Compound and application thereof

Abstract

The invention relates to the field of compounds, in particular to a compound and application thereof. The present invention provides a compound, which is characterized in that the compound is a compound represented by a formula A, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, and a pharmaceutically acceptable salt or prodrug thereof: (A). The compound synthesized by the invention has a very strong activation effect on CXCR7 in vitro and in vivo, can be used as a CXCR7 agonist, and is further used for treating and / or preventing organ fibrosis, organ injury and other application scenes.

Description

[0001] This application claims priority to Chinese Patent Application No. 2024112522951, filed on September 6, 2024, entitled “A CXCR7 agonist,” which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to the field of compounds, and more specifically to a compound and its uses. Background Technology

[0003] Organ fibrosis is a major pathological feature of many diseases, and it accounts for approximately one-third of all disease deaths worldwide. Pulmonary fibrosis leads to respiratory failure and death, with a shorter average survival time than lung cancer. Current clinical drugs, such as nintedanib and pirfenidone, cannot effectively reverse the progression of pulmonary fibrosis. Promoting the regeneration of fibrotic lung tissue holds promise for restoring damaged alveolar and vascular structures, providing a strategy for the treatment of various diseases, including pulmonary fibrosis.

[0004] The lung is a highly vascularized organ, with capillary endothelial cells situated between the bloodstream and epithelial and interstitial cells. Besides performing gas exchange, endothelial cells interact with neighboring epithelial, interstitial, and blood cells by paracrine secretion of the angiocrine factor, regulating lung regeneration and fibrosis. CXCR7, highly expressed specifically in pulmonary capillaries, can serve as a key target in the vascular microenvironment to coordinate lung regeneration and fibrosis. In the vascular microenvironment of fibrotic lung tissue, CXCR7 signaling is inhibited, leading to pro-fibrotic angiocrine signaling that stimulates perivascular fibroblasts, thereby activating the fibrotic response and inhibiting lung regeneration. Targeting CXCR7 in the pulmonary vascular microenvironment to activate this receptor can reprogram the angiocrine signaling in the vascular microenvironment, inhibiting fibroblast activation and stimulating alveolar stem cell activity, thereby promoting the repair and regeneration of fibrotic lung tissue.

[0005] G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins with a seven-transmembrane helix (7TM). They are the largest receptor superfamily discovered to date, widely involved in various important life activities such as reproduction, growth, development, and perception, and therefore attract significant attention in drug development. As of 2017, approximately 34% of all drugs approved by the US FDA target GPCRs. The traditional receptor-ligand interaction model assumes that ligand binding to a receptor mediates multiple downstream intracellular signaling pathways. However, experimental studies of muscarinic cholinergic receptor agonists have revealed that certain ligands can induce receptors to selectively bind to specific G protein subunits, causing intracellular signals to be biased towards a particular downstream pathway—a phenomenon known as "signal bias." Subsequent research has shown that this bias is not only manifested in the selective binding of different G protein subunits to exert drastically different physiological functions, but also in the selective bias towards G protein pathways or G protein-independent pathways. β - One of the inhibitory proteins (β-arrestin) pathways, ultimately leading to completely different biological effects.

[0006] In other words, GPCRs exhibit "signal bias," meaning they are biased towards the activation of G proteins and β-arrestin. CXCR7 specifically activates the intracellular β-arrestin signaling pathway without coupling to G protein signaling pathways. This biased β-arrestin signal transduction property facilitates the design of CXCR7 agonists that can avoid activating G protein signaling pathways when treating organ fibrosis (e.g., pulmonary fibrosis), thereby reducing side effects. However, no small molecule drugs targeting CXCR7 have yet received clinical approval, and highly effective CXCR7 agonists are lacking. Summary of the Invention

[0007] In a first aspect, the present invention provides a compound, characterized in that the compound is a compound represented by formula A as shown below, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt or prodrug thereof: (A) in, L is selected from (C1-C6) alkyl groups; n is selected from 0, 1, 2, or 3; X and Y are each independently selected from C or N; R is selected from -C(=O)NR x R y 、or -C(=O)OR x , or substituted aryl or aromatic heterol groups; R x and R yIndependently selected from hydrogen atom, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1,1,1)pentyl, or ; R Z The substituent is at least one of ortho-substitution, meta-substitution, and para-substitution, wherein the substituent is selected from halogen, methoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, or trifluoromethoxy.

[0008] In some embodiments, R is selected from -C(=O)NR. x R y or -C(=O)OR x R x It is selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

[0009] In some embodiments, R y Selected from hydrogen atoms.

[0010] In some embodiments, R is selected from -C(=O)NR. x R y or -C(=O)OR x R x Selected from or R Z Halogens that are at least one of ortho-substituted, meta-substituted, or para-substituted.

[0011] In some embodiments, the halogen is selected from fluorine, bromine, or chlorine.

[0012] In some embodiments, R y Selected from hydrogen atoms.

[0013] In some embodiments, R Z Halogens that are para-substituted.

[0014] In some embodiments, R is selected from -C(=O)NR. x R y or -C(=O)OR x R x It is selected from ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0015] In some embodiments, R y Selected from hydrogen atoms.

[0016] In some embodiments, L is selected from C3 or C4 alkyl groups.

[0017] In some embodiments, X is N, and Y is selected from C or N.

[0018] In some embodiments, n is selected from 0 or 1.

[0019] In some embodiments, the compound has a formula selected from the group consisting of: , , , , , , , and .

[0020] In some embodiments, the compound is a compound represented by formula B. (B) In this case, X and Y are each independently selected from C or N; R is selected from -C(=O)NHR x 、or -C(=O)OR x Or substituted aryl or aromatic heterol groups; R x It is selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

[0021] In some embodiments, R x It is selected from ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0022] In some embodiments, X is N, and Y is selected from C or N.

[0023] Secondly, the present invention also provides the use of the above-mentioned compound in the preparation of CXCR7 agonists.

[0024] As used herein, an "agonist" is a substance that promotes (e.g., induces, causes, enhances, or increases) the biological activity or effect of another molecule.

[0025] As used herein, “CXCR7 agonist” means a substance that fully or partially activates the CXCR7 receptor. In some embodiments, the CXCR7 agonist is a compound. The term “CXCR7 agonist” and the specific CXCR7 agonists described herein are also intended to cover their salt forms.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventionally non-toxic salts of the parent compound from which they are formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both. Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, while examples of suitable organic acids include carboxylic acids or sulfonic acids, such as formic acid, acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzopentalic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, maleic acid, salicylic acid, trifluoroacetic acid, 3-aminosalicylic acid, ascorbic acid, aconitic acid, nicotinic acid, isonicotinic acid, oxalic acid, gluconic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, or naphthalene-2-sulfonic acid. Examples of suitable inorganic bases include sodium hydroxide, potassium hydroxide, and ammonia, and examples of suitable organic bases include amines, such as tertiary amines, such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, α-methylpyridine, β-methylpyridine, γ-methylpyridine, quinalidine, or pyrimidine.

[0027] Thirdly, the present invention also provides the use of the above-mentioned compounds in the preparation of medicaments for treating and / or preventing organ fibrosis.

[0028] In some embodiments, the organ fibrosis includes one or more of pulmonary fibrosis, liver fibrosis, and kidney fibrosis.

[0029] In some embodiments, the symptoms of organ fibrosis include increased levels of one or more of the following molecules: α-smooth muscle actin (α-SMA), collagen I, and hydroxyproline.

[0030] In some embodiments, the drug is used to alleviate one or more of the following symptoms: degree of organ fibrosis, degree of organ damage, degree of collagen deposition, and degree of fibroblast activation.

[0031] As used in this article, “fibrosis” refers to the abnormal repair process in tissues or organs following excessive or unregulated deposition and damage of extracellular matrix components, such as skeletal muscle, cardiac muscle, liver, lungs, kidneys, and pancreas.

[0032] Fourthly, the present invention also provides the use of the above-mentioned compounds in the preparation of medicaments for treating and / or preventing one or more of lung diseases, liver diseases, and kidney diseases.

[0033] As used herein, “lung disease” means a disease that occurs in the lungs, including diseases of the lungs themselves or lung manifestations of systemic diseases. In some embodiments, the lung disease includes one or more of pulmonary fibrosis, interstitial lung disease, chronic obstructive pulmonary disease, and lung injury.

[0034] In some embodiments, the lung injury includes lung injury following infection or surgery.

[0035] As used herein, “liver disease” means a disease that occurs in the liver, including diseases of the liver itself or liver manifestations of systemic diseases. In some embodiments, the liver disease includes liver fibrosis and / or liver damage.

[0036] As used herein, “kidney disease” means a disease that occurs in the kidneys, including diseases of the kidneys themselves or renal manifestations of systemic diseases. In some embodiments, the kidney disease includes renal fibrosis and / or kidney damage.

[0037] Fifthly, the present invention also provides the use of the above-mentioned compounds in the preparation of medicaments for treating and / or preventing organ damage.

[0038] In some embodiments, the organ includes one or more of the lungs, liver, and kidneys.

[0039] In some embodiments, the organ injury includes one or more of lung injury, liver injury, and kidney injury.

[0040] In some embodiments, the use includes providing protection to the organ after injury to the organ.

[0041] As used herein, “alkyl” includes branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, (C1-C6)alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl. In some cases, straight-chain or branched alkyl groups have six or fewer carbon atoms in their main chain (e.g., straight-chain C1-C6, branched C3-C6), and in others, straight-chain or branched alkyl groups have four or fewer carbon atoms. Similarly, cycloalkyl groups have three to eight carbon atoms in their ring structure, and in others, cycloalkyl groups have five or six carbon atoms in their ring structure. Preferred are (C1-C6)alkyl groups, particularly ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0042] As used herein, “substitution” means the selection of any one or more hydrogen atoms on a specified atom to be replaced by an indicated group, provided that the normal valence of the specified atom does not exceed a certain value and the substitution results in a stable compound.

[0043] As used herein, “aryl” refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, or phenanthrene. In some cases, aryl groups have 6–20 carbon atoms. As used herein, the term “aromatic heterocycle” refers to an aromatic heterocycle having at least one heteroatom ring member such as O, S, or N atom. Aromatic heterocycle groups include monocyclic and polycyclic systems (e.g., having 2, 3, or 4 fused rings). The cyclic N atom in an aromatic heterocycle group can also be oxidized to form an N-oxygen moiety. Examples of aromatic heteroyl groups include pyridinyl, N-oxopyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolinyl, thiazolyl, indoleyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, 1,2,4-thiophenediazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolinyl, and dihydroindoleyl. In some cases, aromatic heteroyl groups have 1 to about 20 carbon atoms, and in others about 3 to 20 carbon atoms. In some cases, aromatic heteroyl groups contain 3 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some cases, aromatic heteroyl groups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0044] In some embodiments, the dosage range of the compound is about 0.1 mg / kg to about 40 mg / kg, 0.1 mg / kg to about 4 mg / kg, or 0.01 mg / kg to about 1.00 mg / kg. In some embodiments, the dosage range of the compound is about 1, 2, 3, 4, 5, 6, 7, 8, or 9 mg / kg to about 10, 20, 30, or 40 mg / kg; about 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mg / kg to about 20, 30, or 40 mg / kg; about 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 mg / kg to about 30 or 40 mg / kg; about 30, 31, 32, 33, 34, 35, 36, or 37 mg / kg. From about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 mg / kg to about 1, 2, 3, or 4 mg / kg; from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 mg / kg to about 2, 3, or 4 mg / kg; from about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, or 2.9 mg / kg to about 3... Or 4 mg / kg; or from about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8 or 3.9 mg / kg to about 4 mg / kg; from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 mg / kg to about 0.10, 0.20, 0.30 or 0.40 mg / kg; from about 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0. 18 or 0.19 mg / kg to about 0.20, 0.30 or 0.40 mg / kg; about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28 or 0.29 mg / kg to about 0.30 or 0.40 mg / kg; or about 0.30 mg / kg to about 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38 or 0.39 mg / kg to about 0.40 mg / kg.

[0045] Compared with the prior art, the beneficial effects of the present invention include at least the following aspects: Previous studies have found that CXCR7 signaling is suppressed in the vascular microenvironment of fibrotic lung tissue, leading to pro-fibrotic angiocrine signaling, which stimulates perivascular fibroblasts, thereby activating the fibrotic response and inhibiting lung regeneration. Targeting CXCR7 in the lung vascular microenvironment to activate this receptor could reprogram the angiocrine signaling in the vascular microenvironment, inhibiting fibroblast activation and stimulating alveolar stem cell activity, thereby promoting the repair and regeneration of fibrotic lung tissue. Even so, highly effective CXCR7 agonists are currently lacking.

[0046] The compounds synthesized in this invention (e.g., compounds represented by Formula A) exhibit strong activating effects on CXCR7 in vitro. In CXCR7 activity tests, most of these compounds achieved high EC50 (half-maximal effective concentration) levels for CXCR7, even exceeding those of existing CXCR7 agonists such as VUF11207. The compounds synthesized in this invention can specifically activate the intracellular β-arrestin signaling pathway without coupling to G protein signaling pathways, thus serving as novel CXCR7 agonists. They efficiently activate CXCR7 in endothelial cells, reprogramming angiocrine signaling in the vascular microenvironment, thereby promoting organ regeneration and inhibiting organ fibrosis. Furthermore, the compounds synthesized in this invention, as CXCR7 agonists, can be further used in the treatment and / or prevention of organ fibrosis, organ damage, and other applications. Attached Figure Description

[0047] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0048] Figure 1 The figure shows the results of discovering novel CXCR7 agonists based on the PRESTO-Tango high-throughput drug screening platform; Figure 2 The synthetic route for compound S1 is shown below. Figure 3 The synthetic route for compound S2 is shown below. Figure 4 The synthetic route for compound S3 is shown below. Figure 5 The synthetic route for compound S4 is shown below. Figure 6 The synthetic route for compound S5 is shown below. Figure 7 The synthetic route for compound S6 is shown below. Figure 8 The synthetic route for compound S7 is shown below. Figure 9 The synthetic route for compound S8 is shown below. Figure 10 The synthetic route for compound S9; Figure 11 The graph shows the activation effect of compound S1 on CXCR7. Figure 12 Figure 1 shows the activation effects of compounds S1, S2, and S9 on CXCR7 detected by the PRESTO-Tango system (results are expressed as mean ± SEM). n= 3)); Figure 13 The figure shows the results of in vivo verification of the therapeutic effect of the CXCR7 agonist S1 on pulmonary fibrosis. Figure 14 This image shows the results of CXCR7 being specifically highly expressed in pulmonary vascular endothelial cells. Figure 15 This is a graph showing the results of compound S1 inhibiting pulmonary fibrosis. Figure 16 The figure shows the results of in vivo verification of the therapeutic effect of the CXCR7 agonist S1 on liver fibrosis. Detailed Implementation

[0049] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0050] In this document, the terms "upper," "lower," "inner," "outer," "front," "rear," "one end," and "the other end," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the present invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the present invention. Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0051] In this document, "and / or" includes any and all combinations of one or more of the listed related items.

[0052] In this article, "multiple" means two or more, that is, it includes two, three, four, five, etc.

[0053] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes that element.

[0054] As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4% of the value, more typically + / -3% of the value, more typically + / -2% of the value, even more typically + / -1% of the value, and even more typically + / -0.5% of the value.

[0055] In this specification, certain embodiments may be disclosed in a range-bound format. It should be understood that this "range-bound" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges and the individual numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This rule applies regardless of the breadth of the range.

[0056] Detailed description of the attached diagram: Figure 1 A. Roadmap for identifying CXCR7 agonists using the PRESTO-Tango high-throughput drug screening platform. The GPCR drug library contains a total of 1132 compounds. BC. Eight compounds capable of activating CXCR7 were identified using the PRESTO-Tango system. Results are presented as mean ± SEM. n= 3).

[0057] Figure 13 Results from hydroxyproline content assay (A), Masson staining (B), Sirius red staining (C), H&E staining (D), and Collagen I (E) and α-SMA immunofluorescence staining (F) showed that compound S1 could alleviate pulmonary fibrosis. Results are expressed as mean ± SEM. n= 5).

[0058] Figure 14 (AB) Single-cell transcriptome sequencing (scRNA-seq) was used to analyze the expression of CXCR7 in different cell types in lung tissue. (C) Immunofluorescence staining showed that CXCR7 was specifically expressed in lung vascular endothelial cells. VE-Cad is a marker for vascular endothelial cells.

[0059] Figure 15 Compound S1 targets CXCR7 in endothelial cells, reprogramming the angiocrine signaling pathway in the vascular microenvironment to promote lung regeneration and inhibit fibrosis. Lung vascular endothelial cells were isolated using magnetic bead sorting, and the expression changes of angiocrine factors, including Hgf, Aplin, Mmp14, Dll4, Kit, Egfl7, Tgfb1, Pdgfb, Igfbp7, Ctgf, Adamts1, and Tgfb2d, were detected. Results are expressed as mean ± SEM (n=3).

[0060] Figure 16 Serum alanine aminotransferase (ALT) level detection (A), Masson staining (C), Sirius red staining (B), H&E staining (D), and α-SMA immunofluorescence staining (E) results showed that compound S1 could alleviate liver fibrosis. Results are expressed as mean ± SEM. n= 5).

[0061] Example 1 To develop novel and highly effective CXCR7 agonists, this embodiment employed the PRESTO-Tango high-throughput drug screening platform, combined with a GPCR small molecule drug library, to screen for small molecule compounds with the potential to activate CXCR7. PRESTO-Tango utilizes a luciferase reporter system to detect the activation of the CXCR7-coupled β-arrestin signaling pathway by small molecule drugs. This is based on the principle that ligands bind to specific G protein-coupled receptors (GPCRs), thereby activating the downstream β-arrestin signaling pathway. This process is mediated by the recruitment of a protease-tagged repressor protein (β-arrestin) to the activated receptor. The protease-tagged repressor protein cleaves the protease site fused to the C-terminus of the GPCR, releasing a non-natural transcription factor. This transcription factor immediately enters the cell nucleus, bypassing additional signal transduction intermediates. Based on the activation of the reporter gene, the degree of interaction between the target receptor and the protease-tagged repressor protein can be quantitatively determined, agonist-mediated receptor activation can be monitored, and the relative potency of different compounds can be evaluated. When CXCR7 on the cell membrane is activated by small molecule drugs, it can further activate the intracellular β-arrestin signaling pathway and stimulate luciferase expression. Figure 1 A).

[0062] Using this system, this embodiment tested 1132 compounds in the GPCR drug library one by one and identified 8 compounds that could activate CXCR7. Figure 1 B Figure 1 C), namely VUF11207, AMD3100, JMS-17-2, Rupatadine, MK-0667, Asenapine, Alverine, and Vilanterol. Despite the EC of S9665 (Motixafortide). 50 The value was low, and since it is a peptide drug, it was not included in the subsequent construction of small molecule compounds.

[0063] Of these eight compounds, VUF11207 and AMD3100 (S3013) are known CXCR7 agonists, while the activation of CXCR7 by the remaining six small molecule compounds has not been reported.

[0064] Therefore, by utilizing the PRESTO-Tango drug screening platform and the GPCR small molecule drug library, this embodiment discovered six novel CXCR7 agonists, including S0135 (JMS-17-2, EC50). 50 The value is 70.7 nM), S3052 (Rupatadine, EC) 50 The value is 384.8 nM), S1151 (MK-0667, ibuprofen mesylate, EC) 50 Value 3.94 μM), S1283 (Asenapine, EC) 50 Value >100 μM), S3054 (Alverine, EC) 50 Values ​​>100 μM) and S3727 (Vilanterol, EC) 50 Value >100 μM) Figure 2 ).

[0065] Example 2 The synthetic route for compound S1 is shown in [reference needed]. Figure 2 .

[0066] Step 1: Synthesis of intermediate 1-3 (methyl(2-nitrophenyl)proline ester) Weigh out 38 mg (0.96 mmol) of NaH and dissolve it in a 10 mL DMF round-bottom flask. Stir at 0 °C for 15 minutes. Add methyl 2-pyrrolecarboxylate (intermediate 1-1, 100 mg; 0.80 mmol), continue stirring, and after 30 minutes add 1-fluoro-2-nitrobenzene (intermediate 1-2, 124 mg; 0.88 mmol). Then stir the reaction mixture overnight at 50 °C. After the reaction is complete, quench with water, extract with ethyl acetate, wash with saturated brine, and dry on anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure to remove the solvent, giving an orange-red solid. Purify by column chromatography to give 95 mg of pure intermediate 1-3 as a bright yellow solid.

[0067] Step 2: Synthesis of intermediate 1-4 (pyrrolo[1,2-a]quinoxaline-4(5H)-one) Intermediate 1-3 (150 mg; 0.61 mmol) and Pd / C (65 mg; 0.061 mmol) were weighed into a two-necked flask, 15 mL of methanol solution was added, and the mixture was purged three times with H2 and stirred at room temperature for 2 days. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to remove the solvent, yielding crude intermediate 1-4. The crude product was dissolved in 50 mL of a mixed solution (petroleum ether: ethyl acetate = 10:1) and stirred for 1 hour. The mixture was then slurried to obtain 62 mg of pure intermediate 1-4.

[0068] Step 3: Synthesis of intermediate 1-6 (5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one) Weigh out 27 mg (0.68 mmol) of NaH and dissolve it in a 10 mL DMF round-bottom flask. Stir at 0 °C for 15 minutes. Add intermediate 1-4 (105 mg; 0.57 mmol), continue stirring, and after 2 hours add 1-bromo-3-chloropropane (intermediate 1-5; 108 mg; 0.68 mmol). Then stir the reaction mixture at 80 °C for 8 hours. After the reaction is complete, quench with water, extract with ethyl acetate, wash with saturated brine, and dry on anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure to remove the solvent, giving a yellow oily substance. Purify by column chromatography to obtain 86 mg of pure intermediate 1-6.

[0069] Step 4: Synthesis of intermediate 1-9 (4-(tert-butylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester) 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (intermediates 1-8, 100 mg; 0.44 mmol) and HATU (251 mg; 0.66 mmol) were weighed and dissolved in 10 mL of DMF. 56 μL of tert-butylamine and 219 μL of DIPEA (intermediates 1-7) were added dropwise using a pipette. The reaction was stirred overnight at room temperature. The product was monitored using Lc-ms. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 90 mg of crude intermediates 1-9.

[0070] Step 5: Synthesis of intermediate 1-10 (N-(tert-butyl)piperidine-4-carboxamide) 90 mg of crude intermediates 1-9 was dissolved in a mixed solution of dichloromethane and dioxane hydrochloride, and stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the solution was evaporated to dryness to obtain 122 mg of crude intermediate 1-10.

[0071] Step 6: Synthesis of compound S1 (N-(tert-butyl)-1-(3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propyl)piperidine-4-carboxamide) Intermediate 1-6 (100 mg; 0.38 mmol), intermediate 1-10 (77 mg; 0.42 mmol), potassium carbonate (105 mg; 0.76 mmol), and potassium iodide (6.3 mg; 0.038 mmol) were weighed sequentially into a round-bottom flask. 10 mL of DMF was added, and the mixture was stirred at 80 °C for 8 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to remove the solvent. Purification by column chromatography yielded 65 mg of pure compound S1.

[0072] 1 H NMR (400 MHz, Chloroform- d ) δ 7.69 (d, J = 8.1 Hz, 1H), 7.66 (t, J =2.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.26 – 7.18 (m,2H), 6.66 (t, J = 3.4 Hz, 1H), 5.36 (s, 1H), 4.32 (t, J = 7.4 Hz, 2H), 3.01 (dt, J= 11.7, 3.7 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.08 – 1.92 (m, 5H), 1.84 (dd, J =12.9, 3.5 Hz, 2H), 1.80 – 1.69 (m, 2H), 1.34 (s, 9H). Example 3 The synthetic route for compound S2 is shown in [link to synthetic route]. Figure 3 .

[0073] Step 1: Synthesis of compound S2 (tert-butyl-1-(3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propyl)piperidine-4-carboxylate) Weigh out 9 mg (0.23 mmol) of NaH and dissolve it in a 10 mL DMF round-bottom flask. Stir at 0 °C for 15 minutes. Add intermediate 1-6 (50 mg; 0.19 mmol), continue stirring, and after 30 minutes add tert-butyl 4-piperidinecarboxylate (intermediate 2-1, 108 mg; 0.68 mmol). Stir the reaction mixture at 80 °C for 8 hours. After the reaction is complete, quench with water, extract with ethyl acetate, wash with saturated brine, and dry on anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure to remove the solvent, and purify by column chromatography to give 33 mg of pure compound S2.

[0074] 1 H NMR (400 MHz, Chloroform- d ) δ 7.69 (dd, J = 8.1, 1.4 Hz, 1H), 7.65(dd, J = 2.8, 1.5 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.34 – 7.29 (m, 1H), 7.24 –7.20 (m, 2H), 6.66 (dd, J = 3.9, 2.8 Hz, 1H), 4.32 (t, J = 7.5 Hz, 2H), 2.90 (dd, J = 10.6, 4.6 Hz, 2H), 2.48 (d, J = 7.0 Hz, 2H), 2.19 (tt, J= 11.0, 4.2 Hz, 1H),2.06 – 1.98 (m, 2H), 1.97 – 1.91 (m, 2H), 1.91 – 1.85 (m, 2H), 1.73 (ddd, J =13.2, 8.4, 3.5 Hz, 2H), 1.44 (s, 9H). Example 4 The synthetic route for compound S3 is shown in [reference needed]. Figure 4 .

[0075] Referring to step 3 of Example 2, intermediate 3-2 can be obtained by replacing intermediate 1-5 with intermediate 3-1.

[0076] Referring to step 6 of Example 2, replacing intermediates 1-6 with intermediate 3-2 yields compound S3.

[0077] 1 H NMR (400 MHz, Chloroform- d ) δ 7.70 (dd, J = 8.1, 1.4 Hz, 1H), 7.66(dd, J = 2.8, 1.5 Hz, 1H), 7.45 (dd, J = 8.6, 1.2 Hz, 1H), 7.37 (ddd, J = 8.5, 7.2,1.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.21 (dd, J = 3.9, 1.5 Hz, 1H), 6.67 (dd, J =3.9, 2.8 Hz, 1H), 5.30 (s, 1H), 4.32 – 4.26 (m, 2H), 3.04 (d, J = 11.1 Hz, 2H),2.51 (s, 2H), 2.05 (s, 1H), 2.02 (s, 1H), 1.87 (s, 2H), 1.79 (q, J = 7.4, 6.5Hz, 4H), 1.74 – 1.69 (m, 2H), 1.34 (s, 9H). Example 5 The synthetic route for compound S4 is shown in [link to synthetic route]. Figure 5 .

[0078] Referring to step 4 of Example 2, intermediate 4-2 can be obtained by replacing intermediate 1-7 with intermediate 4-1.

[0079] Referring to step 5 of Example 2, intermediate 4-2 is used instead of intermediate 1-9 to obtain the hydrochloride salt of intermediate 4-3.

[0080] Referring to step 6 of Example 2, intermediate 1-10 is replaced with intermediate 4-3 to obtain compound S4.

[0081] 1 H NMR (400 MHz, Chloroform- d ) δ 7.71 (d, J = 8.0 Hz, 1H), 7.68 (dd, J =2.9, 1.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.24 (s,1H), 7.21 (d, J = 3.7 Hz, 1H), 6.68 (t, J = 3.6 Hz, 1H), 6.08 (s, 1H), 4.37 (t, J =6.9 Hz, 2H), 3.33 – 3.27 (m, 2H), 2.92 (s, 2H), 2.79 (d, J = 4.7 Hz, 3H), 2.29– 2.10 (m, 6H), 2.02 (s, 3H). Example 6 The synthetic route for compound S5 is shown in [link to synthetic route]. Figure 6 .

[0082] Referring to step 4 of Example 2, intermediate 5-2 can be obtained by replacing intermediate 1-7 with intermediate 5-1.

[0083] Referring to step 5 of Example 2, intermediate 5-2 is used instead of intermediate 1-9 to obtain the hydrochloride salt of intermediate 5-3.

[0084] Referring to step 6 of Example 2, intermediate 5-3 is used instead of intermediate 1-10 to obtain compound S5.

[0085] 1 H NMR (400 MHz, Chloroform- d) δ 7.70 (dd, J = 8.1, 1.4 Hz, 1H), 7.66(dd, J = 2.8, 1.5 Hz, 1H), 7.48 (dd, J = 8.5, 1.3 Hz, 1H), 7.33 (ddd, J = 8.5, 7.3,1.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.21 (dd, J = 3.9, 1.5 Hz, 1H), 6.67 (dd, J =3.9, 2.8 Hz, 1H), 4.33 (t, J = 7.3 Hz, 2H), 3.29 (qd, J = 7.3, 5.5 Hz, 2H), 3.01(d, J = 11.1 Hz, 2H), 2.51 (t, J = 6.9 Hz, 2H), 2.09 – 2.01 (m, 2H), 1.97 (q, J =7.1 Hz, 3H), 1.87 (d, J = 12.7 Hz, 2H), 1.75 (qd, J = 11.8, 3.8 Hz, 3H), 1.14 (t, J = 7.3 Hz, 3H). Example 7 The synthetic route for compound S6 is shown in [link to synthetic route]. Figure 7 .

[0086] Referring to step 4 of Example 2, intermediate 6-2 can be obtained by replacing intermediate 1-7 with intermediate 6-1.

[0087] Referring to step 5 of Example 2, intermediate 6-2 is used instead of intermediate 1-9 to obtain the hydrochloride salt of intermediate 6-3.

[0088] Referring to step 6 of Example 2, intermediate 1-10 is replaced with intermediate 6-3 to obtain compound S6.

[0089] 1 H NMR (400 MHz, Chloroform- d ) δ 7.70 (dd, J= 8.1, 1.5 Hz, 1H), 7.67(dd, J = 2.9, 1.5 Hz, 1H), 7.47 (dd, J = 8.5, 1.2 Hz, 1H), 7.34 (ddd, J = 8.5, 7.3,1.4 Hz, 1H), 7.25 (dd, J = 8.1, 1.2 Hz, 1H), 7.21 (dd, J = 3.8, 1.4 Hz, 1H), 6.67(dd, J = 3.9, 2.8 Hz, 1H), 5.40 (d, J = 8.0 Hz, 1H), 4.34 (t, J = 7.2 Hz, 2H), 4.12– 4.02 (m, 1H), 3.07 (d, J = 11.5 Hz, 2H), 2.59 (t, J = 7.2 Hz, 2H), 2.11 (s,1H), 2.03 (dd, J = 10.2, 4.2 Hz, 3H), 1.92 (d, J = 12.9 Hz, 2H), 1.84 – 1.76 (m,2H), 1.14 (d, J = 6.6 Hz, 6H). Example 8 The synthetic route for compound S7 is shown in [link to synthetic route]. Figure 8 .

[0090] Referring to step 4 of Example 2, intermediate 7-2 can be obtained by replacing intermediate 1-7 with intermediate 7-1.

[0091] Referring to step 5 of Example 2, intermediate 7-2 is used instead of intermediate 1-9 to obtain the hydrochloride salt of intermediate 7-3.

[0092] Referring to step 6 of Example 2, intermediate 1-10 is replaced with intermediate 7-3 to obtain compound S7.

[0093] 1 H NMR (400 MHz, Chloroform- d ) δ 7.66 (d, J= 8.1 Hz, 1H), 7.64 – 7.61(m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.33 – 7.28 (m, 1H),7.20 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 3.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.63(t, J = 3.4 Hz, 1H), 6.28 (d, J = 7.0 Hz, 1H), 4.36 (d, J = 5.8 Hz, 2H), 4.27 (t, J =7.4 Hz, 2H), 2.96 (dt, J = 11.8, 3.5 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.14 (tt, J = 11.5, 4.3 Hz, 1H), 1.98 – 1.88 (m, 4H), 1.84 (dd, J = 13.6, 3.5 Hz, 2H), 1.76 (td, J = 12.1, 3.5 Hz, 2H). Example 9 The synthetic route for compound S8 is shown below. Figure 9 .

[0094] Referring to step 4 of Example 2, intermediate 8-2 can be obtained by replacing intermediate 1-8 with intermediate 8-1.

[0095] Referring to step 5 of Example 2, intermediate 1-9 can be obtained by replacing intermediate 1-9 with intermediate 8-2.

[0096] Referring to step 6 of Example 2, intermediate 1-10 is replaced with intermediate 8-3 to obtain compound S8.

[0097] 1 H NMR (400 MHz, Chloroform- d ) δ 7.69 (dd, J = 8.2, 1.4 Hz, 1H), 7.66(dd,J = 2.9, 1.5 Hz, 1H), 7.57 (dd, J = 8.5, 1.2 Hz, 1H), 7.35 (ddd, J = 8.6, 7.4,1.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.20 (dd, J = 3.9, 1.4 Hz, 1H), 6.66 (dd, J =3.9, 2.8 Hz, 1H), 4.37 (t, J = 7.3 Hz, 2H), 3.45 – 3.38 (m, 2H), 2.64 (t, J = 6.8Hz, 2H), 2.41 (dt, J = 12.3, 6.3 Hz, 1H), 2.11 (t, J = 11.7 Hz, 2H), 2.04 – 1.96(m, 4H), 1.64 (dt, J = 12.2, 4.0 Hz, 4H), 1.34 (s, 9H). Example 10 The synthetic route for compound S9 is shown in [link to synthetic route]. Figure 10 .

[0098] Step 1: Synthesis of intermediate 9-2 (tert-butyl-1-(3-chloropropyl)piperidine-4-carboxylate) tert-butylpiperazine carboxylate (intermediate 9-1, 200 mg; 1.07 mmol), 1-bromo-3-chloropropane (intermediate 1-5, 423 mg; 2.86 mmol), potassium carbonate (967 mg; 3.21 mmol), and potassium iodide (18 mg; 0.11 mmol) were weighed sequentially into a round-bottom flask. 10 mL of acetonitrile was added, and the mixture was stirred at 80 °C for 8 hours. The product was monitored using Lc-MS. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to remove the solvent. 233 mg of crude intermediate 9-2 was obtained.

[0099] Step 2: Synthesis of compound S9 (tert-butyl-4-(3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propyl)piperazine-1-carboxylate) Weigh out 13 mg (0.32 mmol) of NaH and dissolve it in a 10 mL DMF round-bottom flask. Stir at 0 °C for 15 minutes. Add intermediate 1-4 (50 mg; 0.27 mmol) and continue stirring. After 30 minutes, add intermediate 9-2 (78 mg; 0.30 mmol). Stir the reaction mixture at 80 °C for 8 hours. Then dilute the reaction solution with water, extract with ethyl acetate, concentrate the organic phase under reduced pressure to remove the solvent, and purify by column chromatography to obtain 42 mg of pure compound S9.

[0100] 1 H NMR (400 MHz, Chloroform- d ) δ 7.71 (dd, J = 8.1, 1.5 Hz, 1H), 7.66(dd, J = 2.8, 1.5 Hz, 1H), 7.44 (dd, J = 8.4, 1.3 Hz, 1H), 7.31 (ddd, J = 8.4, 7.3,1.5 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.22 (dd, J = 3.8, 1.4 Hz, 1H), 6.67 (dd, J =3.9, 2.8 Hz, 1H), 4.37 – 4.32 (m, 2H), 3.42 (t, J = 5.1 Hz, 4H), 2.51 (t, J = 6.9Hz, 2H), 2.41 (t, J = 5.1 Hz, 4H), 1.95 (p, J = 7.0 Hz, 3H), 1.46 (s, 9H). Example 10 In this embodiment, the activation effect of the compound shown in Formula A on CXCR7 was tested using the PRESTO-Tango system, that is, the activation effect of the new compound on the CXCR7-coupled β-arrestin signaling pathway, to evaluate whether the new compound can act as a CXCR7 agonist.

[0101] (A) in, L is selected from (C1-C6) alkyl groups; n is selected from 0, 1, 2, or 3; X and Y are each independently selected from C or N; R is selected from -C(=O)NR x R y 、or -C(=O)OR x , or substituted aryl or aromatic heterol groups; R x and R y Independently selected from hydrogen atom, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1,1,1)pentyl, or ; R Z The substituent is at least one of ortho-substitution, meta-substitution, and para-substitution, wherein the substituent is selected from halogen, methoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, or trifluoromethoxy.

[0102] Table 1 The results are as follows Figure 11 , Figure 12 As shown in Table 1, the compounds represented by Formula A can efficiently activate CXCR7 (e.g., <10 μM), with compound S1 exhibiting the strongest activation potential, reaching an EC50 value of 4.97 nM. Figure 12 A); the EC50 values ​​for the activation of CXCR7 by compounds S2 and S9 were 270.2 nM and 4.98 μM, respectively. Figure 12 B Figure 12 In other words, the compound represented by formula A can act as a CXCR7 agonist and exhibit therapeutic and / or preventive effects against organ fibrosis and organ damage.

[0103] Example 11 To verify the therapeutic effect of the novel compound S1 on pulmonary fibrosis in vivo, this embodiment established a mouse model of pulmonary fibrosis by intratracheal injection of bleomycin (using an intratracheal injection of 2 mg / kg of bleomycin to induce pulmonary fibrosis). Fourteen days after bleomycin modeling, mice were intraperitoneally injected with different doses of compound S1 (0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 5 mg / kg) to evaluate its therapeutic effect on pulmonary fibrosis.

[0104] This example evaluated the therapeutic effect of compound S1 on pulmonary fibrosis after 7 consecutive days of drug injection. The effect was assessed using hydroxyproline content determination (…). Figure 13 A) Masson staining ( Figure 13 B), Sirius Red staining ( Figure 13 C) H&E staining ( Figure 13 D) and Collagen I ( Figure 13 E) and α-SMA immunofluorescence staining ( Figure 13 (F) Using the technique, this embodiment found that different doses of compound S1 could significantly reduce collagen deposition in lung tissue, alleviate lung damage, and inhibit fibroblast activation, indicating that the CXCR7 agonist compound S1 can alleviate pulmonary fibrosis. Moreover, compound S1 significantly reduced pulmonary fibrosis even at a low dose of 0.5 mg / kg, demonstrating that this compound has a rapid onset of action in the treatment of pulmonary fibrosis. Figure 13 Both in vivo and in vitro results indicate that compound S1 inhibits pulmonary fibrosis by efficiently activating CXCR7.

[0105] Example 12 To further investigate which cells in lung tissue compound S1 targets to exert its anti-fibrotic effect, this embodiment used single-cell transcriptome sequencing (scRNA-seq) and immunofluorescence staining to detect the expression distribution of CXCR7 in mouse lung tissue. Figure 14 As shown, the receptor CXCR7 for compound S1 in mouse lung tissue is mainly expressed in vascular endothelial cells. Figure 14 A), while its expression level is very low or absent in other cells (A). Figure 14 B). The above results indicate that compound S1 inhibits pulmonary fibrosis by activating CXCR7 in pulmonary vascular endothelial cells. Figure 14 C).

[0106] Previous studies have found that vascular endothelial cells regulate lung regeneration and fibrosis by interacting with adjacent epithelial and interstitial cells through paracrine secretion of the angiocrine factor. To investigate the molecular mechanism of compound S1 in treating pulmonary fibrosis, this study used magnetic bead sorting technology to isolate pulmonary vascular endothelial cells and detected changes in the expression of angiocrine factors associated with lung regeneration and fibrosis.

[0107] like Figure 15 As shown, compound S1 upregulates the expression of pro-regenerative angiocrine factors (Hgf, Apln, Mmp14, Dll4, Kit, Egfl7) and inhibits the expression of pro-fibrotic angiocrine factors (Tgfb1, Pdgfb, Igfbp7, Ctgf, Adamts1, Tgfb2). These results indicate that the novel CXCR7 agonist compound S1 promotes lung regeneration and inhibits fibrosis by efficiently activating CXCR7 in endothelial cells and reprogramming angiocrine signaling in the vascular microenvironment.

[0108] Example 13 This embodiment further investigates whether the novel compound S1 can also inhibit liver fibrosis. A mouse model of liver fibrosis was established by intraperitoneal injection of CCl4. After inducing liver fibrosis, mice were intraperitoneally injected with different doses of compound S1 (0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 5 mg / kg) to evaluate the therapeutic effect of the compound on liver fibrosis.

[0109] After 7 consecutive days of drug injections, the therapeutic effect of compound S1 on liver fibrosis was evaluated by monitoring blood biochemical indicators and pathological findings. Serum alanine aminotransferase (ALT) levels were used for detection. Figure 16 A) Masson staining ( Figure 16 C), Sirius red staining ( Figure 16 B), H&E staining ( Figure 16 D) and α-SMA immunofluorescence staining ( Figure 16 E) Technology, this embodiment found that different doses of compound S1 can significantly reduce serum ALT levels, reduce collagen deposition in the liver, alleviate lung damage, and inhibit hepatic stellate cell activation. These results indicate that the CXCR7 agonist S1 can alleviate liver fibrosis. Moreover, compound S1 can significantly alleviate liver fibrosis even at a low dose of 0.5 mg / kg. The above results indicate that compound S1 has a rapid onset of action in the treatment of liver fibrosis. Figure 16 ).

[0110] Treatment results for pulmonary fibrosis and liver fibrosis indicate that the compound represented by Formula A synthesized in this invention can act as a novel CXCR7 agonist, reprogramming the angiocrine signaling in the vascular microenvironment by efficiently activating CXCR7 in vascular endothelial cells, thereby promoting the repair and regeneration of fibrotic organs (e.g., lungs, liver, kidneys).

[0111] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A compound characterized in that, The compound is a compound represented by Formula A as shown below, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, and a pharmaceutically acceptable salt or a prodrug thereof: （A） wherein, L is selected from (C1-C6)alkyl; n is selected from 0, 1, 2, or 3; X and Y are each independently selected from C or N; R is selected from -C(=O)NR x R y , or -C(=O)OR x , or substituted aryl or heteroaryl; R x and R y Independently selected from hydrogen atom, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1,1,1)pentyl, or ; R Z is at least one of ortho-, meta-, or para-substituted substituent selected from halogen, methoxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, trifluoromethyl, or trifluoromethoxy.

2. The compound of claim 1, wherein R is selected from -C(=0)NR x R y or -C(=0)OR x , R x is selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

3. The compound of claim 1, wherein R is selected from -C(=0)NR x R y or -C(=0)OR x , R x is selected from or R Z is halogen at least one of ortho substitution, meta substitution, para substitution.

4. The compound of any one of claims 1-3, wherein L is selected from C3 or C4 alkyl.

5. The compound of any one of claims 1-3, wherein X is N, and Y is selected from C or N.

6. The compound of claim 1, wherein The compound has a formula selected from the group consisting of: , , , , , , , and .

7. Use of a compound according to any one of claims 1 to 6 for the manufacture of a CXCR7 agonist.

8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of organ fibrosis.

9. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of one or more of a pulmonary disease, a liver disease, and a kidney disease.

10. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of organ damage.

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