (39.5 mmol, 1.0 eq) of compounds 1-3, and 55.1 g (197.5 mmol, 3.0 eq) of triphenylchloromethane to a 50 mL reaction flask. Stir the mixture at 50 °C for 2 hours until the reaction is confirmed to be complete by LC-MS. After vacuum concentration, the residue is purified by column chromatography (DCM - DCM:MeOH = 92:8) to give 4.5 g of compounds 1-4, in 20.8% yield.

[0342] Step 4: Add 52 mL of DCM to a 100 mL reaction flask, followed by 1.3 g (2.37 mmol, 1.0 eq) of compounds 1-4, 594 mg (7.11 mmol, 3.0 eq) of methoxyamine hydrochloride, 2.45 g (18.96 mmol, 8.0 eq) of DIPEA, 640 mg (4.74 mmol, 2.0 eq) of HOBT, and 999 mg (5.21 mmol, 2.2 eq) of EDCI. Stir the mixture at room temperature for 5 hours until the reaction is confirmed to be complete by LC-MS. After vacuum concentration, the residue was purified by column chromatography (DCM - DCM:MeOH = 91:9) to give 900 mg of compounds 1-5, in 65.8% yield.

[0343] Step 5: Add 18 mL of DCM and 900 mg (1.56 mmol, 1.0 eq) of compounds 1-5, along with 9 mL of TFA, to a 50 mL reaction flask. Stir the reaction mixture at room temperature for 2 hours until LC-MS shows the reaction is complete. After vacuum concentration, the residue is purified by column chromatography to give 670 mg of compound 1, with a yield of 98.5%. 1H NMR: (400 MHz, DMSO-d6)δ 14.33 (s, 2H), 11.79 (s, 1H), 9.00 (d, J = 0.9 Hz, 1H), 7.67 (d, J = 7.8Hz, 1H), 7.60 (s, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H),7.17 – 7.06 (m, 2H), 6.94 (s, 1H), 6.70 (d, J = 7.2 Hz, 1H), 5.91 (s, 1H),3.69 (s, 3H), 2.26 (s, 3H), 2.13 (s, 3H).LC-MS: [M-TFA+H]⁺ = 336.2 Step 6: Compound 1 was separated by chiral HPLC to obtain compounds 1-A and 1-B. A 30 × 250 mm column packed with CHIRALPAK® IG (10 µm) was used as the chiral stationary phase. A mixture of 60% mobile phase A and 40% mobile phase B (v / v) was used as the mobile phase.

[0344] Mobile phase A: n-hexane + 0.2% NH3 / MeOH Mobile phase B: EtOH + 0.2% NH3 / MeOH The operating conditions are as follows: Temperature: Ambient temperature Flow rate: 25 mL / min Detection: UV 214 nm 500 mg of compound 1 was separated by column chromatography. The first eluted enantiomer (compound 1-A) with a retention time of 4.18 min was obtained from the eluent, with an enantiomer excess (ee) of 100% and a yield of 80%. The second eluted enantiomer (compound 1-B) with a retention time of 5.83 min was obtained from the eluent, with an enantiomer excess (ee) of 99.2% and a yield of 81%.

[0345] In this application, the naming rules for separating enantiomers are systematic. "A" represents the first product eluted in the chromatography, and "B" represents the second. For compounds whose chirality results in four different products, they will be labeled "A", "B", "C", and "D" according to their elution order. Therefore, if a compound is named X, the separated products will be systematically named "XA", "XB", "XC", and "XD".

[0346] Example 2. Synthesis of Compound 8 Step 1: Under nitrogen protection, 200 mL of THF and 9.10 g (34.1 mmol, 1.5 eq) of 2,6-dibromo-1-methoxybenzene were added to a 500 mL three-necked round-bottom flask. At 0 °C, 27 mL (34.1 mmol, 1.5 eq) of isopropyl magnesium chloride lithium chlorate complex was added. The mixture was stirred at 0 °C for 6 hours, and then 10 g (22.7 mmol, 1 eq) of compound 8-1 was added at 0 °C. Stirring continued at room temperature (25 °C) for 16 hours. The reaction mixture was then poured into water, washed with EA, dried over Na2SO4, and purified by rapid silica gel column chromatography to obtain 11.3 g of compound 8-2, in 79% yield.

[0347] Step 2: Under nitrogen protection, add 113 mL of DCM, 11.3 g (18 mmol, 1.0 eq) of compound 8-2, HSiEt3 (21 g, 180 mmol, 10 eq), and TFA (21 g, 180 mmol, 10 eq) to a 250 mL three-necked round-bottom flask, maintaining the temperature at 0 °C. Stir the reaction system for 16 hours and slowly raise the temperature to room temperature. After vacuum concentration, compound 8-3 (17 g, crude product) is obtained.

[0348] Step 3: Under nitrogen protection, 17 g (18 mmol, 1.0 eq) of compound 8-3, TrtCl (12.6 g, 45 mmol, 2.5 eq), 170 mL of DCM, and Et3N (9.1 g, 90 mmol, 5 eq) were added to a 500 mL three-necked round-bottom flask. After stirring at 25 °C for 16 hours, the reaction was confirmed to be complete by LC-MS. Post-processing yielded 7.1 g of compound 8-4, with a yield of 64%.

[0349] Step 4: Under nitrogen protection, 100 mL of DMF, 6 g (9.8 mmol, 1.0 eq) of compound 8-4, Zn(CN)2 (1.26 g, 10.8 mmol, 1.1 eq), and Pd(PPh3)4 (1.26 g, 1.1 mmol, 0.11 eq) were added to a 250 mL three-necked round-bottom flask. After stirring at 120 °C for 2 hours, the reaction was confirmed to be complete by LC-MS. After standard post-treatment, 5.1 g of compound 8-5 was obtained, with a yield of 93%.

[0350] Step 5: Under nitrogen protection, add 60 mL of EtOH, 2 g (3.6 mmol, 1.0 eq) of compound 8-5, and 12 mL of 30% KOH solution to a 100 mL single-necked flask. Reflux the mixture for 72 hours. After vacuum concentration and post-treatment purification, 1.9 g of compound 8-6 is obtained, with a yield of 91%.

[0351] Step 6: Under nitrogen protection, 20 mL of DCM, 1 g (1.73 mmol, 1.0 eq) of compound 8-6, EDCI (0.432 g, 2.25 mmol, 1.3 eq), DIPEA (0.893 g, 6.92 mmol, 4 eq), HOBt (0.234 g, 1.73 mmol, 1.0 eq), and methoxyamine hydrochloride (0.174 g, 2.08 mmol, 1.2 eq) were added to a 100 mL single-necked flask. After stirring at 25 °C for 16 hours, post-treatment yielded 0.43 g of compound 8-7, in 41% yield.

[0352] Step 7: Under nitrogen protection, add 10 mL of DCM, 0.430 g (0.71 mmol, 1 eq) of compound 8-7 and BBr3 (0.435 g, 1.775 mmol, 2.5 eq) to a 25 mL single-necked flask, maintaining the temperature at 0 °C. Continue stirring at 0 °C for 3 hours until LC-MS shows the reaction is complete, then proceed to the next step.

[0353] Step 8: Under nitrogen protection, the reaction mixture from Step 7 and 10 mL of MeOH were added to a 50 mL single-necked flask. The mixture was heated under reflux for 16 hours, and the reaction was verified to be complete by LC-MS. After vacuum concentration, the mixture was further purified (including adding 10 mL of saturated NaHCO3 solution, washing with EA, drying with Na2SO4, and preparing and purifying by liquid chromatography) to obtain 39 mg of compound 8, in a yield of 16%.

[0354] 1 H NMR: (400 MHz, DMSO-d6) δ 12.25 (s, 3H), 7.57 (s, 1H), 7.52 (d, J= 7.8 Hz, 1H), 6.98 (dt, J = 15.0, 6.6 Hz, 3H), 6.79 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 6.37 (s, 1H), 5.87 (s, 1H), 3.35 (s, 1H), 2.22 (s,3H), 2.08 (s, 3H). LC-MS: [M+H]⁺ = 352.2 Example 3. Synthesis of Compound 17 Step 1: Under nitrogen protection, add 4 mL of DCM, 180 mg (0.33 mmol, 1 eq) of compound 17-1, 110 mg (1.00 mmol, 3 eq) of TEA, and 47 mg (0.5 mmol, 1.5 eq) of methylcarbamoyl chloride to a 10 mL single-necked flask, maintaining the temperature at 0 °C. After the reaction system reaches 25 °C, continue stirring for 16 hours. After confirming the completion of the reaction by LC-MS, concentrate the reaction solution under vacuum and purify it by rapid silica gel column chromatography to obtain 150 mg of compound 17-2, with a yield of 75%.

[0355] Step 2: Under nitrogen protection, 3 mL of DCM, 150 mg (0.25 mmol, 1 eq) of compound 17-2, and 1.5 mL of TFA were added to a 10 mL single-necked flask, and the temperature was maintained at 25 °C. After stirring for 2 hours and confirming the completion of the reaction by LC-MS, the reaction solution was concentrated under vacuum and purified by rapid silica gel column chromatography to obtain 33 mg of compound 17, with a yield of 28%.

[0356] Step 3: 438 mg of compound 17 was separated using a chiral column, yielding compound 17-A (133 mg) and compound 17-B (133 mg) respectively. Both were purified by preparative liquid chromatography with neutralization, ultimately yielding 101 mg of pure product each, with a yield of 23.06%.

[0357] 1 H NMR: (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.19 – 7.02 (m, 2H), 6.96 (d,J = 7.2 Hz, 1H), 6.68 (s, 1H), 5.93 (s, 1H), 4.61 (dd, J = 9.3, 4.1 Hz, 1H),3.99 – 3.87 (m, 2H), 3.84 – 3.77 (m, 1H), 3.65 (ddd, J = 17.3, 13.3, 7.2 Hz,5H), 3.46 – 3.31 (m, 2H), 2.66 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H).

[0358] LC-MS: [M-TFA+H]⁺ = 361.3.

[0359] Example 4. Synthesis of Compound 22 Step 1: Add 10 mL of ACN, 300 mg (0.793 mmol, 1 eq) of compound 22-1, 335 mg (1.58 mmol, 2 eq) of N-(2-bromoethyl)carbamate tert-butyl ester, and 387 mg (1.189 mmol, 1.5 eq) of Cs₂CO₃ to a 50 mL three-necked flask. Stir the mixture at 60 °C for 12 hours. After the reaction was complete as shown by LC-MS, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give 300 mg of compound 22-2 (white solid). This crude product was used directly in the next step of the reaction, with a yield of 72.5%.

[0360] Step 2: Add 300 mg of compound 22-2, 10 mL of DCM, and 5 mL of TFA to a 50 mL three-necked flask. Stir the mixture at room temperature (25 °C) for 12 hours. After confirming the completion of the reaction by LC-MS, dilute the reaction solution with water, adjust the pH to 10, and extract with DCM. Dry the organic phase with Na2SO4, concentrate under vacuum, and purify the residue by silica gel column chromatography to give 85 mg of compound 22-3 (yellow solid), with a yield of 45.9%.

[0361] Step 3: Add 5 mL of DMF, 75 mg (0.233 mmol, 1 eq) of compound 22-3, 75 mg (0.583 mmol, 2.5 eq) of DIPEA, and 29 mg (0.257 mmol, 1.1 eq) of methanesulfonyl chloride to a 10 mL three-necked flask. Continue stirring at 25 °C for 2 hours until LC-MS analysis confirms the completion of the reaction. Dilute the reaction solution with water, extract with EA, and concentrate the organic phase under vacuum after drying with Na2SO4. Purify by silica gel column chromatography to give 14 mg of compound 22 (white solid), yield 13.2%.

[0362] Overall yield: 4.4% LC-MS: [M+H]⁺ = 400.2 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.27 (s, 1H), 7.24 (dd, J= 13.6, 5.7 Hz, 2H), 7.04 (d, J = 11.2 Hz, 2H), 6.93 – 6.49 (m, 5H), 5.68 (s,1H), 3.96 (s, 2H), 3.29 (d, J = 4.5 Hz, 2H), 2.91 (s, 3H), 2.24 (s, 3H), 2.12(s, 3H). Example 5. Synthesis of Compound 27 Step 1: Add 10 mL of THF and 860 mg (3.39 mmol, 1.5 eq) of 1,3-dibromo-2-fluorobenzene to a 50 mL reaction flask and cool to -65 °C. Then add 1.4 mL (3.39 mmol, 1.5 eq) of n-butyllithium. After stirring at this temperature for 2 hours, add 1 g (2.26 mmol, 1 eq) of compound 27-1 and another 10 mL of THF. Continue stirring at -65 °C for 30 minutes, then allow to warm naturally to room temperature for 16 hours. After LC-MS verification of the reaction completion, add 20 mL of saturated ammonium chloride solution. Separate the organic phase, concentrate under vacuum, and purify by column chromatography to obtain 600 mg of compound 27-2, in 43% yield.

[0363] Step 2: Add 600 mg (0.971 mmol, 1 eq) of compound 27-2, 1.1 g (9.71 mmol, 10 eq) of triethylsilane, and 1.1 g (9.71 mmol, 10 eq) of TFA to a 50 mL three-necked flask. Stir the mixture at 25 °C for 1 hour. After confirming the reaction was complete by LC-MS, pour the reaction solution into water, adjust the pH to 10, extract with EA, dry to Na₂SO₄, and concentrate under vacuum. Purify by silica gel column chromatography to obtain 170 mg of compound 27-3 (yellow solid), yield 48.7%.

[0364] Step 3: Add 10 mL of DMF, 170 mg (0.473 mmol, 1 eq) of compound 27-3, 158 mg (0.568 mmol, 1.2 eq) of triphenylchloromethane, and 96 mg (0.946 mmol, 2 eq) of TEA to a 25 mL reaction flask. Stir the mixture at 25 °C for 12 hours until LC-MS shows the reaction is complete. Pour the reaction solution into water, extract with EA, dry to Na₂SO₄, concentrate, and purify the crude product by column chromatography to obtain 220 mg of compound 27-4, yield 77.3%.

[0365] Step 4: Add 10 mL of DMF, 170 mg (0.283 mmol, 1 eq) of compound 27-4, 100 mg (0.848 mmol, 3 eq) of Zn(CN)2, and 98 mg (0.0848 mmol, 0.3 eq) of Pd(PPh3)4 to a 25 mL reaction flask. Stir at 150 °C for 30 minutes in a microwave reactor. After confirming the completion of the reaction by LC-MS, 130 mg of compound 27-5 was obtained by post-processing and column chromatography purification, with a yield of 84%.

[0366] Step 5: Add 10 mL of DMSO and 110 mg (0.201 mmol, 1 eq) of compound 27-5 to a 25 mL reaction flask and cool to 0 °C. Then add 3 mL of 30% H2O2 and stir the mixture at 0 °C for 1 hour. After confirming the completion of the reaction by LC-MS, quench with water, separate the organic phase, concentrate under vacuum, and purify by column chromatography to obtain 100 mg of compound 27-6, in 88.1% yield.

[0367] Step 6: Add 10 mL of DCM and 110 mg of compound 27-6 to a 25 mL three-necked flask, and add 5 mL of TFA at 0 °C. Allow the mixture to rise naturally to room temperature and stir for 2 hours. After the reaction is complete as shown by LC-MS, concentrate under reduced pressure, and purify the residue by thin-layer chromatography to give 25 mg of compound 27 (white solid), yield 29.4%.

[0368] Total yield: 3.5% LC-MS: [M-C2HF3O2+1]+=324.2.

[0369] 1 H NMR(400 MHz, DMSO) δ 14.36 (s, 5H), 8.97 (s, 3H), 7.77 (s, 3H),7.64 (s, 3H), 7.60 (t, J= 6.7 Hz, 3H), 7.24 (t, J = 7.7 Hz, 3H), 7.15 (d, J = 7.3Hz, 3H), 7.13 – 6.98 (m, 9H), 6.71 (d, J = 7.5 Hz, 3H), 6.01 (s, 3H), 2.27 (s, 9H), 2.12 (s, 9H).

[0370] Example 6. Synthesis of Compound 28 Step 1: Add 220 mL of DMF, 24.5 g (0.13 mol, 1 eq) of compound 28-1, 26.6 g (0.16 mol, 1.2 eq) of benzyl bromide, and 21.5 g (0.16 mol, 1.2 eq) of K2CO3 to a 500 mL reaction flask. Heat the mixture to 95 °C and react for 16 hours. After confirming the completion of the reaction by GC-MS, the mixture was filtered, concentrated, and purified by column chromatography to obtain 32 g of compound 28-2, with a yield of 88.5%.

[0371] Step 2: Add 5 mL THF, 185 mg (7.6 mmol, 2.1 eq) magnesium shavings, and 2 g (7.2 mmol, 2.0 eq) of compound 28-2 to a 25 mL reaction flask. Stir the mixture at 65 °C for 1 hour, then cool to room temperature. Add 20 mL THF and 1.59 g (3.6 mmol, 1.0 eq) (2,3-dimethylphenyl)-[1-(triphenylmethyl)-1H-imidazol-4-yl] methyl ketone to a 50 mL reaction flask. After adding the Grignard reagent prepared above, heat the reaction system to 80 °C and react for 16 hours. Verify the completion of the reaction by LC-MS, quench with 10 mL of water, extract with EA, dry with Na2SO4, concentrate, and purify by column chromatography to obtain 1.6 g of compound 28-3, with a yield of 69.2%.

[0372] Step 3: Add 14 mL of DCM, 1.4 g (2.18 mmol, 1.0 eq) of compound 28-3, and 2.53 g (21.8 mmol, 10 eq) of TES to a 100 mL reaction flask. After cooling to 0 °C, add 2.48 g (21.8 mmol, 10 eq) of TFA. Heat the mixture to 25 °C and react for 5 hours. Concentrate under vacuum after LC-MS confirmation of reaction completion. The residue was purified by column chromatography to give 500 mg of compound 28-4, in 68.4% yield.

[0373] Step 4: Add 2 mL THF, 100 mg (0.29 mmol, 1.0 eq) of compound 28-4, 7 mg (0.06 mmol, 0.2 eq) of DMAP, 94 mg (0.43 mmol, 1.5 eq) of Boc2O, and 44 mg (0.43 mmol, 1.5 eq) of TEA to a 5 mL reaction flask. React at 25 °C for 4 hours, and LC-MS confirms the completion of the reaction. After vacuum concentration, the residue is purified by column chromatography to give 120 mg of compound 28-5, in 85.5% yield.

[0374] Step 5: Add 1.5 mL of acetic acid, 0.5 mL of water, and 120 mg (0.25 mmol, 1.0 eq) of compound 28-5 to a 10 mL reaction flask. After cooling to 0 °C, add 165 mg (1.24 mmol, 5 eq) of NCS. Stir the mixture at 0 °C for 2 hours. After confirming the reaction is complete by LC-MS, proceed directly to the next step. The yield is assumed to be 100%.

[0375] Step 6: Add 10 mL of 2M CH3NH2 / THF solution to a 50 mL reaction flask, cool to 0°C, and then add the crude compound 28-6 from the previous step. Stir at 25°C for 16 hours, and monitor the reaction progress by LC-MS. After vacuum concentration, the mixture is purified by column chromatography to obtain 40 mg of compound 28-7, with a yield of 40%.

[0376] Step 7: Add 1 mL of DCM and 40 mg (0.088 mmol, 1.0 eq) of compound 28-7 to a 5 mL reaction flask. After cooling the mixture to 0°C, add 0.5 mL of TFA, then heat to 25°C and react for 2 hours. LC-MS showed that the reaction was complete. After concentration, the compound 28 was purified by prep-HPLC to obtain 14 mg of compound 28, with a yield of 44.8%.

[0377] Overall yield = 6.4%.

[0378] LC-MS: [M+1-TFA] + = 356.1 1 H NMR (400 MHz, 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, 6.3 Hz, 2H), 7.12 (dt,J =15.1, 7.4 Hz, 2H), 6.95 (s, 1H), 6.68 (d, J = 7.4 Hz, 1H), 2.37 (d, J = 4.9 Hz, 3H), 2.26 (s, 3H), 2.12 (s, 3H).

[0379] Example 7. Synthesis of Compound 31 Step 1: Add 120 mL of THF and 5.08 g (27.15 mmol, 4.0 eq) of 4-bromo-2-methoxypyridine to a 250 mL three-necked reaction flask. Slowly add 10 mL of a 2.5 M n-butyllithium solution in n-hexane (25.1 mmol, 3.7 eq) at -65 °C. Maintain the solution at -65 °C for 1 hour, then add 3 g (6.79 mmol, 1 eq) of compound 31-1. Continue the reaction at -65 °C for 0.5 hours, then allow the reaction to proceed overnight at room temperature. LC-MS confirms the completion of the reaction. Quench the reaction with 100 mL of saturated ammonium chloride, separate the organic layer, and concentrate. Mix the residue with 50 mL of DCM, stir for 5 minutes, filter, and dry under an infrared lamp to give 2.88 g of compound 31-2, yield 77%.

[0380] Step 2: Add 20 mL of 57 wt.% HI, 2.35 g (4.599 mmol, 1.0 eq) of compound 31-2, and 1.43 g (45.99 mmol, 10 eq) of red phosphorus to a 50 mL sealed reaction vessel. Stir overnight at 160 °C. After the reaction is complete as detected by LC-MS, cool the mixture to room temperature and concentrate to obtain 5 g of crude compound 31-3, with a yield of 100%.

[0381] Step 3: Add compound 31-3 (1 g, crude) and 15 mL POCl3 to a 5 mL reaction flask. Reflux overnight and verify the reaction completion by LC-MS. Cool the mixture, concentrate under vacuum, and neutralize the residue to pH 8 with saturated sodium bicarbonate solution. Extract with 40 mL EA (three times), dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography to give 174 mg of compound 31-4, yield 30%.

[0382] Step 4: Add 174 mg (0.586 mmol, 1 eq) of compound 31-4, 10 mL of MeOH, 296 mg (2.93 mmol, 5 eq) of TEA, and 48 mg (0.0586 mmol, 0.1 eq) of PdCl2 (dppf) to a 200 mL high-pressure reactor. React at 120 °C for 48 hours under a carbon monoxide pressure of 5 MPa. LC-MS showed 5% of the starting material remaining. After filtration and concentration, 270 mg of compound 31-5 was obtained by column chromatography, with a yield of 100%.

[0383] Step 5: Add 100 mg (0.312 mmol, 1 eq) of compound 31-5 and 5 mL of MeOH / NH3 solution (15 mol / L) to a 50 mL sealed reaction vessel. Stir the mixture overnight at 68 °C, cool to room temperature, concentrate under vacuum, and purify by prep-HPLC to obtain 10 mg of compound 31, yield 10%.

[0384] LC-MS: [M+1] + =307.2.

[0385] 1 H NMR (400 MHz, DMSO) δ 12.53 (s, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.10(s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.35 (d, J = 3.8 Hz, 1H),7.10 – 7.00 (m, 2H), 6.81 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 5.80 (s, 1H), 2.24 (s, 3H), 2.11 (s, 3H).

[0386] Example 8. Synthesis of Compound 32 Step 1: Add 300 mg (0.51 mmol, 1 eq) of compound 32-1, 108 mg (1.54 mmol, 3 eq) of 2-cyanoethylamine, 213 mg (1.54 mmol, 3 eq) of K2CO3, 47 mg (0.051 mmol, 0.1 eq) of Pd2(dba)3 and 55 mg (0.10 mmol, 0.2 eq) of BrettPhos to a 50 mL single-necked flask. Under nitrogen protection, stir the mixture at 120 °C for 1 hour. After the reaction was complete as monitored by TLC, pour the reaction mixture into 100 mL of water and extract three times with 50 mL of EA. Wash the organic layer with 50 mL of brine, dry to Na2SO4, and concentrate under vacuum to obtain 1 g of yellow oily crude product. Purification by column chromatography (PE:EA = 1:0 → 1:1) yielded 216 mg of compound 32-2 (yellow powder), with a yield of 73.36%.

[0387] Step 2: Add 200 mg (0.35 mmol, 1 eq) of compound 32-2, 5 mL of DCM, and 1 mL of TFA to a 50 mL single-necked flask. Stir the mixture at room temperature for 1 hour, and confirm the completion of the reaction by TLC. After vacuum concentration of the solution, the crude product was purified by column chromatography (DCM:MeOH = 1:0 → 90:10) to obtain 120 mg of compound 32, which was then purified by preparative HPLC to obtain 93 mg of compound 32 (yellow powder). The yield of this step was 59.92%.

[0388] Total yield = 43.96%.

[0389] LC-MS: [M+1] + =331.2. 1H NMR(400 MHz, DMSO) δ 14.18 (s, 2H), 8.91 (s, 1H), 7.15 – 7.01 (m,3H), 6.90 (s, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.41(s, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 5.65 (s, 1H), 3.49 – 3.13(m, 5H), 2.67 (t, J = 6.5 Hz, 2H), 2.25 (s, 3H), 2.13 (s, 3H). Y=59.92%.Total yield = 43.96%. Example 9. Synthesis of Compound 58 Step 1: Add 40 mL of THF and 4 g (15.5 mmol, 2.5 eq) of 2-chloro-3-fluoro-4-iodopyridine to a 100 mL reaction flask. After cooling the mixture to 0 °C, add 12 mL (15.5 mmol, 2.5 eq) of isopropyl magnesium chloride lithium chlorate complex. Stir the reaction at 0 °C for 3 hours, then add 1.16 g (2.63 mmol, 1.0 eq) of (2,3-dimethylphenyl)[1-(triphenylmethyl)-1H-imidazol-4-yl] methyl ketone and stir at 80 °C for 16 hours. After confirming the completion of the reaction by LC-MS, quench the reaction with 40 mL of water and extract with EA. Dry the organic layer with Na2SO4 and concentrate under vacuum. Purify the residue by column chromatography to give 2.6 g of compound 58-1, yield 29.3%.

[0390] Step 2: 1 g (1.74 mmol, 1.0 eq) of compound 58-1, 40 mL of MeOH, 40 mL of DMSO, 530 mg (5.24 mmol, 3.0 eq) of TEA, and 148 mg (0.17 mmol, 0.1 eq) of PdCl2 (dppf) were added to a 200 mL high-pressure reactor. The reaction was carried out at 100 °C for 48 hours under a carbon monoxide pressure of 5 MPa. LC-MS showed a 5% residue of starting material. After concentration, the residue was purified by column chromatography to give 53 mg of compound 58-2, with a yield of 51.2%.

[0391] Step 3: Add 25 mL of 16 M NH3 / MeOH solution and 530 mg (0.89 mmol, 1.0 eq) of compound 58-2 to a 50 mL sealed tube. Stir at 30 °C for 16 hours. After the reaction was confirmed by LC-MS, the residue was purified by column chromatography to give 360 ​​mg of compound 58-3, with a yield of 67.8%.

[0392] Step 4: Add 3 mL of DCM, 100 mg (0.17 mmol, 1.0 eq) of compound 58-3, and 195 mg (1.7 mmol, 10 eq) of TES to a 10 mL reaction flask. After cooling to 0 °C, add 191 mg (1.7 mmol, 10 eq) of TFA. Heat the reaction system to 100 °C and react for 3.5 hours. After the reaction is complete as shown by LC-MS, concentrate under vacuum, and purify the residue by prep-HPLC to obtain 16 mg of compound 58, with a yield of 28.8%.

[0393] LC-MS: [M +1]+ = 325.2 1 H NMR (400 MHz, CD3OD) δ 8.36 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 0.9Hz, 1H), 7.13 (dt, J = 22.7, 10.1 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.72 (d,J = 7.7 Hz, 1H), 6.53 (s, 1H), 6.05 (s, 1H), 2.32 (s, 3H), 2.21 (s, 3H). Example 10. Synthesis of Compound 60 Step 1: Add 29 mL of THF and 2.9 g (43.9 mmol, 7.5 eq) of zinc powder to a 100 mL three-necked flask. Cool the mixture to -10 °C and stir under nitrogen protection. Then, slowly add 4.1 g (21.6 mmol, 3.7 eq) of titanium tetrachloride at -10 °C. Stir the reaction mixture at 70 °C for 16 hours, then add 950 mg (6.08 mmol, 1.04 eq) of methyl 3-oxocyclohexanecarboxylate and 2.6 g (5.85 mmol, 1 eq) of (2,3-dimethylphenyl)(1-triphenylmethyl-1H-imidazol-4-yl) methyl ketone. Continue stirring at 80 °C for 4 hours. After confirming the reaction is complete by LC-MS, dilute with 100 mL of water and 100 mL of EA, filter, and extract the filtrate with EA. The product was washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 950 mg of crude compound 60-1, with a yield of 50%.

[0394] Step 2: Add 10 mL of DCM, 0.5 g (1.54 mmol, 1 eq) of compound 60-1, and 10 mL of HCl / Et2O solution to a 25 mL three-necked flask. Stir the mixture at room temperature for 3 hours. LC-MS showed that the reaction was complete. After concentration under reduced pressure, 400 mg of crude compound 60-2 was obtained, with a yield of 100%.

[0395] Step 3: Add 1.2 mL AcOH, 0.9 mL hydroiodic acid (55%-58%), 50 mg (0.15 mmol, 1.0 eq) of compound 60-2, and 167 mg (5.4 mmol, 35 eq) of red phosphorus to a 250 mL three-necked flask. Stir the reaction mixture at 100 °C for 16 hours. After confirming the completion of the reaction by LC-MS, pour the mixture into water, adjust the pH to 7, and extract with EA. Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain 70 mg of crude product. Purify by liquid chromatography to obtain 6 mg of compound 60, yield 10%.

[0396] Total yield: 5% LC-MS: [M-TFA-1]-=311.2 1H NMR(400 MHz, 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, 9.0 Hz, 3H), 4.26 – 4.06(m, 1H), 2.28 – 2.08 (m, 8H), 1.91 – 0.73 (m, 8H). Example 11. Synthesis of Compound 61 Step 1: Add 20 mL of toluene, 3.8 g (16.7 mmol, 1.0 eq) of methyl 3-(bromomethyl)benzoate, and 3.04 g (18.3 mmol, 1.1 eq) of triethyl phosphite to a 50 mL reaction flask. Stir the mixture at 110 °C for 16 hours. After confirming the completion of the reaction by LC-MS, concentrate the solution. Purify the residue by column chromatography to give 5.3 g of compound 61-1, 99% yield.

[0397] Step 2: Add 40 mL THF, 2 g (7.0 mmol, 1.0 eq) of compound 61-1, and 3.4 g (7.7 mmol, 1.1 eq) of (2,3-dimethylphenyl)(1-triphenylmethyl-1H-imidazol-4-yl) methyl ketone to a 100 mL reaction flask. After cooling to 0 °C, add 2.35 g (21 mmol, 3.0 eq) of potassium tert-butoxide. Stir at 27 °C for 16 hours. After confirming the completion of the reaction by LC-MS, concentrate the solution and purify by column chromatography to obtain 1.03 g of compound 61-2, with a yield of 26.3%.

[0398] Step 3: Add 10 mL of DCM and 500 mg of compound 61-2 to a 25 mL reaction flask, followed by 2.5 mL of TFA. Stir the reaction mixture at 27 °C for 1 hour. After the reaction was complete as indicated by LC-MS, concentrate the reaction solution, and purify the residue by column chromatography to give 240 mg of compound 61-3, with a yield of 84.5%.

[0399] Step 4: Add 3 mL THF, 240 mg of compound 61-3, and 120 mg of Pd / C (50%) to a 10 mL reaction flask. Stir at 27 °C for 16 hours, and filter after confirming the completion of the reaction by LC-MS. After concentrating the organic phase, the residue was purified by column chromatography to give 150 mg of compound 61-4, with a yield of 62.1%.

[0400] Step 5: Add 3 mL of DMF, 80 mg (0.25 mmol, 1.0 eq) of compound 61-4, and 209 mg (2.5 mmol, 10 eq) of methoxyamine hydrochloride to a 10 mL reaction flask. After cooling to 0 °C, add 386 mg (3 mmol, 12 eq) of DIPEA and 142 mg (0.37 mmol, 1.5 eq) of HATU. Stir at 27 °C for 4.5 hours. LC-MS showed 40% of the starting material remaining. Vacuum concentration yielded 160 mg of compound 61-5, 100% yield.

[0401] Step 6: Add 1 mL of DCM and 160 mg of compound 61-5 to a 10 mL reaction flask, followed by 0.5 mL of TFA. Stir at 27 °C for 1 hour. After confirming the completion of the reaction by LC-MS, concentrate under vacuum. The residue is purified by prep-HPLC to obtain 25 mg of compound 61, with a yield of 15.3%.

[0402] Total yield: 2.1% LC-MS: [M –C2HF3O2+1]+= 350.2 1H NMR (400 MHz, DMSO) δ 14.20 (s, 2H), 11.69 (s, 1H), 8.96 (d, J =0.9 Hz, 1H), 7.61 (d, J = 4.6 Hz, 2H), 7.55 – 7.48 (m, 1H), 7.31 (t, J = 6.4Hz, 2H), 7.07 (dt, J = 12.8, 4.6 Hz, 3H), 4.74 (t, J = 7.9 Hz, 1H), 3.70 (s,3H), 3.39 (d, J = 8.5 Hz, 1H), 3.19 (dd, J = 13.8, 7.3 Hz, 1H), 2.21 (s, 3H), 2.12 (s, 3H). Example 12. Synthesis of Compound 139 LC-MS: [M-C₂HF₃O₂+1]⁺=422.2 1H NMR (400 MHz, DMSO) δ 14.20 (s, 2H), 9.00 (s, 1H), 7.58 (s, 1H), 7.21 – 6.95 (m, 3H), 6.86 (d, J = 7.5 Hz, 1H), 4.65 (dd, J = 8.2, 5.3 Hz,1H), 3.90 (t, J = 9.3 Hz, 1H), 3.78 (dd, J = 16.0, 8.9 Hz, 3H), 3.50 (d, J =5.1 Hz, 2H), 3.28 (t, J = 11.2 Hz, 2H), 3.09 (dd, J = 11.1, 5.4 Hz, 2H), 2.92(d, J = 6.3 Hz, 2H), 2.28 (s, 6H), 2.00 (d, J = 4.4 Hz, 1H), 1.72 (d, J =12.9 Hz, 2H), 1.28 (qd, J = 12.2, 4.1 Hz, 2H). Example 13. Synthesis of Compound 156 Step 1: In a 100 mL single-necked flask, under a nitrogen atmosphere, add 50 mL of THF, 5 g (11.29 mmol, 1.0 eq) of (2,3-dimethylphenyl)(1-triphenylmethyl-1H-imidazol-4-yl) methyl ketone, 2.3 g (18.1 mmol, 1.6 eq) of ethyl chloroacetate, and 1.35 g (33.9 mmol, 3 eq, 60% wt) of sodium hydride. The mixture is stirred at 25 °C for 16 hours, and the reaction is confirmed by LC-MS under vacuum concentration. 50 mL of 10% KOH solution is added, and the mixture is stirred at 100 °C for another 16 hours. After post-treatment, the mixture is purified by rapid silica gel column chromatography to obtain 3.4 g of compound 139-1, with a yield of 65.9%.

[0403] Step 2: Add 60 mL of ACN, 3.2 g (7.01 mmol, 1 eq) of compound 139-1, 3.14 g (14.02 mmol, 2 eq) of CAS 39684-80-5, and 3.42 g (10.51 mmol, 1.5 eq) of Cs₂CO₃ to a 100 mL three-necked flask. Stir at 60 °C for 12 hours. After LC-MS confirmation of the reaction completion, 930 mg of compound 139-2 was obtained after post-processing and purification, with a yield of 22.1%.

[0404] Step 3: Add 300 mg of compound 139-2, 3 mL of DCM, and 3 mL of 4M HCl / dioxane solution to a 25 mL three-necked flask. Stir at 25 °C for 3 hours. After confirming the completion of the reaction by LC-MS, neutralize the reaction solution to pH=10 and extract and purify to obtain 130 mg of compound 139-3 (white solid), yield 52%.

[0405] Step 4: Add 5 mL of THF, 130 mg (0.260 mmol, 1 eq) of compound 139-3, 40 mg (0.390 mmol, 1.5 eq) of TEA, and 57 mg (0.286 mmol, 1.1 eq) of (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (CAS 264608-29-9) to a 25 mL three-necked flask. Stir at 25 °C for 18 hours. After the reaction was confirmed by LC-MS, the product was purified by post-processing to give 80 mg of compound 139-4 (white solid), yield 46.5%.

[0406] Step 5: Compound 139-4 (80 mg) was mixed with Pd(OH)2 / C (80 mg), 5 mL methanol, and 5 mL THF, and stirred at 40 °C for 18 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated. 10 mL DCM and 5 mL TFA were added, and the mixture was stirred for 10 minutes and dried. The residue was purified by preparative HPLC to give 30 mg of compound 139 (white solid), with a yield of 46.3%.

[0407] Total yield: 3.5% LC-MS: [M-C₂HF₃O₂+1]⁺=338.2 1H NMR(400 MHz, DMSO) δ 14.25 (s, 2H), 8.97 (s, 1H), 7.65 – 7.48 (m,4H), 7.09 (dt, J = 14.4, 7.2 Hz, 5H), 4.78 (t, J = 7.9 Hz, 1H), 3.42 (dd, J =13.9, 8.5 Hz, 1H), 3.22 (dd, J = 13.9, 7.3 Hz, 1H), 2.23 (s, 3H), 2.16 (s,3H). Example 14. Synthesis of Compound 182 Step 1: Add 20 mL of DMF, 2 g (9.66 mmol, 1.0 eq) of 4-bromo-2-thiophenecarboxylic acid, 2.93 g (28.98 mmol, 3.0 eq) of TEA, and 1.21 g (14.49 mmol, 1.5 eq) of methoxyamine hydrochloride to a 50 mL reaction flask. After adding 4.41 g (11.59 mmol, 1.2 eq) of HATU, stir the mixture at room temperature for 12 hours. After confirming the completion of the reaction by LC-MS, quench the reaction with water and extract with EA. Dry the sample with Na2SO4, filter, and purify the concentrate by column chromatography (PE:EA=67:33) to give 1.25 g of compound 182-1 (white solid), yield 54.8%.

[0408] Step 2: In a 25 mL three-necked flask, 598 mg (2.53 mmol, 2.0 eq) of compound 182-1 was dissolved in 6 mL of THF and cooled to -80 °C under nitrogen protection. Butyllithium (2.5 M, 2.5 mL, 6.33 mmol, 5.0 eq) was added, and the mixture was stirred for 40 minutes. Then, 6 mL of THF solution containing 560 mg (1.27 mmol, 1.0 eq) of (2,3-dimethylphenyl)(1-triphenylmethyl-1H-imidazol-4-yl) methyl ketone was added. After stirring for 1 hour, the mixture was quenched with water, heated, and extracted with EA. The organic phase was dried, filtered, concentrated, purified by column chromatography (DCM:MeOH = 90:10), and recrystallized from PE:MTBE = 2:1 to give 67 mg of compound 182-2 (a pale yellow solid), in 8.8% yield.

[0409] Step 3: Add 1 mL DCM, 1 mL TFA, 65 mg (0.11 mmol, 1.0 eq) of compound 182-2 and 38 mg (0.33 mmol, 3.0 eq) of TES to a 10 mL reaction flask. Stir for 2 hours, confirm the reaction is complete by LC-MS, concentrate and purify by preparative HPLC to obtain 20 mg of compound 182 (white solid), yield 42.1%.

[0410] Total yield = 2.03% LC-MS: [M-C₂HF₃O₂+1]⁺=342.1 1H NMR (400 MHz, DMSO) δ 14.36 (s, 2H), 11.75 (s, 1H), 9.06 (s, 1H), 7.46 (s, 2H), 7.12 (p, J = 7.4 Hz, 3H), 6.75 (d, J = 7.3 Hz, 1H), 5.88 (s,1H), 3.67 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H). Example 15. Synthesis of Compound 188 Step 1: Thionyl chloride (0.582 mL, 8.03 mmol, 0.1 eq) was added to a methanol solution of adamantane-1,3-dicarboxylic acid (18 g, 80.27 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 85 °C for 12 hours, and the reaction was confirmed to be complete by LC-MS. After concentration, the mixture was diluted with water (50 mL), neutralized to pH 8 with saturated NaHCO3, extracted with EA (30 mL × 3), dried, and concentrated to give 20 g of compound 188-1 (white solid), with a yield of 100%.

[0411] Step 2: Compound 188-1 (20 g, 79.27 mmol, 1.0 eq) was dissolved in methanol (350 mL), and NaBH4 (14.99 g, 0.39 mol, 5.0 eq) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours until the reaction was confirmed to be complete. The reaction solution was concentrated, diluted with EA, washed with water, and dried to obtain 5 g of compound 188-2 (white solid), with a yield of 11.7%.

[0412] Step 3: Add DMSO (50 mL), compound 188-2 (4 g, 17.83 mmol, 1.0 eq), Py·SO3 (7.1 g, 44.58 mmol, 2.5 eq), and TEA (4.51 g, 44.58 mmol, 2.5 eq) to a 250 mL reaction flask. Stir at 25 °C for 1 hour. After LC-MS verification, the mixture was purified to obtain 2 g of compound 188-3 (white solid), yield 51.3%.

[0413] Step 4: In a 50 mL reaction flask, THF (20 mL) was mixed with zinc powder (1.1 g, 16.87 mmol, 7.5 eq) and TiCl4 (1.58 g, 8.32 mmol, 3.7 eq) at -70 °C. Then, compound 188-3 (500 mg, 2.25 mmol, 1.0 eq) and a THF solution of the specific compound were added. The mixture was stirred at 80 °C for 2 hours. After the reaction was complete, post-treatment purification yielded 270 mg of compound 188-4 (yellow solid), with a yield of 19.1%.

[0414] Step 5: Compound 188-4 (200 mg) was reacted with NaOH (5 mL, 8 M) in methanol at 20 °C, heated to 115 °C and reacted for 12 hours. After cooling, the pH was adjusted to 4, and the mixture was extracted and concentrated to obtain 80 mg of compound 188-5 (yellow solid), with a yield of 40.8%.

[0415] Step 6: Compound 188-5 (60 mg, 0.096 mmol, 1.0 eq) was mixed with oxaloyl chloride (36.92 mg, 0.291 mmol, 3.0 eq) in DCM (1 mL) at 0 °C and stirred at 15 °C for 1 hour. The mixture was concentrated to obtain 60 mg of compound 188-6 (white solid) in 100% yield, which was used directly in the next step.

[0416] Step 7: Dissolve compound 188-6 (60 mg) in THF (0.5 mL), treat with ammonia / THF solution (8 mL) at 0 °C, stir at 15 °C for 1 hour, and concentrate to obtain 60 mg of compound 188-7 (white solid), with a yield of 100%, which can be used directly in the next step.

[0417] Step 8: Compound 188-7 (60 mg) and Pd(OH)2 (60 mg) were mixed in MeOH:THF (16 mL, 1:1) and stirred under a hydrogen atmosphere at 45 °C. After concentration, the mixture was treated with DCM (1 mL) and TFA (0.5 mL) and purified to give 20 mg of compound 188 (white solid), with a yield of 43.4%.

[0418] Total yield = 0.2%.

[0419] LC-MS: [M-C₂HF₃O₂+1]⁺=378.2 1H NMR (400 MHz, DMSO) δ 14.20 (s, 2H), 8.96 (s, 1H), 7.66 (s, 1H), 7.03 (t, J = 6.2 Hz, 3H), 6.89 (s, 1H), 6.67 (s, 1H), 4.53 (dd, J = 8.5, 3.6Hz, 1H), 2.27 (d, J = 16.9 Hz, 6H), 2.06 (dd, J = 14.4, 9.0 Hz, 1H), 1.95 (s,2H), 1.68 – 1.21 (m, 13H). Example 16. Synthesis of Compound 196 Step 1: Add zinc powder (5.6 g, 85 mmol, 19 eq) to THF (20 mL), and slowly add TiCl4 (8.2 g, 43 mmol, 9.6 eq) dropwise at 0 °C. Heat the reaction system to 70 °C and reflux for 1 hour. After cooling to 30 °C, add a THF solution containing 2,3-dihydro-benzo[1,4]dioxane-6-carboxaldehyde (1.8 g, 10.8 mmol, 2.4 eq) and (2,3-dimethylphenyl)(1-triphenylmethyl-1H-imidazol-4-yl) methyl ketone (2 g, 4.5 mmol, 1 eq), and reflux at 65 °C for 2 hours under nitrogen protection. After confirming the completion of the reaction by LC-MS, quench the reaction with water, extract with EA, and concentrate by drying. The compound 196-1 (white solid) was purified by column chromatography, yielding 2.1 g of compound 196-1 in 100% yield.

[0420] Step 2: Compound 196-1 (100 mg, 0.37 mmol, 1 eq) 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 the completion of the reaction by LC-MS, the mixture was filtered and concentrated to obtain the crude product. DCM (2 mL) and TFA (1 mL) were added to the crude product, and after concentration, it was purified by preparative HPLC to obtain 12 mg of compound 196 (white solid), with a yield of 9.7%.

[0421] Overall yield = 9.7%.

[0422] LCMS: [M-C₂HF₃O₂+1]⁺=335.2 1H NMR (400 MHz, 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, 4.9 Hz, 2H), 6.59 (dd, J = 8.2, 1.6Hz, 1H), 4.64 (t, J = 7.7 Hz, 1H), 4.16 (s, 4H), 3.22 (dd, J = 13.9, 8.8 Hz, 1H), 3.01 (dd, J = 13.9, 6.8 Hz, 1H), 2.23 (s, 3H), 2.15 (s, 3H). Example 17. Synthesis of Compound 401 Step 1: Add 50 mL of DCM and 4-iodo-1-triphenylmethyl-1H-imidazole (11.8 g, 27 mmol, 1.0 eq) to a 100 mL reaction flask. After cooling the mixture to 0 °C, add iPrMgCl·LiCl (1.3 mol / L, 20.7 mL, 27 mmol, 1.0 eq). Stir the mixture at 0 °C for 2 hours, then add 3-bromobenzaldehyde (5 g, 27 mmol, 1.0 eq). Continue stirring at 28 °C for 16 hours until the reaction is confirmed to be complete by LC-MS. After cooling to 0 °C, quench the reaction with 44 mL of saturated ammonium chloride, separate the organic layer, concentrate and purify by EA column chromatography to give 7.1 g of compound 401-1, yield 53%.

[0423] Step 2: Add 180 mL of DCM, compound 401-1 (6.1 g, 12.35 mmol, 1.0 eq), and MnO2 (6.44 g, 74.1 mmol, 6.0 eq) to a 200 mL high-pressure tube. Stir the mixture at 72 °C for 5 hours. After LC-MS verification of the reaction completion, filter to obtain 5.6 g of compound 401-2, yielding 83.9%.

[0424] Step 3: Add 500 mL of Et₂O and 20 g (82.67 mmol, 1 eq) of 3,4-dibromothiophene (CAS: 3141-26-2) to a 1 L reactor. After cooling to -78 °C, slowly add 36.37 mL (90.94 mmol, 1.1 eq) of n-butyllithium. Stir the mixture at -78 °C for 30 minutes, then slowly add 14.02 g (90.94 mmol, 1.1 eq) of diethyl sulfate. Continue stirring at 25 °C for 5 hours until the reaction is confirmed to be complete by LC-MS. After adding 25 mL of ammonia, separate the organic phase, dry it with anhydrous Na₂SO₄, filter and concentrate to give 10 g of compound 401-3, yield 63.3%.

[0425] Step 4: Add 5 mL of THF and 387.28 mg (2.03 mmol, 2 eq) of compound 401-3 to a 50 mL reaction flask. After cooling to -78 °C, slowly add 0.81 mL (2.03 mmol, 2 eq) of n-butyllithium. After stirring at -78 °C for 30 min, add 5 mL of THF solution containing 500 mg (1.01 mmol, 1.0 eq) of compound 401-2. Then stir at 25 °C for 12 h, and LC-MS shows the reaction is complete. Dilute the reaction solution with 20 mL of water, extract the aqueous phase with EA (3 × 5 mL), combine the organic layers, wash with brine (3 × 5 mL), dry to anhydrous Na₂SO₄, filter and concentrate. The crude product is purified by column chromatography to give 400 mg of compound 401-4, yield 65.2%.

[0426] Step 5: Add 7 mL of dioxane, 340 mg (0.561 mmol, 1.0 eq) of compound 401-4, 64.08 mg (0.67 mmol, 1.2 eq) of methanesulfonamide, 10.28 mg (0.011 mmol, 0.02 eq) of Pd2(dba)3, 9.54 mg (0.022 mmol, 0.04 eq) of tBuXPhos, and 365.85 mg (1.12 mmol, 2 eq) of Cs2CO3 to a 25 mL reaction flask. Stir the mixture at 100 °C for 5 hours. After LC-MS confirmation of reaction completion, concentrate under vacuum and purify by column chromatography to obtain 100 mg of compound 401-5, in 35.2% yield.

[0427] Step 6: Add 1 mL DCM, 0.1 mL TFA, 0.3 mL TES, and 100 mg (1.0 eq) of compound 401-5 to a 5 mL reaction flask. Stir the mixture at 25 °C for 2 hours. LC-MS showed the reaction was complete. After vacuum concentration, the mixture was purified by prep-HPLC to obtain 10 mg of compound 401, with a yield of 17.2%.

[0428] Total yield = 2.5%.

[0429] LCMS: [M-C2HF3O2+1]+=362.1 1H NMR (400 MHz, DMSO) δ 14.37 (s, 2H), 9.79 (s, 1H), 9.06 (d, J = 0.7Hz, 1H), 7.34 (dd, J = 10.3, 5.4 Hz, 1H), 7.25 (d, J = 3.0 Hz, 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 = 7.4 Hz, 3H). Example 18. Synthesis of Compound 502 Step 1: Add 250 mL of ACN, 25 g (0.15 mol, 1 eq) of compound 502-1, 31.5 g (0.16 mol, 1.05 eq) of diethyl chloromalonic acid, and 43 g (0.31 mol, 2 eq) of K2CO3 to a 500 mL three-necked flask. Reflux the reaction mixture overnight at 80 °C. After confirming the completion of the reaction by LC-MS, concentrate under vacuum and purify by silica gel column chromatography to give 40 g of compound 502-2, in 83% yield.

[0430] Step 2: In a 1 L three-necked flask, add 250 mL of DMF and 8 g (0.21 mol, 1.5 eq, 60%) NaH and cool to 0 °C. Then, at 0 °C, add 100 mL of a 100 g (0.125 mol, 1 eq) solution of compound 502-2 in DMF and stir for 1 hour. Subsequently, at 0 °C, add 100 mL of a 100 g (0.154 mol, 1.1 eq) solution of 3-(bromomethyl)benzonitrile in DMF, and stir the mixture overnight at 58 °C. After confirming the completion of the reaction by LC-MS, quench the reaction with water, extract with EA, dry with Na2SO4, and concentrate. Purify by silica gel column chromatography to obtain 36 g of compound 502-3, yield 64%.

[0431] Step 3: Add 300 mL DMSO, 36 g (0.08 mol, 1 eq) of compound 502-3, 9 g (0.15 mol, 2 eq) of NaCN, and 11 g (0.3 mol, 4 eq) of H2O to a 500 mL three-necked flask. Stir the mixture overnight at 150 °C. LC-MS showed incomplete reaction. Purification with similar post-treatment yielded 25 g of compound 502-4, in 86% yield.

[0432] Step 4: Add 200 mL DMSO, 20 g (0.055 mol, 1 eq) of compound 502-4, 13 g (0.11 mol, 2 eq) of H2O2 and 15 g (0.11 mol, 2 eq) of K2CO3 to a 500 mL three-necked flask. Stir the mixture overnight at room temperature, and after standard post-treatment, purify to give 8 g of compound 502-5, yield 38%.

[0433] Step 5: Add 40 mL of EtOH, 8 g (0.021 mol, 1 eq) of compound 502-5, and 12.6 g (0.21 mol, 10 eq) of ethylenediamine to a 100 mL three-necked flask. Stir the mixture overnight at room temperature. After purification, 7 g of compound 502-6 is obtained, with a yield of 84%.

[0434] Step 6: Add 1 g (2.53 mmol, 1 eq) of compound 502-6, 7.5 mL of HMDS, and 0.5 mL of TMSI to a 25 mL single-necked flask. Stir the mixture overnight at 130 °C, concentrate under vacuum, add 2 mL of DCM and 1 mL of TFA, stir at room temperature for 1 hour, concentrate and purify to obtain 10 mg of compound 502, with a final yield of 1%.

[0435] Total yield = 0.15%.

[0436] LCMS: [M-C2HF3O2+1]+=378.0 1H NMR (400 MHz, DMSO) δ 10.45 (s, 2H), 7.98 (s, 1H), 7.85 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.43 (dt, J = 14.9, 7.6Hz, 3H), 7.26 (t, J = 8.1 Hz, 1H), 5.23 (t, J = 7.1 Hz, 1H), 3.81 (dd, J =14.5, 6.8 Hz, 4H), 3.60 (d, J = 7.7 Hz, 1H), 3.50 (d, J = 5.7 Hz, 1H). Example 19. Synthesis of Compound 503 Step 1: Add 250 mL of ACN, 25 g (0.15 mol, 1 eq) (3-bromophenyl)acetic acid, 31.5 g (0.16 mol, 1.05 eq) diethyl chloromalonic acid, and 43 g (0.31 mol, 2 eq) K₂CO₃ to a 500 mL three-necked flask. Reflux the mixture at 80 °C overnight. After confirming the completion of the reaction by LC-MS, concentrate and purify by silica gel column chromatography (EA / PE = 1 / 20 → 1 / 10) to give 20 g of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (503-1) (yellow oil), yield 73.60%.

[0437] 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-butyllithium (2.5 M hexane solution, 62 mL, 155 mmol) was slowly added dropwise. After stirring at -78 °C for 30 minutes, a solution of 503-1 (20 g, 77.5 mmol) in anhydrous THF (100 mL) was slowly added dropwise. The solution was then heated to room temperature and stirred for 16 hours. The reaction was quenched with saturated NH4Cl solution, extracted with EA, and purified by silica gel column chromatography (EA / PE = 1 / 50) to give 10 g of 2-(3-bromophenyl)-1-(2-methoxyphenyl)ethyl ketone (503-2) (yellow oil), yield 40.13%.

[0438] Step 3: A solution of 503-2 (1.5 g, 4.9 mmol), PdCl2(dppf) (360 mg, 0.49 mmol), and sodium carbonate (1.04 g, 9.8 mmol) in toluene:MeOH (10 mL, 1:1) was heated at 100 °C for 3 days under a carbon monoxide atmosphere. The reaction solution was diluted with water, extracted with EA, and purified by silica gel column chromatography (EA / PE = 1% → 10%) to give 700 mg of methyl 3-[2-(2-methoxyphenyl)-2-oxoethyl]benzoate (503-3) (yellow oil), yield 46.94%.

[0439] Step 4: LiHMDS (1 M, 8.4 mL, 8.44 mmol) was added to a toluene (8 mL) 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), and the mixture was stirred at 25 °C for 3 hours. The solution was diluted with NH4Cl, extracted with EA, and purified by silica gel column chromatography (DCM / MeOH = 1 / 20) to give 400 mg of N-methoxy-3-[2-(2-methoxyphenyl)-2-oxoethyl]benzamide (503-4) (yellow oil), yield 60.45%.

[0440] Step 5: A solution of N-methoxy-3-[2-(2-methoxyphenyl)-2-oxoethyl]benzamide (400 mg, 1.3364 mmol) and ammonium acetate (1.545 g, 20.046 mmol) in IPA (8.0 mL) was stirred at 25 °C for 30 min, followed by the addition of sodium cyanoborohydride (335.92 mg, 5.34 mmol) and heating at 80 °C for 3 h. The pH was adjusted to 8 with 2 M NaOH, extracted with DCM, and purified by silica gel column chromatography (MeOH / DCM = 1 / 10) to give 320 mg of 3-[2-amino-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (503-5) (white solid), yield 71.75%.

[0441] Step 6: Add 1-chloro-2-isocyanate ethane (421.59 mg, 3.9952 mmol) to a DCM:DMF (5.0 mL, 10:1) solution of 3-[2-amino-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (300 mg, 0.9988 mmol, 1 eq) and stir at 25 °C for 6 hours. Dilute with water, extract with DCM, wash the combined organic phases with brine, dry to Na₂SO₄, and concentrate under vacuum. 250 mg of crude product (yellow oil) was obtained, yield 46.26%, which was used directly in the next step.

[0442] Step 7: A solution of 3-(2-{[(2-chloroethyl)carbamoyl]amino}-2-(2-methoxyphenyl)ethyl)-N-methoxybenzamide (200 mg, 0.4927 mmol) in water (5.0 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the solution was purified using a Biotage C18 column (5% → 95% MeCN / H2O, containing 0.1% NH4OH) to give 48.25 mg of 3-[2-(4,5-dihydro-1,3-oxazol-2-ylamino)-2-(2-methoxyphenyl)ethyl]-N-methoxybenzamide (503) (white solid), yield 24.65%.

[0443] Total yield = 11.40%.

[0444] LCMS(ESI): m / z found 370.10 [M + H] +. [M+1] + =370.10 1 H NMR(400 MHz, DMSO) δ 11.69 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 6.8Hz, 1H), 7.34 (dt, J = 18.4, 7.6 Hz, 3H), 7.21 (t, J = 8.0 Hz, 1H), 6.93 (dd,J = 16.8, 8.4 Hz, 3H), 5.06 (d, J = 6.4 Hz, 1H), 4.02 (t, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.71 (s, 3H), 3.38 (t, J = 8.4 Hz, 2H), 2.89 (dd, J = 13.6, 4.0Hz, 1H), 2.75 (dd, J = 13.6, 10.0 Hz, 1H). Example 20. Synthesis of Compound 504 LCMS: [M-HCl+1]+=390.1 1H NMR (400 MHz, MeOD) δ 7.40 (t, J = 7.9 Hz, 1H), 7.27 – 7.20 (m,2H), 7.17 (t, J = 7.6 Hz, 2H), 7.00 (dd, J = 23.2, 7.5 Hz, 2H), 6.16 (s, 1H), 4.02 (t, J = 7.5 Hz, 2H), 3.65 (t, J = 7.6 Hz, 2H), 2.95 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H). Example 21. Synthesis of Compound 505 Step 1: A solution of 2-(3-bromophenyl)-1-(2-methoxyphenyl)ketene (503-2, 2.0 g, 6.6 mmol), methanesulfonamide (0.75 g, 7.92 mmol), palladium(II) acetate (150 mg, 0.663 mmol), Xantphos (0.76 g, 1.32 mmol), and cesium carbonate (4.30 g, 13.20 mmol) in dioxane (20.0 mL) was heated at 100 °C for 16 hours under nitrogen protection. After cooling, the solution was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purified by silica gel column chromatography (methanol / dichloromethane, 1% to 10%), N-{3-[2-(2-methoxyphenyl)-2-oxoethyl]phenyl}methanesulfonamide (505-1, 400 mg, 16.17% yield) was given as a yellow oil.

[0445] Step 2: A mixture of N-{3-[2-(2-methoxyphenyl)-2-oxoethyl]phenyl}methanesulfonamide (400 mg, 1.07 mmol) and ammonium acetate (1.448 g, 18.785 mmol) in isopropanol (8.0 mL) was stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (314.80 mg, 5.01 mmol) was added, and the mixture was heated at 80 °C for 4.5 h. After cooling, the reaction solution was filtered through diatomaceous earth and concentrated. Preparative thin-layer chromatography (ethyl acetate / petroleum ether, 1 / 3) was used to obtain N-{3-[2-amino-2-(2-methoxyphenyl)ethyl]phenyl}methanesulfonamide (505-2, 240 mg, 53.82% yield) as a yellow oil.

[0446] 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-imidazolium-2-sulfonic acid (224.96 mg, 1.4982 mmol) in n-butanol:water (5:1, 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 ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by passing through a Biotage C18 column (elution gradient: 10% to 95% acetonitrile / water, containing 0.1% trifluoroacetic acid) to give N-{3-[2-(imidazolidine-2-imideamino)-2-(2-methoxyphenyl)ethyl]phenyl}methanesulfonamide (505, 8.38 mg, 4.31% yield) as a white solid.

[0447] LCMS: [M+1] + =388.38 1 H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.74 (d, J = 9.2 Hz, 1H), 8.31 (s, 1H), 7.67 (s, 1H), 7.33 – 7.16 (m, 3H), 7.11 (s, 1H), 7.03 (dd, J = 17.2,8.4 Hz, 3H), 6.94 (t, J = 7.6 Hz, 1H), 4.96-4.90 (m, 1H), 3.88 (s, 3H), 3.48(s, 5H), 3.09 (dd, J = 13.6, 4.8 Hz, 1H), 2.94 – 2.87 (m, 4H). Example 22. Synthesis of Compound 510 Step 1: Add 20 mL of ACN, 2 g (10 mmol, 1.0 eq) of 2,3-dimethylbenzyl bromide, 2 g (20 mmol, 2.0 eq) of trimethylsilyl cyanide, and 20 mL (50 mmol, 2.0 eq) of TBAF / THF solution to a 100 mL reaction flask. After reflux for 1.5 hours, the reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated and purified by column chromatography (PE:EA = 85:15) to give 1.42 g of compound 510-1, with a yield of 97.9%.

[0448] Step 2: Add 28 mL of ethanol, 5.7 mL of 30% KOH solution, and 1.42 g (9.8 mmol, 1.0 eq) of compound 510-1 to a 100 mL reaction flask. After reflux for 18 hours, concentrate the solution, dilute with 20 mL of water, adjust the pH to 2 with 6 M HCl, filter and dry to obtain 1.35 g of compound 510-2 (solid), yield 84.0%.

[0449] Step 3: Add 15 mL of methanol and 1.3 g (8 mmol, 1.0 eq) of compound 510-2 to a 50 mL reaction flask. After cooling to 0 °C, add 1.89 g (15.9 mmol, 1.5 eq) of thionyl chloride. Stir at 60 °C for 18 hours, concentrate, and purify by column chromatography (PE:EA=68:32) to obtain 1.37 g of compound 510-3, with a yield of 96.2%.

[0450] Step 4: Add 10 mL of THF and 497 mg (2.81 mmol, 1.0 eq) of compound 510-3 to a 25 mL reaction flask and cool to -80 °C under nitrogen protection. Add LDA (3.37 mL, 3.37 mmol, 1.2 eq), followed by 2 mL of THF solution containing 731 mg (2.95 mmol, 1.05 eq) of CAS 823-78-9. Slowly heat to room temperature and react overnight. After quenching, purify by column chromatography to obtain 670 mg of compound 510-4, yield 68.9%.

[0451] Step 5: Add 10 mL of DMF, 570 mg (1.65 mmol, 1.0 eq) of compound 510-4, 1.07 g (3.3 mmol, 2.0 eq) of Cs₂CO₃, 235 mg (2.47 mmol, 1.5 eq) of methanesulfonamide, 151 mg (0.165 mmol, 0.1 eq) of Pd₂(dba)₃, and 141 mg (0.33 mmol, 0.2 eq) of t-BuXPhos to a 50 mL reaction flask. Stir at 105 °C for 2 hours under nitrogen protection. After post-treatment and purification, 600 mg of compound 510-5 was obtained, with a yield of 85.7%.

[0452] Step 6: Add 5 mL of toluene, 200 mg (0.554 mmol, 1.0 eq) of compound 510-5, 166.5 mg (2.77 mmol, 5.0 eq) of ethylenediamine and TMAI (1.39 mL, 2.77 mmol, 5.0 eq) to a 10 mL reaction flask. Stir overnight at 110 °C, cool, and then purify to obtain 29 mg of compound 510-6, yield 13.5%.

[0453] Step 7: Add 1 mL of toluene and 29 mg (0.0745 mmol, 1.0 eq) of compound 510-6 to a 5 mL reaction flask, followed by 57 mg (0.37 mmol, 5.0 eq) of phosphorus oxychloride. Stir at 110 °C for 3 hours, filter, and purify to obtain 3.6 mg of compound 510, yield 11.9%.

[0454] Total yield = 6.1%.

[0455] LC-MS = [M-HCl+1]+ = 372.2 1H NMR(400 MHz, DMSO) δ 9.98 (s, 2H), 7.35 (d, J = 7.1 Hz, 1H), 7.24(t, J = 7.7 Hz, 1H), 7.15 (dd, J = 18.1, 7.2 Hz, 2H), 7.09 – 7.00 (m, 2H), 6.95 (d, J = 7.4 Hz, 1H), 4.44 (t, J = 7.5 Hz, 1H), 3.78 (s, 4H), 3.46 – 3.40(m, 1H), 3.07 (dd, J = 13.4, 7.1 Hz, 1H), 2.90 (s, 3H), 2.22 (s, 3H), 2.11(s, 3H). The remaining compounds were synthesized using a similar method to those described above. Compound characterization data are shown in Table 2.

[0456] Table 2

[0457] Biological analysis Example 1. α2AAR FLIPR Analysis This experimental protocol involved seeding and FLIPR analysis using an α2AAR (α2A-adrenergic receptor) cell line expressed in 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 bleomycin S HCl (BS) (A11139-03, Gibco).

[0458] Day 1: Cell inoculation First, remove the culture medium and wash the cells with DPBS (21-031-CVC, Corning). Then treat the cells with 0.05% EDTA-trypsin (25300-062, Gibco) and incubate at 37°C for 1-2 minutes, observing under an inverted microscope. After cell detachment, resuspend the cells in growth medium and centrifuge at 1000 rpm for 5 minutes at room temperature. Discard the supernatant, resuspend the cell pellet in growth medium, and adjust the cell concentration to 10 × 10⁶ cells / mL. 5 cells / mL. Add this cell suspension to a 384-well plate (19-Jul-38, Greiner) at a volume of 20 µL per well and incubate overnight at 37°C and 5% CO2.

[0459] Day 2: FLIPR Analysis First, prepare the analysis buffer, which consists of 20 mM HEPES (15630-106, Invitrogen), 1× HBSS (14025-076, Invit), and 0.5% BSA (B2064, Sigma). Prepare a 250 mM probenecid solution in this buffer. Then, prepare the Fluo-4 Direct™ loading buffer by dissolving Fluo-4 Direct™ crystals (F10471, Invit) in the FLIPR analysis buffer and adding probenecid. Vortex the buffer and incubate in the dark for at least 5 minutes.

[0460] For the FLIPR procedure, the test compounds were serially diluted and transferred to 384-well compound plates (25-Jan-39, Greiner). The plates were then treated with 2× Fluo-4 Direct™ loading buffer and incubated at 37°C, 5% CO2 for 50 minutes, followed by a 10-minute incubation at room temperature. FLIPR analysis buffer was then added to the compound plates, and the plates were centrifuged.

[0461] Fluorescence signals from cell plates were analyzed using the FLIPR Tetra+ system. In the agonist assay, a reference compound was added to the cell plate, and fluorescence intensity was measured. The "maximum-minimum" calculation started from reading 1 and proceeded to the maximum permissible value. Data were analyzed using Prism software to calculate the percentage of activation for the agonist and the percentage of inhibition for the antagonist. The EC50 value for the agonist was determined by fitting the results to a specific model.

[0462] This experimental protocol utilized a variety of 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 an important part of this analysis.

[0463] Example 2. α2AAR Binding Analysis This analysis was performed using the HEK293 cell line stably expressing α2AAR, constructed by WuXi AppTec. The analysis primarily detected radioligands […]. 3 The binding activity of H]-RX 821002 (PerkinElmer, NET1153250UC) to α2AAR was measured at a membrane protein concentration of 0.5 μg / well and a radioligand concentration of 0.5 nM. Key equipment required for the experiment included a Unifilter-96 GF / C filter plate (Perkin Elmer, 6005174), a 96-well conical polypropylene plate (Agilent, 5042-1385), a TopSeal-A sealing membrane (Perkin Elmer, 6050185), a MicroBeta2 reader (CNLL0153, Perkin Elemer, 1310887), and a cell harvester (UNIFILTER-96, Perkin Elemer, 1951369), all purchased from Perkin Elmer. Analysis and washing buffers were 50 mM Tris-HCl (Tris base, Sigma, T1503-1KG) at pH 7.4.

[0464] The experimental procedure began with the preparation of the test compound and the reference compound yohimbine (Sigma, Y3125) through 8-point 4-fold serial dilutions, with 1 μL of each transferred to an analytical plate. 100 μL of membrane protein solution (0.5 μg / well) and 100 μL of 0.5 nM [ ] were added to each well. 3H]-RX 821002. After sealing, incubate with shaking at room temperature for one hour. Then, pre-soak the Unifilter-96 GF / C filter plate in 0.3% PEI (Sigma, P3143) for at least half an hour. Filter the reaction mixture using a Perkin Elmer cell harvester and wash four times with cold wash buffer. After filtration, dry the filter plate at 50°C for one hour. Next, seal the bottom of the filter plate with PerkinElmer Unifilter-96 back sealing tape and add 50 μL of MicroScint-O scintillation solution (PerkinElmer, 6013611) to each well. After sealing the top of the filter plate with TopSeal-A sealing film, quantify the bound cells using a Perkin Elmer MicroBeta2 reader. 3 H radioactivity. The inhibition rate was calculated using the formula: %inhibition rate = (1 - (analytical well average value_LC) / (average value_HC - average value_LC)) × 100%. Finally, the data were fitted using the "log(inhibitor) vs. response - variable slope" model in Prism 5.0 software. This complete procedure ensured accurate assessment of the binding affinity of the compound to α2AAR.

[0465] The results of α2AAR FLIPR analysis and binding analysis are shown in Table 3.

[0466] Table 3. α2AAR agonist activity (EC50) and affinity (Ki)

[0467] A: <10nM B: 10nM-50nM C: 50nM-250nM D: 250nM-1000nM E:>1000nM Example 3. MDR1-MDCK Permeability Analysis MDR1-MDCK II cells (purchased from Piet Borst, Netherlands Cancer Institute) were used at a rate of 3.33 × 10⁻⁶. 5Cells / mL were seeded onto polycarbonate membranes in 96-well insert plates and cultured for 4–7 days to form a dense cell monolayer. The α2AR agonists selected in Table 3 were diluted from DMSO stock solution to 2 μM concentration (DMSO < 1%) with transfer buffer (HBSS containing 10.0 mM Hepes, pH 7.4) and added to the apical or basal side of the cell monolayer, respectively. Digoxin was used as a positive control for the P-glycoprotein substrate, while clonidine, dexmedetomidine, fadomidin, and brimonidine were used as negative controls. Osmosis assays of the test compounds from A to B and / or B to A were performed in duplicate. Digoxin was tested at a concentration of 10.0 μM in duplicate wells from A to B and B to A. The culture plates were incubated statically for 2.5 hours in an incubator at 37.0 ± 1.0 °C, 5.0% CO2, and saturated humidity. The efflux rate of each compound was measured simultaneously. Quantification was performed by LC / MS / MS analysis based on the analyte / internal standard peak area ratio and reference compound.

[0468] After the transport experiment, the integrity of the cell monolayer was assessed using a fluorescein rejection assay. The buffer solutions in the top and bottom chambers were removed, and 75 μL of transport buffer containing 100 μM fluorescein and 250 μL of transport buffer were added, respectively. The culture plates were incubated at 37.0 °C, 5.0% CO2, and 95.0% relative humidity for 30 minutes. After incubation, 20 μL of fluorescein sample was taken from the top side and 60 μL of transport buffer was added, followed by 80 μL of fluorescein sample taken from the bottom side. The relative fluorescence units of fluorescein were measured using an Envision microplate reader at 425 / 528 nm (excitation / emission) wavelengths.

[0469] The formula for calculating the apparent permeability coefficient Papp (cm / s) is as follows: Papp = (dCr / dt) × Vr / (A × C0) Where dCr / dt is the change in cumulative compound concentration in the receiving chamber over time (μM / s); Vr is the solution volume in the receiving chamber (0.075 mL on the top side, 0.25 mL on the bottom side); and A is the transport surface area (i.e., the monolayer membrane area of ​​0.143 cm²). 2 C0 represents the initial concentration (μM) in the donor chamber.

[0470] The formula for calculating the efflux ratio is: Efflux Ratio = Papp (BA) / Papp (AB) The results of the MDR1-MDCK permeability analysis are shown in Table 4.

[0471] Table 4. P-gp efflux ratio in the MDCK-MDR1 experiment

[0472] Example 4. Drug distribution in vivo This study evaluated the binding affinity of various compounds to plasma proteins, including clonidine hydrochloride, dexmedetomidine hydrochloride, 1-B hydrochloride, and 44-B hydrochloride, with warfarin as a control. HT dialysis plates (HTD 96b) and dialysis membranes with a molecular weight cutoff of 12–14 kDa were used. Plasma was derived from male C57BL / 6J mice and treated with EDTA-K2 anticoagulation.

[0473] The experimental procedure is as follows: The plasma was first thawed in a cold water bath, centrifuged at 3220 ×g for 5 minutes to remove clots, and the pH was adjusted to 7.4 ± 0.1. The dialysis membrane was first hydrated with ultrapure water for about 1 hour, and then treated with a 20:80 ethanol-water mixture for 20 minutes. The treated membrane can be used immediately or stored at 2-8℃ for up to one month. It must be rinsed with ultrapure water before use.

[0474] The stock solutions of the test and control compounds were diluted to 400 μM with DMSO, and further diluted to prepare 2 μM loading matrix solutions, which were then thoroughly mixed. In the experiment, 50 μL of the above solution was divided into three aliquots and added to the sample collection plate, with the volume brought to 100 μL per well using blank PBS. After adding the stop solution containing acetonitrile, tolbutamide, and labetalol, the samples were mixed thoroughly and cooled at 2–8 °C.

[0475] During dialysis, 100 μL of loading matrix solution was added to the donor side of the dialysis cell, and an equal volume of PBS was added to the recipient side. The cells were incubated at 37°C for 4 hours. After dialysis, samples from both sides were collected, and the volume was brought up to 100 μL with the appropriate blank solution. Stop solution was added, and the cells were vortexed and centrifuged before LC-MS / MS analysis.

[0476] Data analysis included calculating the percentage of unbound compounds, the percentage of bound compounds, and the recovery rate after dialysis. Specifically: Unbound percentage = (receptor-side compound peak area / internal standard peak area) × 100%, reflecting the fraction of free drug that permeates the membrane. Bound percentage = 100% - Unbound percentage, representing the fraction of bound drug retained on the donor side. Recovery rate is calculated based on the ratio of peak areas on both sides of the membrane and is used to evaluate the retention efficiency of the dialysis system for compounds. These indicators provide important parameters for elucidating the distribution characteristics of compounds in dialysis systems. The plasma protein binding results are shown in Table 5.

[0477] Table 5. Plasma protein binding rate

[0478] Brain protein binding rate assay This study evaluated the binding affinity of various compounds to brain proteins, including clonidine hydrochloride, dexmedetomidine hydrochloride, 1-B hydrochloride, and 44-B hydrochloride, with propranolol as a control. At the start of the experiment, brain tissue homogenates were thawed in a room temperature water bath, followed by heating at 37°C for 10 minutes. The dialysis apparatus used was an HT dialysis plate (model HTD 96b) from HT Dialysis LLC and a dialysis membrane with a molecular weight cutoff of 12-14 kDa.

[0479] The dialysis membrane requires system pretreatment: first, hydrate it in ultrapure water at room temperature for about 1 hour, then separate and immerse it in a 20:80 ethanol:water solution for about 20 minutes. After this treatment, the membrane can be used immediately or stored at 2-8℃ for up to one month. A final rinse with ultrapure water is required before the experiment.

[0480] During compound preparation, the test and control compounds were first prepared into working solutions using DMSO: 4 μL of stock solution was mixed with 96 μL of DMSO to prepare a 400 μM working solution. Subsequently, 3 μL of this working solution was mixed with 597 μL of blank matrix, thoroughly mixed, and then diluted to a concentration of 2 μM.

[0481] During the experiment, 50 μL of the 2 μM compound-matrix mixture was added to the sample collection plate in three aliquots. An equal volume of blank PBS was added to each sample to normalize the total volume per well to 100 μL (matrix to PBS ratio 1:1). 500 μL of acetonitrile stop solution containing 250 nM tolbutamide and labetalol was added to stabilize the sample at time T0. The sample was then shaken at 800 rpm for 10 minutes and stored at 2–8 °C.

[0482] The dialysis procedure includes assembling the dialysis device according to the manufacturer's specifications, adding the matrix sample to the donor side of the dialysis cell, and performing dialysis for 4 hours in a humid atmosphere of 37°C and 5% CO2.

[0483] After dialysis, 50 μL of sample was transferred from both the recipient and donor sides to new 96-well plates. The volume was adjusted to 100 μL by adding an equal volume of the corresponding blank matrix or PBS. The samples were then thoroughly vortexed and prepared for LC-MS / MS analysis. Blank control samples were prepared and processed in the same manner to simulate the test conditions.

[0484] Data analysis included calculating the undiluted unbound percentage, bound percentage, and compound recovery. Among these: Undiluted unbound percentage = 100 × 1 / D / ((1 / (F / T) - 1) + 1 / D), where D is the dilution factor (10) Undiluted binding percentage = 100 - Undiluted unbound percentage Recovery = 100 × (F + T) / T0, where F and T represent the peak area ratios of the acceptor and donor compounds to the internal standard after 4 hours of incubation, respectively. The results of brain protein binding rates are shown in Table 6.

[0485] Table 6: Results of Brain Protein Binding Rate

[0486] In vivo distribution experiments were conducted using male C57BL / 6J mice, and brain tissue, spinal cord, and serum samples were collected for drug distribution analysis.

[0487] Prior to the experiment, mice were acclimatized to the testing facility for at least 3 days. During this period, their overall health was assessed by a veterinarian or other authorized personnel. Mice were housed in groups of four in polysulfone cages using certified aspen shavings or corn cob bedding. Both bedding materials were tested for environmental contaminants by the manufacturer. The facility environment was strictly controlled, maintaining a temperature range of 20–26°C and a relative humidity of 40–70%, and a 12-hour light / 12-hour dark cycle (this cycle may be interrupted as needed for the experiment). Temperature and humidity data were continuously monitored using the Vawasala ViewLinc system.

[0488] Accurately weigh an appropriate amount of the compound and mix it with a suitable volume of solvent to prepare a clear solution. This preparation process may require vortexing or sonication in a water bath. Animals should be administered the formulation within four hours of preparation, and samples from each formulation should be collected for dose validation via LC / UV or LC-MS / MS analysis.

[0489] Oral administration was performed according to the facility's standard operating procedures, with the volume of administration determined based on the animal's body weight measured on the morning of the administration day. The compounds included 5 mg / kg clonidine hydrochloride, 5 mg / kg dexmedetomidine hydrochloride, 5 mg / kg and 80 mg / kg compound 1-B, and 5 mg / kg and 80 mg / kg compound 44-B. All were administered using a 20% hydroxypropyl-β-cyclodextrin aqueous solution, and samples were collected at 0.5, 1, 2, and 8 hours post-administration.

[0490] Blood samples were collected via the saphenous vein or other suitable sites, approximately 0.1 mL at each time point into pre-chilled commercially available EDTA-K2 blood collection tubes. Samples were stored on moist ice until centrifugation at 4°C, 3,200 g for 10 minutes. After centrifugation, plasma was transferred to pre-labeled 96-well plates or polypropylene tubes, flash-frozen on dry ice, and stored at -60°C or lower for LC-MS / MS analysis.

[0491] Brain and spinal cord tissues were obtained immediately after sampling, rinsed with cold saline, aspirated, and weighed. The tissue samples were homogenized in ice-cold 15 mM PBS (pH 7.4):methanol = 2:1 solution (tissue to buffer ratio 1:9). The homogenate was aliquoted into two portions: one was immediately analyzed by LC-MS / MS, and the other was stored at -70±10℃ as a backup. This comprehensive method ensured standardized pharmacokinetic data acquisition and analysis under controlled and rigorous scientific conditions.

[0492] Pharmacokinetic parameter calculation AUC ratio = tissue AUC0-last / plasma AUC0-last LogBB = log10(brain tissue AUC0-last / plasma AUC0-last) LogSB = log10(Brain tissue AUC0-last / Spinal cord tissue AUC0-last) Kp = Brain tissue AUC0-last / Plasma AUC0-last Kp,uu,brain = AUCb,u / AUCp,u = AUCbrain / AUCplasma × (fu,brain / fu,plasma) The results of drug distribution in vivo are shown in Table 7.

[0493] Table 7: Results of drug distribution in vivo

[0494] The drug concentration in the brain and spinal cord was below the limit of detection (DL). DL = 10 ng / mL. Distribution parameters are unavailable. Example 5. Efficacy study of a mouse model of selective sciatic nerve branch injury. This study used 50 male C57BL / 6 mice weighing 20-30 g, with 6 mice in the sham-operated group and the rest undergoing selective sciatic nerve branch injury surgery. Several days after the SNI surgery, all animals underwent a mechanical hyperalgesia test to obtain the baseline paw withdrawal threshold. The eligible mice were randomly divided into different groups according to their baseline paw withdrawal threshold (PWT). Mice with a baseline PWT < 0.6 g were randomly assigned to the solvent group and the test compound group based on their threshold level. Six sham-operated mice (n=8 per group) were used to evaluate the efficacy of the compound.

[0495] Animals should acclimatize to the facility for 3-7 days after arrival. For the first three days prior to the mechanical pain hypersensitivity test, allow animals to acclimatize to the test environment for 15 minutes daily.

[0496] All surgical procedures were performed using aseptic techniques. Surgical instruments, including scissors, forceps, scalpels, sterile cotton pads, suture needles, and metal clips, were sterilized preoperatively. Animals were anesthetized via intraperitoneal injection of Zoltil 50 and xylazine hydrochloride. A toe-pinching test was performed before the incision to ensure complete anesthesia, and eye ointment was applied to the rodent's eyes to prevent corneal dryness. The hair on the hind legs was shaved tightly. The surgical area was wiped three times alternately with povidone-iodine and 70% ethanol. After drying, an incision was made on the lateral thigh, and the biceps femoris muscle was severed to expose the sciatic nerve and its terminal branches. The common peroneal and tibial nerves were severed, leaving only the sural nerve intact. The wound was sutured in layers, and the skin was sutured in alignment. Postoperatively, surgical instruments were cleaned and sterilized using a glass bead sterilizer. The animal was resuscitated on a warming mat, and 1 mL of sterile saline was injected subcutaneously to prevent dehydration. Once fully awake and able to move independently, the animal was returned to its cage.

[0497] On day 11, the animals were placed individually in plastic enclosures with a mesh base, ensuring their paws were in full contact with the mesh. They were allowed 15 minutes of acclimatization time each day for three consecutive days. On day 14, baseline measurements of mechanical hyperalgesia were performed. Mice that did not exhibit hyperalgesia were excluded, resulting in 24 eligible animals and 6 sham-operated mice forming four experimental groups of 6-8 animals each.

[0498] Compound 1-B was administered at a gradient dose from 1 mg / mL to 20 mg / mL, while compounds 10-B, 44-B, 45-B, 46-B, 47-B, 121, 136, 118, 156, and 175 were administered at a fixed dose of 1 mg / mL. All compounds were administered orally. Positive control drugs included 1 mg / kg morphine (subcutaneous injection) and 3 mg / kg pregabalin (oral administration). All formulations were prepared using a 20% hydroxypropyl-β-cyclodextrin solution. 1-B, 10-B, 44-B, 45-B, 46-B, and 47-B were the active enantiomers of compounds 1, 10, 44, 45, 46, and 47, respectively, while 121, 136, 118, and 156 were racemic mixtures. All solutions were vortexed to ensure thorough homogenization, and the administration volume was calculated at 10 mL / kg body weight.

[0499] Mechanical hypersensitivity testing was performed on the left hind limb of mice. Mice were placed individually in a plastic enclosure with a mesh base, ensuring their paws were fully in contact with the mesh surface, and allowed 15 minutes of acclimatization before testing. After acclimatization, the midfoot and plantar region of the hind limb were stimulated with eight different stiffness Von Frey fibers (logarithmically increasing stiffness: 0.02 g, 0.04 g, 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1 g, and 1.4 g). The fibers were applied vertically to the plantar surface with a force sufficient to cause slight flexion, maintaining contact for 6–8 seconds. Each stimulation was spaced 5 seconds apart to ensure clear observation of the animal's response. A positive response was defined as rapid paw retraction or withdrawal upon fiber removal. Responses during movement were considered ambiguous and required repeated stimulation. The test began with 0.16 g of fiber, and the intensity of subsequent fibers was adjusted according to the mouse's response using the Dixon up-and-down method, with a maximum stimulation intensity of 1.4 g of fiber. A positive response was defined as an immediate and obvious paw retraction or withdrawal immediately after fiber removal.

[0500] Data analysis was performed using Prism 8.0 software (Graph Pad Software, Inc.) with one-way or two-way ANOVA, followed by Dunnett's test, Tukey's multiple comparison test, or t-test for two-tailed comparisons. Results are presented in... Figure 1A-1H .

[0501] Example 7. Efficacy study of a mouse model of bone cancer pain Animals were allowed 3 to 7 days to acclimatize upon arrival at the facility. Male C3H / He mice were anesthetized via intraperitoneal injection of a mixture of Tylosin 50 and xylazine hydrochloride, and then placed in a supine position. Hair was removed from the right hind limb, and the area was disinfected. A small incision was made in the right hind limb to transection the patellar ligament, exposing the distal femoral condyle. A 0.3 mL syringe needle was used to puncture the proximal femur. A solution containing 2×10... 4 10 μL of a suspension of NCTC-2472 cells was slowly injected into the femoral medullary cavity. Control animals were injected with 10 μL of PBS. After three days of acclimatization to the test environment, baseline paw withdrawal threshold determination was initiated.

[0502] Baseline mechanical hyperalgesia was measured on day 14. Animals that did not exhibit hyperalgesia were excluded. The remaining eligible animals were randomly divided into four groups based on their baseline PWT values. Single-dose regimens included: pregabalin 3 mg / kg orally, morphine 1 mg / kg subcutaneously, 44-B 1 mg / kg orally, and 1-B 20 mg / kg orally and 44-B 20 mg / kg orally, with a dosage volume of 10 mL / kg body weight. Mechanical hyperalgesia was tested at different time points. Each mouse was placed individually in a mesh-based plastic enclosure with its paws freely in contact with the mesh surface, allowing for a 15-minute acclimatization period before testing. The mechanical hyperalgesia testing method was the same as described in the SNI model in Example 6. Results are shown below. Figure 2A-2D .

[0503] Example 8. Pharmacological evaluation of a mouse postoperative pain model Animals are acclimatized for 3 to 7 days after arriving at the facility. For three days prior to the surgical procedure, all animals are placed in the test environment for at least 15 minutes daily to acclimatize.

[0504] All surgical personnel strictly adhered to aseptic techniques. All surgical instruments—including scissors, pointed forceps, scalpels, sterile cotton pads, suture needles, and metal clips—were sterilized before use. Animals were anesthetized via intraperitoneal injection of a mixture of Tylosin 50 and xylazine hydrochloride. The depth of anesthesia was confirmed by a toe-clamping test before incision. Eye ointment was applied to the animal's eyes to prevent corneal dryness. The left hind limb paw area was disinfected three times by alternating wiping with povidone-iodine and 70% ethanol, and then allowed to air dry. A 0.5 mm longitudinal incision was made in the skin and fascia, 2 mm proximal to the heel, towards the toe. The plantar muscle group was longitudinally incised while preserving its origin and insertion points. After gentle pressure hemostasis, the skin was closed with two mattress sutures. Postoperatively, all surgical instruments were cleaned and then sterilized using a glass bead sterilizer. The animal was revived on a heated resuscitation mat and given 1 ml of sterile saline orally to prevent dehydration. Once fully awake and able to move independently, the animal was returned to its original cage.

[0505] On the first day after surgery, all animals, including the control group, underwent mechanical hyperalgesia testing using a tactile sensory evaluation device. Surgical animals that did not exhibit hyperalgesia were excluded, and the final 24 qualified surgical animals were randomly divided into three groups based on their baseline paw withdrawal threshold, forming four experimental groups together with the control group.

[0506] Dosage regimen: Morphine 3 mg / mL subcutaneously, 1-B hydrochloride 10 mg / mL orally, and 44-B hydrochloride 10 mg / mL orally, all administered at a dose of 10 mL / kg body weight. Animals in the control group were evaluated but not treated. The mechanical hyperalgesia test method was the same as described in the SNI model in Example 6. Results are shown in... Figures 3A-3C .

[0507] Example 9. In vivo efficacy study of MC38, an allograft model for treating subcutaneous colon cancer. This study aimed to evaluate the in vivo efficacy of the test substance in a female C57BL6 / J mouse subcutaneous colon cancer allogeneic transplantation model (MC38). The mice were female Mus musculus C57BL6 / J, provided by Beijing Huafukang Biotechnology Co., Ltd., with an average age of 6-8 weeks. They were housed in polysulfone IVC cages at a temperature of 20-26℃ and humidity of 40-70%, with a 12-hour light / 12-hour dark photoperiod. They were fed irradiated standard rodent feed with free access. Autoclaved water filtered through reverse osmosis and softened was provided for free drinking.

[0508] Clonidine and compound 1-B hydrochloride were used as the control and test items, respectively, and the study protocol was designed according to Table 8. Due to the poor condition of the mice caused by the high dose, the clonidine dose in group G2 was adjusted from 5 mg / mL to 2 mg / mL from day 4, and the 1-B hydrochloride dose in group G4 was adjusted from 10 mg / kg to 5 mg / kg. The specific experimental design and formulation are shown in Table 8.

[0509] Table 8. Experimental Design and Formulation

[0510] The dosage was adjusted on day 4. MC38 cancer cells were cultured in vitro in DMEM medium containing 10% fetal bovine serum and 50 μg / mL hygromycin B, and incubated at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected before tumor inoculation and quantified using a cell counter. Each mouse was subcutaneously inoculated with 1 × 10⁻⁶ MC38 tumor cells in the right posterior ventral region. 6 (Number of tumors) were suspended in 0.1 mL PBS for tumor induction. The average tumor volume reached approximately 121.36 mm². 3 Randomization began at a certain time, with a total of 30 mice enrolled and randomly assigned to 5 study groups of 6 mice each. The "matched distribution" method was used for randomization, and the day of randomization was recorded as day 0.

[0511] According to the study design, treatment was initiated on the day of randomization (day 0). Following tumor cell inoculation, animal morbidity and mortality were observed daily. During routine monitoring, the effects of tumor growth and treatment on animal behavior were examined, including activity level, food and water intake, weight changes (weight was measured twice weekly after randomization), coat condition, and other abnormalities. Individual animal mortality and clinical signs were meticulously recorded. Twice weekly after randomization, the two-dimensional dimensions of the tumor were measured using calipers, and the tumor volume was calculated using the formula "V = (L × W × W) / 2", where V is the tumor volume, L is the long axis (maximum dimension), and W is the wide axis (maximum dimension perpendicular to L). Drug administration and tumor weight measurements were performed in a laminar flow hood, and weight and tumor volume data were recorded using StudyDirector™ software.

[0512] All animals were monitored for weight changes throughout the process, and euthanasia was performed if their weight decreased by more than 20% compared to the day of randomization. Additionally, individual mice with tumors exceeding 3000 mm² were also monitored. 3 Euthanasia is also performed. To avoid cannibalism, animals with ulcers or necrotic tumors are immediately separated into individual cages and monitored daily until euthanasia is performed or the tumor has completely regressed. Euthanasia should be performed immediately if: a) the tumor ulcer is larger than 5 mm in diameter, or pus or necrosis is present; or b) the tumor burden (including metastases) affects the animal's normal physiological functions.

[0513] Weight distribution during random grouping is shown in the figure. Figure 4A Tumor growth curves for each treatment group and the control group are shown in the figure. Figure 4B Mice were sacrificed on day 17, and tumors were dissected and measured. Results are shown below. Figure 4C The tumor growth inhibition rate and T / C value were calculated based on tumor size data from the last administration day (day 17): tumor volume is expressed as mean ± standard error, T / C% = (tumor volume in treatment group / tumor volume in control group) × 100%, TGI% = (1-T / C) × 100%. Pharmacokinetic analysis results are shown in Table 9.

[0514] Table 9: Pharmacokinetic Analysis of Different Groups in the MC38 Subcutaneous Colon Cancer Allograft Model

[0515] Example 10. Spontaneous Activity Test in Mice This study evaluated the effects of clonidine, brimonidine tartrate, compound 1-B hydrochloride, and compound 44-B hydrochloride on spontaneous activity in male C57BL / 6 mice. Mice were acclimatized to the test environment for 8 hours the day before the experiment and continued acclimatization for at least 2 hours on the day of the experiment. Mice were randomly assigned to groups of 6 mice per group to ensure group balance. Drugs were prepared using a 20% hydroxypropyl-β-cyclodextrin aqueous solution. In the first test, freshly prepared 1 mg / kg clonidine and 1 mg / kg, 10 mg / kg, and 20 mg / kg compound 1-B hydrochloride were administered orally at a volume of 10 mL / kg. In another test, freshly prepared 1 mg / kg clonidine, 1 mg / kg brimonidine tartrate, and 1 mg / kg compound 44-B hydrochloride were administered orally at the same volume.

[0516] Mice were placed in the center of the test chamber, and their spontaneous activity was monitored using a video tracking system. Movement distance was recorded every 5 minutes for 60 minutes. The test began immediately after drug administration (T=0 minutes) and ended at T=60 minutes. Data analysis was performed using Prism 8.3.0 software: two-way ANOVA combined with Bonferroni multiple comparison test was used to analyze changes in movement distance at different time points; one-way ANOVA combined with Dunnett multiple comparison test was used to assess the total movement distance of each group. p<0.05 was set as the statistical significance standard. As shown in Figure 5, in the first test, 1 mg / kg, 10 mg / kg, and 20 mg / kg of compound 1-B hydrochloride, and in the second test, 1 mg / kg of compound 44-B hydrochloride, did not induce significant sedation. However, 1 mg / kg of clonidine in the first test and 1 mg / kg of brimonidine tartrate in the second test both caused significant sedation. The total movement distance results from 0 to 60 minutes in the two tests are shown in Figure 5. Figure 5A and 5B .

[0517] Example 11. Study on the effects on motor function in mice Animals were acclimatized for one week after arriving at the facility. The day before the start of rotato training, they were randomly grouped according to their weight to ensure a balanced weight distribution among the treatment groups.

[0518] Spinner training was conducted for the first two days of the testing phase. On the first training day, mice underwent three training sessions at 6 rpm, each lasting 120 seconds, with a 30-minute interval between sessions. If a mouse fell off before completing 120 seconds, it was immediately placed back on the spinner to complete the remaining training time. On the second day, training was changed to a single 300-second continuous training session at 6 rpm. Mice that fell off before completing 300 seconds were also placed back on the spinner until the training was completed.

[0519] On the day of the test, the drugs were administered orally at a volume of 10 mL / kg based on body weight. The treatment groups included the solvent group, clonidine (1 mg / kg), and three doses (1 mg / kg, 10 mg / kg, and 20 mg / kg) of 44-B hydrochloride. The time point at which the compounds were administered was recorded as time zero.

[0520] Rotor tests were performed at 30, 60, and 120 minutes after drug administration, with each test lasting 300 seconds at 6 rpm. The primary endpoint was the latency period before mice fell off the rotator, used to assess the compound's effect on motor function.

[0521] Data were recorded in Microsoft Excel and statistical analysis was performed using GraphPad Prism. A p-value less than 0.05 was set as the threshold for statistical significance.

[0522] The specific analysis method is as follows: First, the normality and homogeneity of variance of the data are tested. If the data are normally distributed and have homogeneity of variance, a t-test is used for comparisons between two groups, and one-way ANOVA is used for comparisons among multiple groups. If the data are normally distributed but have unequal variances, a Welch t-test is used for comparisons between two groups, and non-parametric tests are used for comparisons among multiple groups. If the data do not conform to a normal distribution, a Mann-Whitney test is used for comparisons between two groups, and a Kruskal-Wallis test is used for comparisons among multiple groups. The results are shown below. Figures 6A to 6D .

Claims

1. A compound of formula (IA), (IB), or (IC): , , or , Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in: In formula (IA), Y is C(R) 1 ), N, -OC-, -C-NH-, -CH2-C(O)- or -CH=N-; when Y is C(R 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A, and the carbon atom is attached to both RT and B; When Y is -C-NH-, the carbon atom is simultaneously attached to RT and A, and the nitrogen atom is attached to B; A is selected from the following rings: phenyl, pyridinyl, thiopheneyl, furanyl, pyrroleyl, 4H-pyran, 4H-thiopyran, 1,2,3,4-tetrahydro-1-naphthyl, tetrahydrozoline, quinoxalinyl, pyrimidinyl and 2,1,3-benzothiadiazole; B is , ,or Where X is NH, O or S, and R a It consists of H and methyl groups; n is 0, 1, 2, or 3; R 2 Each is independently selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, ester, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, OR 4 -CN, N3, NO2, N(R) 4 2. SR 4 C(O)R 4 SO2N(R) 4 )2、CH2SR 4 ; wherein the alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryl, heterocyclic, or heterocyclic alkyl groups are optionally surrounded by one or more R groups. 5 replace; R 4 Selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, and said alkyl, alkenyl, alkynyl, alkoxy, esteryl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, optionally separated by one or more R 5 replace; R 5 Selected from halogens, hydroxyl groups, -CN, -NO2, alkyl groups, alkoxy groups, alkenyl groups, alkenyloxy groups, alkynyl groups, cycloalkyl groups, cycloalkoxy groups, aryl groups, aryloxy groups, aralkyl groups, heteroaryl groups, heteroaryl groups, heterocyclic groups, and heterocyclic alkyl groups; or, When two R 2 When the two Rs are substituted at adjacent positions on the benzene ring, 2 The group, together with the carbon atom it is attached to, forms a bicycle fused with ring A, such as quinolinyl, indolyl, benzothiophenyl, benzofuryl, benzofuranyl, benzodioxolyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, zolinyl, quinoxalinyl, or 1,2,4-benzotriazineyl; m is 0, 1, 2, or 3; R 3 Each is independently selected from H, deuterium, halogen, -OH, -SH, optionally substituted alkyl, optionally substituted heterocyclic and optionally substituted aryl; or, R 3 It is a group linked through the imidazole ring -NH- group, and R 3 It has the following formula: , , , ,or , in, R 5 It is hydrogen or alkyl; R 6 It is hydrogen, alkyl, cycloalkyl, or alkenyl; R 7 It is an amino acid residue; and R 8 It is an alkyl or cycloalkyl group; R T It is R L -R P And R P Optionally R C replace; in: R L It is a connector, one end of which is connected to R. P The other end is connected to Y; R P It is connected to R L One end portion; and R C It is an end cap base, which is connected to R P Part of; In formula (IB), Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R) 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and A, B, R 2 n, R 3 m and R T As defined in the above formula (IA); and In formula (IC), Y is a bond, CH(R) 1 ), NH, -O-CH-, -C-NH-, -CH2-C(O)- or -CH=N-; When Y is C(R) 1 When R 1 Selected from H, deuterium, and halogens; When Y is -OC-, the oxygen atom is attached to A and the carbon atom is attached to B; When Y is -C-NH-, the carbon atom is attached to A and the nitrogen atom is attached to B; and A, B, R 2 n, R 3 m and R T As defined in the above formula (IA).

2. A compound of formula (II): Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates; in: A is selected from one of the following: 、 、 ; n1 is 1 or 2; R 1 Each is independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl and -COOH; B is selected from one of the following: , , ,and , Where X is S, O, or NH; R T yes or Ring M is C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 heteroaryl, wherein the C 3-12 The cycloalkyl group is optionally fused with the aryl group; r is 1 or 2; n2 is 0, 1, or 2; R 2 Each is independently selected from hydrogen, halogens, hydroxyl groups, and alkoxy groups; R 3 Selected from CN, hydroxyl, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclic groups, -SO2-alkyl groups, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene-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’ ), -NH-R 7 or ; wherein -C 0-12 Alkylene-R 3’ One of the -CH2- groups is optionally replaced by an oxygen atom or Instead, the -C 0-12 Alkylene-R 3’ Optionally substituted with one or more substituents selected from amino and alkylamino groups, and the C 2-12 Heterocyclic groups and the C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 3’ Selected from -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 and C 0-12 Alkylene-C 1-12 Mixed aromatics; R 4a Each is independently selected from hydroxyl, alkyl, oxo, ketone and -C 2-12 Heterocyclic groups; R 4 and R 4’ Each of these components is independent of hydrogen, alkyl, alkoxy, -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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Or, R 4 and R 4’ Together with the nitrogen atom to which it is attached, it forms a heterocycle comprising one or more heteroatoms selected from O, N, and S; Or, when an R 2 Adjacent to R 3 At that time, R 2 and R 3 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 4a Replacement ring; R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl, or optionally alkyl groups substituted with cyano, amide, trialkylamine, or thiolate; wherein, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6a Each is independently selected from hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 6-12 Aryl and -C 0-12 Alkylene-C 1-12 Heteroaryl; wherein the alkyl, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6 It is an alkoxy, amino, sulfonamide, urea, or optionally substituted alkyl group; R 7 It is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted C 3-12 cycloalkyl, C 2-12 Aryl, 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 groups; R 8 It is an alkoxy group, amino group, alkylamino group, amide group, sulfonamide group, or urea group; 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. The compound of claim 2, wherein, A is or .

4. The compound of claim 2, wherein, A is or 。 5. The compound of claim 2, wherein, A is or 。 6. The compound according to any one of claims 2-5, wherein, n1 is 2.

7. The compound according to any one of claims 2-6, wherein, R T yes .

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

9. The compound according to any one of claims 2-8, wherein M is C 3-12 cycloalkyl or C 2-12 Heterocyclic groups, such as cyclopentyl, cyclohexyl, or pyrrolidinyl, wherein, The C 3-12 cycloalkyl or C 2-12 The heterocyclic group may optionally fuse with the aryl group.

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

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

12. The compound of claim 2 is a compound having formula (II-A): ,in, R 1 R 2 R 3 and n1 as defined in claim 2.

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

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

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

16. The compound according to any one of claims 12-15, wherein R 3 It is -C(O)-NR 4 R 4’ or -SO2-NR 4 R 4’ ;in, R 4 With R 4’ Each of these components is independent: 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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a Or hydroxyalkyl, and said hydroxyalkyl may optionally be substituted with alkoxy; wherein said alkyl, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace.

17. The compound according to any one of claims 12-15, wherein, R 3 It is 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 , where R 4 It is hydrogen or alkyl, and R 5 It is amino, alkylamine, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl or, optionally, alkyl substituted with cyano or amide groups; wherein the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace.

18. The compound according to any one of claims 12-15, wherein, R 3 It is hydroxyl group, -COOH, -CH(CH3)-COOH, -CN, , , , , , or .

19. The compound according to any one of claims 12-15, wherein R 3 yes m is 0, 1, 2, 3, 4 or 5, and R 6 It is a sulfonamide, a urea group, or an alkyl group optionally substituted with a cyano group.

20. The compound according to any one of claims 12-15, wherein R 3 It is -NH-R 7 And R 7 It is hydrogen, and the C is optionally substituted. 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 Alkyl groups, or optionally substituted with cyano groups.

21. The compound according to any one of claims 12-15, wherein, R 3 yes n can be 3 or 4, with 4 being the preferred choice.

22. The compound of claim 2 is a compound having formula (II-B): ,in, R 1 R 8 and n1, n3 and n4 as defined in claim 2.

23. The compound of claim 22, wherein, R 8 It is -OCH3, -NH2, -NHCH3, -NHC(O)CH3, sulfonamide, or urea group.

24. The compound of claim 23, wherein, The sulfonamide is or .

25. The compound of claim 23, wherein, The urea group is or .

26. A compound 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 as described in any one of the preceding claims and a pharmaceutically acceptable carrier.

28. A method of treating or preventing a disease in a subject in need, the method comprising administering to the subject a compound as described in any one of claims 1-26 or a pharmaceutical composition as described in claim 27.

29. A method as claimed in claim 28, wherein, The diseases mentioned include pain, glaucoma, spasms, nasal congestion, rosacea, rhinitis, anesthesia, presbyopia, acute kidney injury, insomnia, inflammatory diseases, or cancer.

30. A method for activating α2-adrenergic receptors (α2AR) in a subject in need, the method comprising administering to the subject a compound as described in any one of claims 1-26 or a pharmaceutical composition as described in claim 27.

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

32. The method of claim 31, wherein the Kp,uu,brain of the peripherally selective α2AR agonist is less than 0.05, 0.02, or 0.

01.

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

34. The method of any one of claims 31-33, wherein the sedative effect induced by treatment with the peripherally selective α2AR agonist is weaker than that induced by treatment with a non-peripherally selective α2AR agonist.

35. The method of any one of claims 31-34, wherein the peripherally selective α2AR agonist comprises a covalently linked α2AR activation portion and a peripherally distributed portion.

36. The method of claim 31, wherein, The α2AR activation component is an α2AR agonist.

37. The method of claim 36, wherein the α2AR activating moiety is an α2AR agonist selected from the following: (R)-3-nitrobenzidine, A-193080, ADX-415, AGN-192836, AGN-191103, AGN-197075, AGN-201781, AGN-241622, Amitraz, Apraclonidine, AR-08, Bethanidine, Brimonidine, BRL-48962, Bromocriptine, Cirazoline, Clonidine, Detomidine, Detomidinecarboxylic acid. acid), dexmedetomidine, dipivfrin, DL-methylephedrine, droxidopa, epinephrine, ergotamine, etilefrine, etomidate, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, indanidine, lofexidine, medetomidine, mephentermine, methamphetamine, metaraminol, methoxamine, methyldopa, methyldopate, methyldopate hydrochloride.hydrochloride, methylnorepinephrine, mivazerol, moxonidine, naphazoline, norepinephrine, norfenefrine, octopamine, ODM-105, oxymetazoline, pergolide, phenylpropanolamine, povafonidine, propanediol Propylhexedrine, pseudoephedrine, racepinephrine, rezatomidine, rilmenidine, romifidine, synephrine, talipexole, tasipimidine, tiamenidine, tizanidine, xylazine, xylometazoline and their functional derivatives.

38. The method of claim 36 or 37, wherein, The α2AR activation component is dexmedetomidine.

39. The method of any one of claims 35-38, wherein the peripheral distribution portion comprises a substrate element of an active efflux transporter.

40. The method of claim 39, wherein, The active efflux transporter protein is a P-glycoprotein (P-gp).

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

42. The method of claim 39 or 40, wherein, The substrate elements of the P-glycoprotein (P-gp) are selected from the following: and 。 43. The method of claim 39, wherein the active efflux transporter is a breast cancer resistance protein (BCRP) transporter.

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

45. The method of any one of claims 35-38, wherein the peripheral distribution portion comprises a structure selected from the group consisting of: -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 Alkylenes -COOH, -SO2-OH and .

46. ​​The method of claim 35, wherein, The α2AR activation part has the formula Where A is selected from one of the following: , and n1 is 1 or 2; R 1 Each element is independently selected from hydrogen, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkyl, and -COOH; B is selected from... , , and , where X is S, O or NH.

47. The method of claim 35, wherein, The outer peripheral distribution portion has the following formula: , where R T yes or Ring M is C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 Heteroaryl, wherein the C 3-12 cycloalkyl or C 2-12 The heterocyclic group is optionally fused with the aryl group; r is 1 or 2; n2 is 0, 1, or 2; R 2 Each is independently selected from hydrogen, halogen, hydroxyl, and alkoxy; R 3 Selected from CN, hydroxyl, alkoxy, -C(O)-C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 2-12 Heterocyclic groups, -SO2-alkyl groups, -C(O)-NR 4 R 4’ -SO2-NR 4 R 4’ -C 0-12 Alkylene-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’ ), -NH-R 7 or ;in, The -C 0-12 Alkylene-R 3’ One of the -CH2- groups is optionally composed of an oxygen atom or Instead, 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 Heterocyclic groups and the C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 3’ Selected from -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 Mixed aromatics; R 4a Each group is independently selected from hydroxyl, alkyl, oxo, ketone and -C groups. 2-12 Heterocyclic groups; R 4 and R 4’ Each of these components is independent of hydrogen, alkyl, alkoxy, -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 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 0-12 Alkylene-OR 6a or hydroxyalkyl, wherein the hydroxyalkyl group is optionally substituted with an alkoxy group; wherein the alkyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; Or, R 4 and R 4’ Together with the nitrogen atoms they are attached to, they form heterocycles containing one or more heteroatoms selected from O, N, and S; Or, when an R 2 Adjacent to R 3 At that time, the R 2 and R 3 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 4a Replacement ring; R 5 It is amino, alkylamino, C 1-12 Halogenated alkyl, -C 0-12 Alkylene-OR 6a -C 0-12 Alkylene-N(R) 6a ) t -C 0-12 Alkylene-SR 6a -C 0-12 Alkylene-CN, -C 0-12 Alkylene-C 3-12 cycloalkyl, -C 0-12 Alkylene-C 2-12 Heterocyclic group, -C 0-12 Alkylene-C 1-12 heteroaryl, -C 2-12 Alkenyl or optionally substituted with cyano, amide, trialkylammonium or thiolate; wherein, the C 3-12 cycloalkyl, C 2-12 Heterocyclic groups and C 1-12 Each of the heteroaryl groups is optionally bounded by one or more R 4a replace; R 6 It is an alkoxy, amino, sulfonamide, urea, or optionally alkyl group substituted with a cyano group; R 7 It is hydrogen, alkyl, -C 0-12 Alkylene-COOH, optionally substituted C 3-12 cycloalkyl, C 2-12 Aryl, 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 groups; R 8 It is an alkoxy group, amino group, alkylamino group, amide group, sulfonamide group, or urea group; 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.

48. A process for preparing a peripherally active α2AR agonist, the process comprising the step of covalently linking a non-peripherally selective α2AR agonist to a peripherally distributed portion.

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